Heliyon 9 (2023) e22841

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Heliyon
journal homepage: www.cell.com/heliyon

Review article

Achillea millefolium: Mechanism of action, pharmacokinetic,

clinical drug-drug interactions and tolerability
Bahareh Farasati Far a, *, Golnaz Behzad b, Hasti Khalili c
a
Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
b
Lorestan University of Medical Science, Lorestan, Iran
c
Pharmaceutical Sciences Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Achillea millefolium, known as Yarrow, is a medicinal plant in the Asteraceae family
Achillea millefolium which is one of the oldest known botanicals used by humans and itis one of the most important
Pharmacodynamics medicinal plants in the pharmaceutical field. Purpose: This review discusses pharmacodynamics,
Pharmacokinetics
pharmacokinetics, and mechanism of action of the most important component of Achillea mil­
Drug interactions
lefolium. There are a variety of same species such as white, red and yellow yarrow and all of these
Toxicity
Mechanism of action species have been discussed in this manuscript. We focus on previously discovered hormonal,
antibiotic, and anticancer drug interactions with Achillea millefolium that may decrease or in­
crease the concentration of certain drugs. We categorized different interactions of this herb into
minor and serious ones, such as affecting Cytochromes P450 metabolism enzyme, resulting in a
concentration rise in drugs such as Erythromycin, Diazepam, and Cyclosporine.
The reason of writing a review article in this field is our enthusiasm for pharmacology of herbal
ingredients and also, we want to gather other scientists’ and our knowledge in this review for
future researchers who like to know more about this plant pharmacological criteria in order to
make their way.
Method: Pharmacological and phytochemical-specific details of Achillea millefolium, as well as
related keywords, were used to conduct a literature search across the following essential col­
lections of electronic databases: Web of Science, Google Scholar, PubMed, and Science Direct.
Outcome: Achillea millefolium medical indications are the treatment of spasmodic gastrointestinal
ulcers, inflammation, wound healing, and cancers, as well as excellent antioxidant activity.
Camphene, Limonene, Apigenin and some other components show anti-inflammatory effects by
cyclooxygenase inhibition, prostaglandin E2 inhibition and other mechanisms. Studies showed
90 % of its essential oil consists of monoterpenes which can be mutually beneficial with extract
components.
Conclusion: A. millefolium can play a significant role as a strong antioxidant and anticancer source,
positively affecting gastrointestinal inflammations.

1. Introduction

Herbal medicine can be a viable supplement for pharmaceutical industrial applications, where threats to human health

* Corresponding author. Iran University of Science and Technology, Narmak, Tehran, Iran.
E-mail addresses: bahar.ferasati@gmail.com (B. Farasati Far), golnazbehzad973@gmail.com (G. Behzad), hastikhalili78@gmail.com (H. Khalili).

https://doi.org/10.1016/j.heliyon.2023.e22841
Received 9 March 2023; Received in revised form 20 November 2023; Accepted 20 November 2023
Available online 30 November 2023
2405-8440/© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
B. Farasati Far et al. Heliyon 9 (2023) e22841

List of abbreviation

ATP Adenosine Triphosphate

CAT Catalase
CDK Cyclin-Dependent Kinase
CFA Chondrocytes and Freund’s Complete Adjuvant
CYP Cytochrome P450 Enzymes
DPPH 2,2-Diphenyl-1-Picrylhydrazyl
ERK Extracellular Signal-Regulated Kinase
GBM Glioblastoma
GPx Glutathione Peroxidase
NLS Nuclear Localization Signal
NMDA N-Methyl-d-Aspartate
NSCLC Non-Small Cell Lung Cancer
MTP Microsomal triglyceride transfer
PARP Poly (ADP-Ribose) Polymerase
PERK Phosphorylation of Extracellular Signal-Regulated Kinase
PKG Protein Kinases Mediated Relaxation
ROS Reactive Oxygen Species
SOD Superoxide Dismutase

continuously rise while synthetic drugs become less effective and include many side effects. The use of medicinal plants for the
treatment of diseases is not new; in fact, humans have always attempted to treat diseases with medicinal plants []. In the investigation
for innovative drugs, natural compounds, particularly plant-based medicines, have provided significant new leads [1]. One of these
medicinal herbs frequently utilized in pharmaceutical fields is Achillea millefolium (A. millefolium).
A. millefolium, also known as the Yarrow or milfoili, the most well-known and widely distributed species in the Asteraceae family,
has been used for medicinal purposes for more than three thousand years in both traditional and alternative medicine [2]. Essential oil
and derivatives of flavonoids, notably Apigenin [3], Rutin [4], Lutein [5], and Camphor [6], are the primary phytochemical substances
extracted from A. millefolium. The A. millefolium essential oil has a mixture of monoterpenes and sesquiterpenes, with the former
making up around 90 % of the total [7]. Variations in essential oil content may be caused by ecotype, chemotype, phenophases,
altitude, and environmental parameters like temperature, sunlight, relative humidity, and irradiance that affect plant growth. In
addition, the genetic background may be relevant for altering the chemistry of secondary metabolites in plants [8]. Some of the
flavonoids found in A. millefolium include Morin, Myricetin, Naringin and Naringenin [9], Millifolide A, Millifolide B, Millifolide C
[10], 3-methoxytanapartholide, Seco-tanapartholide A, Seco-tanapartholide [11], Achillinin A [12], Apigenin [3], Rutin [4]. Flavo­
noid like aglycones, flavones and flavonol like O-glycosides are present in A. millefolium as well [3]. Generally, the flowering tops of the
A. millefolium plant, which contain the essential oil, are the most efficient parts of a plant and are primarily used for the treatment of
influenza [13], hemorrhage [14], dysmenorrhea [15], and diarrhea [16]. The main forms of A. millefolium extracts and oils include
essential oil, infusion, alcohol extract, decoction, hydroalcoholic extract, and aqueous extract [17]. Also, the antioxidant activity and
phenolic chemicals have a connection. comparatively high concentrations of the phenolic chemicals (Carvacrol and Thymol) in
essential oil may be responsible for its antioxidant action [18]. It is believed that A. millefolium possesses a wide variety of pharma­
cological effects, such as analgesic [19], anti-inflammatory [20], antidiabetic [21], cholagogue [22], spasmolytic [23], antitumor
[24], antioxidant [25], antifungal [26], antiseptic [27]. Several chemical compounds, such as essential oils, sesquiterpenes, phenolic
compounds, etc., are responsible for the liver-protective actions, including essential oils, sesquiterpenes, and phenolic compounds
[28]. Also, previous studies indicate that A. millefolium acts as an antiulcer agent. In a study by Sadeghi et al. (2013) ileum contractions
of Wister rats were elicited by KCl or acetyl choline. The addition of the extract attenuated ileum contractions which may be
attributable to flavonoids, specifically Quercetin and Apigenin [29].
The pharmacological evidence for the traditional use of A. millefolium extract for the treatment of dyspepsia was found to be
provided by the extract’s prokinetic effect, which was discovered by studying the effect of the aqueous extract collected from the
flowering tops of A. millefolium on stomach motility [30]. Also in another study, To determine whether or not ethanol extract of
A. millefolium aerial parts affected Interleukin-1 (IL-1) and iNOS gene expression in pancreatic tissue in Streptozotocin-induced dia­
betic rats, Zolghadri et al. (2014) conducted a study. They found that giving Streptozotocin-diabetic rats A. millefolium extract
recovered their body weight, IL-1, and iNOS gene expression. Up-regulation of the protective gene iNOS and decreased production of
the inflammatory cytokine IL-1 may be responsible [31]. It is reported by Jenabi et al. (2015) that A. millefolium is employed in treating
disorders associated with the gastrointestinal tract, including digestive problems, dyspepsia, flatulence, abdominal pain, diarrhea, and
stomachache [15]. However, other aspects of A. millefolium’s toxicity, such as its biophysical impacts on male reproduction, are not
fully understood. The purpose of this review is to study the efficacy, pharmacological properties, safety, toxicity, pharmacokinetics and
pharmacodynamics of this plant and its extract.
The main purpose of selecting A. millefolium for the pharmacological research review article is because it is a widely used traditional
medicinal plant with a range of potential pharmacological properties that have been reported in several studies. Some unique

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Table 1
The most important phytochemical compound of A. millefolium.
No Compound Class of Structure Effect Part of Extract/ Half life Mechanism of action Ref.
name compound plant essential
oil

1 Camphene Monoterpenes Anti-inflammatory, Leaf Essential 9.12 days Prostaglandin e2 inhibition, [15]
reducing triglyceride oil cyclooxygenase (cox) [33]
level inhibition. (Fig. 1), [34]
Inhibition of MTP [35]
[36]

2 α-pinene Monoterpenes Antibacterial, anti Leaf Essential 1.4 h inhibit the growth of [15]
inflamatory anti- oil bacteria, Decrease in [33]
tumor inflammatory factors such as [37]
TNF-α [38]
, down-regulating Cdc25C [39]
mRNA and protein [36]
expression,
3 β-pinene Monoterpene Antibacterial, Leaf Essentia 4.9 h Decreasing inflammatory [15]
Inhibitory effects on oil factors such as TNF-α [33]
breast cancer and [36]
leukemia

4 Limonene Monoterpene anti-inflammatory, Leaf Essential 12–24 h Reducing no production and [40]
antioxidant, oil nerve activation, thus [41]
neuroprotective reducing neuron cell (Fig. 2) [42]
[36]

5 Camphor Terpenoid Antitussive, Leaf Essential 4–8 h reducing TRPA1-mediated [33]

ketones analgesic, nasal oil cough, Activating heat- [43]
decongestant sensitive trpv1 and trpv3 [44]
receptors [45]
[46]
[36]

(continued on next page)

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Table 1 (continued )
No Compound Class of Structure Effect Part of Extract/ Half life Mechanism of action Ref.
name compound plant essential
oil

6 1,8-cineole Monoterpene Anti-inflammatory Leaf Essential 6.7 min Induced enzymatic and [33]
Antioxidant effects oil nonenzymatic cellular [47]
antioxidants and metabolic [48]
phase ii detoxifying enzymes [36]

7 Linalool Monoterpenoid , decrease anxiety, Leaf Essential 3.2 h A competitive antagonist of [33]
sedative effects, oil glutamate, and as a non- [49]
Hepatoprotective, competitive antagonist of [50]
dermal sensitizer NMDA receptors in brain
cortical membranes

8 Luteolin Flavonoid , anti-tumor, and anti- Whole Essential Less than 5 h inhibited cell proliferation [51]
inflammatory Plant oil/extract by inducing G0/G1 and/or [52]
G2/M cell cycle arrest, [53,
Binding to the thromboxane 54]
a2 receptor

(continued on next page)

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Table 1 (continued )
No Compound Class of Structure Effect Part of Extract/ Half life Mechanism of action Ref.
name compound plant essential
oil

9 Isochlorogenic Polyols antioxidant and anti- Leaf Extract 227~292 min High restoration of [55]
acid inflammatory glutathione levels [56]
[53]
[57]

10 Apigenin Estrogenic An antioxidant, anti- Whole Extract 91.8 h oxidant enzymes inhibition, [58]
flavonoid inflammatory Plant modulation of redox [59]
signaling pathways (NF-kB, [60]
Nrf2, MAPK, and P13/Akt), [53]
Regulating a p53-bax- [61]
caspase-3 apoptotic
pathway

11 Kaempferol Flavonoid Anti-inflammatory, Water 2.93–3.79min Cell cycle arrest at the G2/M [62]
anticancer extract phase, reducing pro- [63]
inflammatory cytokines, [36]
inducing apoptosis

12 Caffeic acid Phenolic Hepatoprotective, Whole Extract 0.14 h Inhibition of lipid [64]
glycoside anticarcinogenic, plant peroxidation and shielding [65]
antioxidant, anti- against ldl oxidation (Fig. 3) [66]
inflammatory [67]
[68]

13 Quercetin f Anti-inflammatory, Whole Extract 3.5 h Inhibiting [65]

anti-bacterial plant lipopolysaccharide (lps)- [69]
induced tumor necrosis [70]
factor α (TNF-α) production
in macrophages

14 Betonicine Alkaloids Positive effect on Whole Extract N.m Not explored [71]
digestive system and plant [72]
the blood stream

*N.E: Not explored.

advantages of A. millefolium over other plants include its widespread availability, low toxicity, and affordability. While it is true that
there are countless plants with pharmacological characteristics, A. millefolium is a plant with a long history of traditional use and has
been studied extensively for its potential pharmacological benefits. Additionally, it is widely used in complementary and alternative
medicine, and it has been reported to have various therapeutic properties, such as anti-inflammatory, antimicrobial, and antioxidant
activities. Therefore, it is a promising candidate for further research in developing new therapeutic agents. By synthesizing the
available evidence from in vitro, in vivo, and clinical studies, this review article aims to provide researchers and clinicians with a better
understanding of the potential benefits and limitations of using A. millefolium as a therapeutic agent. The present review article aims to
contribute to advancing research in the field of herbal medicine and provide valuable insights for clinical practice. Overall, the purpose
of the review article is to provide a comprehensive overview of the mechanism of action, pharmacokinetic properties, clinical drug-
drug interactions, and tolerability of A. millefolium. This review will help researchers and clinicians better understand the potential

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benefits and limitations of using this plant as a therapeutic agent. Although, there are many more components in A. millefolium, we
discussed the pharmacodynamics and pharmacokinetics of the top components below in the table due to the percentage of presence
and importance of action.

2. Research methodology

A comprehensive search was conducted using electronic databases such as PubMed, Scopus, Web of Science, and Google Scholar to
identify relevant studies published in the English language from inception to September 2021. The search terms used included
“Achillea millefolium,” “pharmacology,” “mechanism of action,” “pharmacokinetics,” “clinical drug interactions,” and “tolerability.”
The inclusion criteria for the review article were studies that investigated the pharmacological properties of A. millefolium in vitro, in
vivo, or in clinical trials. Both experimental and clinical studies that reported the effects of A. millefolium on various disease conditions
were included in the review. The exclusion criteria included studies that were unrelated to the pharmacological properties of
A. millefolium or were not published in English. After the initial search, the titles and abstracts of the studies were screened for
relevance, and full-text articles were obtained for the selected studies. The selected studies (228 papers) were critically appraised for
quality, relevance, and validity, and the data were extracted and synthesized systematically. Therefore, the methodology used for the
search, inclusion and exclusion criteria, and data synthesis were aimed at ensuring the comprehensiveness, relevance, and quality of
the review article.

3. Pharmacokinetics and pharmacodynamics of A. millefolium

We have prepared a table including components of A. millefolium with their details.

Table 1As mentioned, A. millefolium is indicated for some medical purposes such as inflammation, spasmodic diseases, wounds, etc.
This plant contains many bioactive components with different pharmacokinetics and pharmacodynamics. In this section, these
properties are discussed. There are some main components that are found in A. millefolium with the following concentrations:
β-Thujone, 0.4–55.3 %; Germacrene-D, 2–20.6 %; 1,8-Cineole, 1.2–19.8 %; Isospathulenol, 0.5–36 %; Camphor, 0.6–25.5 %; Trans-

Fig. 1. Camphene anticancer mechanism of action. Camphene has an anticancer effect through entering the cell, increasing calcium release from
endoplasmic reticulum, increasing ROS (reactive oxygen species) and finally leading to apoptosis [74].

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Fig. 2. Neuroprotective mechanism of Limonene. Limonene has neuroprotective effects on brain cells by decreasing ROS, having anti-inflammatory
effects, ACE activation. These effects lead to lessen neuron death and preventing brain atrophy [42].

Fig. 3. Anti-inflammatory mechanism of Caffeic acid. Many modulators involve inflammation to tumor progression, including NF-kB, COX-2, TNF-
a, IL-6, Nrf2, iNOS, NFAT, and HIF-1α. Caffeic acid is an agent that target NF-κB and COX-2. This can suppress cancer angiogenesis. The role of
Caffeic acid is illustrated in Fig. 3 [73].

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Fig. 4. The mechanism of anticancer action and potential clinical use of kaempferol in the treatment of breast cancer [75].

nerolidol, 0.4–48.1 %; and Cubenol, 0.1–42.9 % [32]. Kaempferol, Luteolin and Apigenin are also found as main flavonoids in
A. millefolium [3].
According to Table 1, caffeic acid has anti-inflammatory effects. Inflammation occurs in reaction to a stimuli, such as tissue injury.
It is a physiological mechanism that may contribute to cancer growth via many intermediates. Many modulators, including NF-kB,
COX-2, TNF-a, IL-6, Nrf2, iNOS, NFAT, and HIF-1α, play a role in tumor growth. caffeic acid demonstrated an inhibitory influence
on NO production that also strongly inhibited the production of COX-2 and iNOS. Cancer angiogenesis can be suppressed by thera­
peutic drugs that target NF–B and COX-2. caffeic acid strongly inhibits ceramide-mediated NF–B action, as well as UVB-mediated COX-
2 production. As a result, multiple studies have found caffeic acid to be a cell death inducer in tumor cells as well as a cancer growth
inhibitor and failure in animals. In other words caffeic acid illustrated its inhibitory action on NO-making that also sturdily blocked the
creation of COX -2 and iNOS which is shown in Fig. 3. Fig. 3 [73] Also, due to apoptotic effect of camphene, this plant has anti-cancer
effect as shown in Fig. 1. Fig. 1 [74] and limonene has neuroprotective effects. Fig. 2 [42].

3.1. Kaempferol

Kaempferol is a typical organic component found in a wide variety of herbs. It is the most frequent flavonoid with a weak affinity for
water, heated ethanol, and alkaline ether [62]. Several anti-cancer effects have been attributed to it. Kaempferol is a widely consumed
flavonol. Recent research has shown that Kaempferol has promising results as a chemotherapeutic treatment for breast cancer. It has
been discovered that Kaempferol primarily has anti-breast cancer effects by doing the following three things: preventing breast cancer
cell growth, causing breast cancer cell death, and stopping breast cancer cell migration and invasion [75].
It is shown in Fig. 4that how Kaempferol can prevent and stop cancer [75].

3.1.1. Kaempferol pharmacokinetic

Kaempferol shows a high net transfer towards the defensive side. The net absorption of this compound is high because of the less
secretion of its conjugates. The rate of secretion of Kaempferol conjugates is also high which shows that considerable amounts of free
Kaempferol in portal vein blood and this demonstrates the hepatic metabolism of this compound [76]. Because of Kaempferol lip­
ophilicity, it will be absorbed in the small intestine through active transport or passive and facilitated diffusion. Metabolic transforms
will give us glucuronides and sulfoconjugates formed from absorbed Kaempferol in the liver and small intestine by intestinal conju­
gation enzymes. Also, some bacterial microflora in the colon metabolize Kaempferol and its glycosides. These reactions lead to
releasing aglycones and compounds such as 4-methylphenol, Phloroglucinol, and 4-hydroxyphenylacetic acid. There are two paths for
these compounds. They can be absorbed and reach the systemic circulation or exerted in urine and feces [77].

3.1.2. Kaempferol pharmacodynamics

Kaempferol role in anti-inflammation: Kaempferol increases the number of activated macrophages and in result decreases lipo­
polysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α), IL-1, and also interleukin 10 (IL-10) expression. In conclusion
Kaempferol plays a role as an anti-inflammatory compound which increases anti-inflammatory cytokines such asIL-1, IL-10 and re­
duces pro-inflammatory cytokine levels [62]. Kaempferol role in suppressing inflammation in colitis: As ulcerative colitis is an in­
flammatory disease, Park et al. (2012) has proved that the pathogenesis of ulcerative colitis is related to an imbalance between
pro-inflammatory cytokines and anti-inflammatory cytokines and Kaempferol can have a role in increasing pro-inflammatory cytokine
secretion. Also, Kaempferol has many other beneficial medical effects such as preventing atherosclerosis, improving metabolic
functions, anticancer efficacies, anti-inflammatory effects, etc. [62,78].

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Fig. 5. Camphor leads to desensitization through the TRPV-1 pathway. Camphor is one of the agents that has recently been shown to activates
TRPV3, and also activates heterologously expressed TRPV1.

3.2. Camphor

Camphor is a natural compound which is found in the bark of the tree Cinnamomum camphora. It has demonstrated different
medicinal effects since decades ago. The presence of camphor is responsible for part of A. millefolium, contraceptive [79], analeptic
[80], anti-gastrointestinal disorders [81], anti-irritant [82], and anti-hypertensive properties [83]. It has demonstrated different
medicinal effects since decades ago such as anti-septic, analgesic, antipruritic, rube efficient, and counter irritant [84].

3.2.1. Camphor pharmacokinetics

Camphor can be absorbed in all administration sites, including topical, inhalation, and ingestion. The peak plasma level of
Camphor after ingestion is 3 h when taken alone and 1 h when it is taken with a solvent. This component can be distributed throughout
the whole body with the volume of distribution 2–4 L/kg. It also passes through the placenta thus it is not recommended in pregnancy
and lactation. Its protein binding in plasma is estimated at around 61 %. Finally, it undergoes metabolic procedures by the liver, which
bring into hydroxycamphor metabolites by hydroxylation. This procedure is mainly done by cytochrome P450 [85]. Then, hydrox­
ylated metabolites conjugated with glucuronic acid and excreted in the urine. The half-life of 200 mg of camphor was 167 min when
ingested alone, and 93 min when ingested with a solvent (Tween 80) [86].

3.2.2. Camphor pharmacodynamics

It has been shown that camphor can be effective in bronchoconstriction through being effective on histamine H1 and muscarinic
M3. This can be associated with cough inhibition [84]. Also, Camphor is somehow a TRPV1 agonist, and its antipruritic activity is
related to the potential of activating TRPV1 (Fig. 5) [87]. Since decades ago, Camphor has been shown to activate TRPV3 resulting in
several medicinal uses such as antiseptic, analgesia, antipruritic, antispasmodic, and anti-irritant effects. Xu et al. (2005) revealed that
camphor also activates the expression of TRPV1 heterologously, requiring higher concentrations than capsaicin [45]. In other in­
vestigations, camphor is considered to reduce bronchoconstriction caused by histaminergic H1 receptors and muscarinic M3 receptors.
So, this function can also reduce coughs [88].

3.3. 1,8-Cineole

1,8-Cineole which is known as 11-Eucalyptol, is an aromatic component of some plants such as Salvia and Eucalyptus leave, and
Arabidopsis [89]. The biological and pharmacological properties of 1,8-cineole include insecticidal and antibacterial, antiallergic and
anti-inflammatory, hepatoprotective, anticancer, and gastroprotective properties. Caldas et al. (2015) proved the importance of 1,
8-cineole as an ulcer healing agent and suggested that antioxidant and cytoprotective mechanisms are involved in its gastro­
protective activity [90].

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Fig. 6. 1,8-cineole is metabolized to its metabolites by cytochrome P450. Microsomal investigations have shown that P450 enzymes are involved in
cineole metabolism. The predominant metabolite in liver microsomes is 2 -hydroxycineole, but 3 -hydroxycineole has also been detected in human
microsomes. Both investigations discovered that CYP3A enzymes catalyzed cineole oxidation.

3.3.1. 1,8-Cineole pharmacokinetics

1,8-cineole is quickly absorbed and oxidized to its alcohol and carboxylic acid metabolites. So, after IV administration, the con­
centration of 1,8-cineole falls rapidly due to forming metabolites. Despite its quick metabolism, it has a slow elimination [91]. Cineole
has a very limited bioavailability in the majority of animals following doses of 30 and 100 mg kg − 1. As there is not seen any unchanged
1,8-cineole in feces, oral absorption is complete [91]. It is metabolized to hydroxycineoles: 3-hydroxy, 2-hydroxy, 9-hydroxy, and
7-hydroxy. Fig. 6 represents the metabolization of 1,8-cineole to its metabolites by cytochrome P450.

3.3.2. 1,8-Cineole pharmacodynamics

1,8-cineole can have an anti-inflammatory and antioxidant effect. In the cases that we have a respiratory infection or in the case of
cell activity, some cytokines and ROS (reactive oxygen species) are produced. These agents will lead to hypersecretion of the mucosa
and inflammation. Linalool can limit mucus hypersecretion and recurrent exacerbations as it blocks the link of ROS and cytokines with
hypersecretion and inflammation [92].

3.4. Linalool

Linalool is a monoterpene alcohol with cardiovascular benefits and antihypertensive effects. It has been found in plants like

Fig. 7. Anticancer mechanism of action of Linalool which represent inhibition of angiogenic activity of endothelial cells by downregulating
intracellular ATP levels and activating TRPM8. Linalool stimulates the transient receptor potential cation channel subfamily M (melastatin)
member (TRPM) and enhances the activation of extracellular signal-regulated kinase (ERK)8. Furthermore, ATP totally reverses linalool-induced
ERK phosphorylation. Furthermore, ERK activation produced by linalool inhibits the production of bone morphogenetic protein (BMP)-2. These
data suggest that linalool has an anti-angiogenic impact, which is mediated via lowering intracellular ATP levels and activating TRPM8.

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A. millefolium, Ocimum canum, etc. It is a component of volatile oil, fragrance, plant metabolite, and an antimicrobial substance [93].

3.4.1. Linalool pharmacodynamics

Linalool reduces morphine-induced conditioned place preference and tolerance, which can be associated with the inhibition of
NMDA (N-methyl-D-aspartate) receptors, the effect on nitric oxide (NO) signaling and adenosine receptor stimulation properties [94].
Angiogenesis relates to various illnesses, such as diabetic retinopathy, cancer, endometriosis and psoriasis. As represented in Fig. 7,
Linalool acts as an anti-oxidative and anti-inflammatory agent and also inhibits the angiogenic activity of endothelial cells by
downregulating intracellular adenosine triphosphate (ATP) levels and activating transient receptor potential cation channel subfamily
M member 8 (TRPM8) [95]. Linalool increases phosphorylation of extracellular signal-regulated kinase (PERK), decreasing intra­
cellular ATP levels and activating the TRPM8. Linalool blocks the activity of glutamate receptors in the brain by competing with them,
and it also blocks the activity of NMDA receptors in the cortex by blocking them without competing with glutamate [96].

3.4.2. Linalool pharmacokinetics

Linalool is absorbed quickly through oral and gavage routes of administration. 10 % of administrated dose will be excreted in the
urine. It’s noticeable that volatile components can be absorbed and enter the blood through the lung and nasal mucosa. A study by
Bickers et al. (2003) mentioned that after 72 h of administration of Linalool, 0.8 % in the skin, 1.2 % in the skeletal muscle, 0.5 % in the
liver, and 0.6 % in the gut [97]. In the process of metabolization, there will be a more polar and water-soluble compound instead of
Linalool to facilitate excretion. Approximately 55 % of administrated doses of excreta Linalool were found in the conjugated form with
glucuronic acid via urine. 23 % of it was excreted in the form of CO2. 15 % was excreted in feces. Also, 25 % of the initial dose will be
conjugated in bile, and it has enterohepatic circulation [98].

Fig. 8. Anticancer mechanism of Apigenin. In tumor cells, apigenin can reduce cyclin- and cycline-dependent kinases and activate inhibitor pro­
teins, which causes cell cycle arrest. Apigenin can suppress tumor metastasis and angiogenesis in addition to inducing apoptosis by regulating anti/
proapoptotic proteins. Apigenin exerts its effects through controlling gene expression and cellular signal transmission.

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3.5. Apigenin

Apigenin is a kind of flavone that stimulates autophagy in leukemia cells it can be an anticancer function. It can have other
functions, such as being an anti-neoplastic agent and a metabolite. It is found in Matricaria chamomilla, and A. millefolium [99].
Apigenin develops cell death in lung epithelium cancers, and also, besides curcumin, it has a synergic effect on the apoptosis of cells, so
it can be a solution in the treatment of different types of cancers [100].

3.5.1. Apigenin pharmacodynamics

Apigenin regulates CDK inhibitors, CDK4 and CDK6 kinases, and as a result, it induces cell cycle arrest at different proliferation
stages such as G1/S-phase or G2/M phase. It regulates the intrinsic apoptotic pathways, inducing the release of cytochrome C in the
cytoplasm and finally leading to apoptosis (Fig. 8). Apigenin also suppresses PI3K activity by blocking the ATP-binding site of PI3K,
leading to inhibiting AKT kinase activity [101].

3.5.2. Apigenin pharmacokinetics

Apigenin is ingested in a glycosylated form. This form will be glycosylated by stomach enzymes such as β-glucosidases or microflora
of the colon before systemic absorption. Free apigenin is absorbed easily or undergoes different phases of metabolism in the small
intestines and liver. It can cause hydroxylated metabolites such as luteolin and others. These metabolites undergo four different op­
tions that one of them is elimination [102].
About the exertion of Apigenin, it is found that Apigenin gets out of the body through urine in rats with a difference in the per­
centage of ingested radioactivity recovered between male and female ones. In conclusion, it is found that less than 40 % of ingested
dose will be excreted in gastric acid in 5 days [103].

4. Main safety and toxicity issues of A. millefolium

A. millefolium is one of the world’s most commonly used medicinal herbs, with various applications, pharmacological effects, safety,
and toxicity. The anti-inflammatory [20], spasmolytic [23], hemostatic [14], antibacterial activity against pneumonia [104],
anti-kidney stones [105], anti-diarrhea [16],anti-abdominal pain [106], anticancer/tumor [24], Antiproliferative [107], analgesic
effect [19], anxiolytic activity [108], skin-rejuvenating activity [109], and anthelmintic activity are linked to the safety of
A. millefolium [110]. A. millefolium is also considered safe for use as a supplement [111].
Some features of A. millefolium toxicity, such as probable effects on the male reproductive system [112], are related to its extracts.
The effects of an aqueous extract of A. millefolium leaves on fertility were also investigated by Dalsenter et al. (2004) in a study using
Wistar rats (sperm and spermatid numbers, sperm morphology and reproductive organ weights). They were also evaluated for the level
of toxicity caused by the extract. The adult male rats were given A. millefolium extract daily to be treated. With the higher dosage of
A. millefolium extract, the proportion of abnormalities in sperms was shown to increase significantly. However, no other significant
changes were found in any of the other reproductive endpoints studied in the male rats [113]. The findings made it abundantly clear
that there would be no long-term reproductive toxicological risk associated with doses of A. millefolium that humans typically consume.
However, the findings also demonstrated that the long-term use of A. millefolium extract in high doses can cause toxicity [114].
Whether prolonged exposure to A. millefolium extracts poses any health risks is unknown. Despite the plant’s classification as non-
poisonous and approval for use in alcoholic beverages by the Food and Drug Administration, certain harmful consequences have been
reported following its use by people and in animal tests [115,116]. An investigation into the genotoxicity of the oil produced by
A. millefolium was carried out by Ahmady et al. (2018). They have found that induction of mitotic non-disjunction or crossing over was
correlated with the genotoxicity of the oil. As a result, the findings indicated that further research is required to determine whether or
not A. millefolium essential oil can interfere with the recombinational process in mammalian cells. As a result, it is recommended that
the oil be utilized with caution [117,118]. In this part, we will investigate various chemicals that play significant roles in the toxicity or
safety of this plant and the extracts it produces.

4.1. Thujone

The monoterpene ketones α-Thujone (3-Thujone) and β-Thujone (3-isothujone) are naturally occurring compounds found in the
Achillea species of the Asteraceae family that are frequently utilized as flavoring agents in foods and beverages [119]. Essential oil of
A. millefolium, which contains Thujone as a significant constituent, has been widely used in folk medicine for the treatment of
rheumatism [120], psoriasis [121], irritable bowel syndromes [122], warts, acne, and uterine carcinomas [112]. The safety of Thujon
is related to these pharmacological actions. In addition to (− )-α-Thujone and (+)-β-Thujone, two more enantiomeric forms are known:
(+)-α-Thujone and (− )-β-Thujone [123]. Current instruments, pharmacological, and clinical research have partially validated the
toxicity and safety of Thujone. Neurotoxicity is one of Thujone’s harmful consequences. also α-Thujone is more neurotoxic than
β-Thujone [124]. Thujone has a totally reversible neuronal action. Thujones are GABA-gated chloride channel modulators, with
α-Thujone acting around two to three times more potently than β-Thujone (GB62). However, the concentrations required in humans
are unclear [125].
Additionally, Czyzewska et al. (2013) discovered that due to the different sensitivity of GABAA receptor subtypes, the action of
α-Thujone may vary [126]. Also Waidyanatha et al. (2013) reported that the elimination of α-Thujone in the brain is slower than in the
plasma. This effect can impact the neurotoxic effect of Thujone [127]. In addition, cannabinoid CB1 and serotonin 5-HB3 receptors

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were proposed as potential Thujone targets [125]. Also, Sultan et al. (2000) reported that Thujone suppressed reversibly ACh-induced
currents in Xenopus oocytes with an IC50 of 24.7 M(GB65), and previous studies show that 25 mg/kg Thujone altered the behavior,
mortality, organ weight, and hepatic and renal functioning of 6–8 week-old mice. Also in single-dose toxicity tests, the i. p. LD50 was
45 mg/kg body weight [128]. Chronic toxicity may result from the long-term administration of sub convulsive dosages. According to
the latter authors, the optimum estimate for daily intake by humans in food or herbal preparations is around 3–7 mg/day [125,128].
Apart from neurotoxicity, thujones may be genotoxic and carcinogenic; antimutagenic and anticarcinogenic effects may also be
observed [129]. These effects most likely depend on the cell type studied, genetic background, experimental setup, and concentration.
According to Nikoli et al. (2011) a 20-h treatment of monkey Vero cells with 1–4 mM Thujone produces antigenotoxic effects at low
concentrations but significant genotoxicity at high concentrations [130]. An in vitro study by Biswas et al. (2011) discovered that
Thujone had a pro-apoptotic and cytotoxic effect on the A375 cell line [131]. In a rat model, Küpeli Akkol et al. (2015) showed that
-Thujone had a favorable effect in treating polycystic ovarian syndrome [112]. According to Zhou et al. (2019) -Thujone enhances
anticancer immune response. At 0.15 mol/L, this chemical increases the proliferation of CD3AK (anti-CD3 antibody-induced activated
killer) cells and the cytotoxicity to colon cancer cell lines. A recent in vitro study found that β-Thujone had promising effects on
glioblastoma cells, losing viability and invasive potential. Thujone reduced cancer cell proliferation and worked as a pro-apoptotic
agent in a dose-dependent manner, likely via inducing oxidative stress in GBM cells (Glioblastoma) [120] (Nikoli et al., 2015). also
discovered cytotoxicity (IC50: 1.0–2.8 mM) and cell growth suppression following the treatment in different human cell lines. Thujone
may also act as an antigenotoxic agent and activate the DNA repair machinery when used in low dosages [129].

4.2. Camphor

Camphor (2-bomanone, 2-camphonone) is a bicyclic monoterpene widely used in industry. It is a natural substance and one of
A. millefolium’s most volatile essential oils (more than 20 %). The presence of camphor is responsible for part of A. millefolium con­
traceptive [79], analeptic [80], anti-gastrointestinal disorders [81], anti-irritant [82], and anti-hypertensive [83] properties. The
presence of camphor accounts for the majority of the safety of A. millefolium in the home treatment of colds [132]. The dangers of
camphor-containing products in general, and camphorated oil in particular, are mostly linked to incorrect usage [133]. Its toxic
properties were first studied in the 19th century, and it is now known that the substance can be utilized medically but under specific
circumstances and dosages. According to Santos et al. (2015), the fatal dose of camphor for adults is between 50 and 500 mg/kg. In
addition, a dose of 2 g or more has harmful consequences, while 4 g might be fatal. The lethal dose for children is between 0.5 and 1 g,
while for babies, it is 70 mg/kg [134]. Camphor is widely used, but it has high toxicity that manifests in the ovary [135], testes [135],
nerves [136], liver [137], heart [138], fetus [139], pregnant women [138], the apparent toxicity to the kidneys and urinary system
[140], less genotoxic [141] potential toxicity, and toxicity effects such as depression, central nervous system symptoms such as
headache, dizziness, restlessness, anxiety, hallucinations, myoclonus, and hyperreflexia [140].
Camphor poisoning in children is widespread, particularly in Asia. This compound can cause poisoning through eating or skin
contact [142]. The lipophilic character of camphor and its ability to permeate cell membranes must be emphasized while considering
the action mechanisms. Transdermal, stomach, and inhalational absorption pathways are also possible. The liver is believed to oxidize
and conjugate the monoterpene before its elimination via the kidneys [134].

4.3. Chamazulene

Chamazulene (15.84 %) is a proazulene component found in the A. millefolium essential oil which has an inhibitory effect against
Staphylococcus spp [143]. It is a blue extract of A. millefolium that has antibacterial [144], anti-inflammatory [145] and antifungal
effects [146] as well as antioxidant properties [147] that make it safe and the intensity of extract odor and blue color depended upon
the amount of chamazulene formed by degradation of matricide during distillation. One of the important safety features of chama­
zulene is determined to be non-sensitizers [148]. Ding Ma et al. (2020) evaluated the protective effects of chamazulene against
IL-1-induced oxidative stress. Chondrocytes and Freund’s complete adjuvant (CFA) promote osteoarthritic inflammation in rats.
Markers of oxidative stress, pro-inflammatory cytokines, and regulatory proteins were detected. Chamazulene significantly reverses
lipid peroxidation levels, as demonstrated by the measured study. Increased the levels of superoxide dismutase (SOD), glutathione
peroxidase (GPx), and catalase (CAT) enzymes against oxidative damage generated by IL-1 and CFA [149]. Chamazulene has been
suggested as a safe, free radical scavenger. Its chemical nature indicates its passage through cell membranes and possible interaction
with radical species. This mechanism demonstrates the safety of chamazulene [150].

4.4. p-Cymene

p-Cymene, also known as p-cymol or p-isopropyl toluene [1-methyl-4-(1-methyl ethyl)-benzene], is a monoterpene found in more
than 100 plant species, such as A. millefolium, and utilized for medicinal purposes. The majority of A. millefolium’s safety is related to p-
cymene. The antioxidant [151], antifungal activity [152], anti-inflammatory [153], anti-nociceptive [154], anxiolytic [155], anti­
cancer [156], antiparasitic activity [154], and antimicrobial properties [157] of this compound are well-known. Previous studies show
that its anticancer effects are related to some mechanisms, such as the inhibition of apoptosis (Fig. 9) and cell cycle arrest, and
p-cymene acts as a safe compound in anticancer properties. P-cymene exerts several anticancer effects on numerous tumor cell lines,
according to several recent studies [154,158]. Zhou et al. (2013) demonstrated that p-cymene inhibits the proliferation of gastric
carcinoma SGC-7901, liver carcinoma BEL-7404, and nasopharyngeal carcinoma CNE-1 cell lines with respective IC50 values of 20.7,

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Fig. 9. Anticancer mechanisms of p-cymene on apoptosis and cell cycle arrest. In HT1080 human fibrosarcoma cell lines, p-cymene inhibits 12-O-
tetradecanoyl-phorbol-13-acetate (TPA)-induced MMP-9 production through inhibiting the ERK1/2 and p38 MAPK signaling pathways.

71.1, and 42.6 μM [159]. p-Cymene significantly inhibits 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 production
via inhibition of ERK1/2 and p38 MAPK signaling pathways in HT1080 human fibrosarcoma cell lines, according to Li et al. (2016)
[160]. p-cymene also triggered apoptosis in NSCLC (Non-Small Cell Lung Cancer) cells by activation of caspase-3/-9, activation of Poly
(ADP-ribose) polymerase (PARP), and up-regulation of p53, p21, and p15 tumor suppression protein expression, which are crucial for
apoptosis and cell cycle regulation [161].
The antimicrobial effects appear to be used in treating communicable diseases and antimicrobial resistance [18]. This application
was recently discussed in SARS-CoV-2, which showed at non-toxic concentrations, p-cymene is not genotoxic and inhibits SARS-CoV-2
and influenza H1N1 viral replication in vitro [157]. p-Cymene has been shown to reduce biofilm formation in Burkholderia xen­
ovorans. Bacterial membrane p-Cymene accumulation and the structural changes brought on by this aromatic molecule have both been
linked to this process [162]. Food product contamination by microorganisms is a major problem, especially in third-world countries.
Api et al. (2021) demonstrated that essential oils and plant extracts containing diverse phytochemicals, including p-Cymene, can be
utilized as a fungicide, herbicide and insecticide, for the use of monoterpenes, notably p-Cymene, in food products. This issue it proves
that p-Cymene is safe to use as an antibacterial and food preservative [163].

4.5. Bornyl acetate

Bornyl acetate is an oxygenated monoterpene. One of the most important effects of A. millefolium is its anti-inflammatory properties
[164], most of which are attributed to Bornyl acetate. A recent study found that Bornyl acetate reduced the production of LPS-induced
pro-inflammatory cytokines like TNF-α, IL-1, and IL-6, as well as regulating T-lymphocyte subsets [165]. The antioxidant activity of
bornyl acetate, which was extracted from the A. millefolium aerial part of essential oil, was examined using the DPPH assay. Bornyl
acetate had the least effective free radical scavenging activity against DPPH (IC50 25 ± 0.1 μg/mL) [18]. The safety of using Bornyl
acetate during pregnancy has also been confirmed because it has an anti-abortive effect via immunological balance modulation at the
maternal-fetal interface [166].

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4.6. Limonene

Limonene is a monocyclic monoterpene (1-methyl-4-(1-methyl ethenyl)cyclohexane). Limonene is a colorless liquid with two
optical isomers, d- and L-limonene, and a racemic combination. Limonene’s low toxicity to humans and lack of mutagenic, carcino­
genic, or nephrotoxic potential have earned it a spot on the safe compound [167]. Limonene has been extensively investigated for its
therapeutic benefits, which include anti-inflammatory [168], antidiabetic [169], anticancer [170], antioxidant [168], antinociceptive
[171], antihyperalgesic [172], gastroprotective [173] and antiviral [174] properties.
In vivo research using mouse and rat models has shown that limonene affects cancer development and has allergic or sensitizing
potential. Nonetheless, a comprehensive investigation of limonene’s mode of action indicated that the toxicity was irrelevant to human
health [175]. In terms of limonene’s effect on reproduction, there were no signs of teratogenic or embryotoxic effects. Still, the
compound may indirectly affect fertility by making mothers gain less weight and grow slower. Therefore, this makes their offspring
much more likely to have skeletal abnormalities and delayed ossification. In the clinical management of limonene exposure, numerous
adverse consequences were reported. The most prevalent is cutaneous sensitization. Ingestion of limonene has also been associated
with nausea, coughing, vomiting, tongue and throat burning, ataxia, choking, fever, and tachycardia [176]. According to the
harmonized classification and labelling authorized by the European Union, monoterpene is extremely harmful to aquatic life with
long-lasting effects, as well as causing skin irritation and allergic skin reactions. Moreover, if limonene enters the airways after being
ingested, it can be lethal [177].

4.7. Miscellaneous toxicities under investigation

A. millefolium inhibits spermatogenesis by decreasing the levels of testosterone and LH hormones in the hypophysis-gonadal
hormonal axis. By making the adenylate cyclase system more sensitive, the flavons in this plant can attach to sex hormone re­
ceptors and inhibit the synthesis of sex hormones. The plant’s Apigenin component inhibits phosphatidylinositol 3-kinase and aro­
matase and promotes the development of cell death enzymes. Takzare et al. (2011) investigated the effect of A. millefolium flower
ethanol extract on spermatogenesis in mature Wistar rats. For 22 days, every other day, extract doses of 200, 400, and 800 mg/kg/day
were delivered through IP injection or gavage. At a dosage of 400 mg/kg/day (IP), scattered immature cells on the basal membrane of
seminiferous tubules were detected, as well as a considerable reduction in cell accumulation and vacuolization [178]. A dosage of 800
mg/kg (IP) induced thickening of the basal membrane of the seminiferous tubules, a reduction in cell accumulation in the tubules,
severe disarrangement, degenerative cells, and a significant drop in sperm count. Oral dosing of 800 mg/kg/day of the extract resulted
in basal membrane thickness and cell disarray. The findings indicate that A. millefolium has transitory antifertility action in adult male
animals [179,180].

5. Drug-drug interactions of A. millefolium

5.1. Anti-nociceptive synergistic interaction

The effects of concomitant use of A. millefolium and Origanum vulgare L. extract encapsulated on liposomes in mice were investi­
gated in a study. The mentioned study (Hassanzadeh-Kiabi F et al.,0.2018) reported that the extract encapsulated in liposome reduced
the nociceptive behavior induced by formalin. The interaction index and iso-biologic analysis revealed that the extracts had a syn­
ergistic analgesic (anti-nociceptive) effect. Naloxone also reduced the anti-nociceptive effect of the co-administered liposome
encapsulated extract [65,181].

5.2. Hypertension synergistic interaction

There is evidence that A. millefolium can help reduce blood pressure, and it may even enhance the effectiveness of drugs used to
treat hypertension. Significant antihypertensive and vasorelaxant effects of A. millefolium can be attributed to the presence of the
chemicals Leucodin and Achillin (epimeric compounds). Vasorelaxation, mediated in part by the endothelium and including NO
release and cGMP increase, as well as by the blocking of membrane calcium channels, contributes significantly to the antihypertensive
effect of both compounds [27].
Extract and pure chemicals like Leucodin and Achillin appear to effect independently by producing NO and blocking Ca2+ channels.
No diffuses into smooth muscle cells and activates soluble guanylate cyclase (sGC). Activating sGC increases intracellular cGMP, which
relaxes cells. cGMP-dependent protein kinases mediated relaxation (PKG). cGMP-PKG signaling affects cell motility, migration, and
proliferation in vascular smooth muscle cells, which is crucial for angiogenesis and vascular permeability [182]. By phosphorylating
the inositol trisphosphate receptor (IP3R), a protein involved in cellular relaxation, PKG-I helps reduce free cytosolic Ca2+. Myosin
light chain phosphatase is partially activated by PKG-I; this decreases myosin’s identification of actin and promoting relaxation. Also,
cGMP-dependent ionic channels are activated, which contributes to the overall decrease in intracellular Ca2+ (through many channels)
that results in cellular relaxation (Fig. 10) [27].
It should be noted that a fixed combination of hawthorn and camphor has been used in the therapy of hypotension for decades, and
simultaneous use of A. millefolium and hawthorn due to the existence of camphor in the A. millefolium in people with hypertension
causes toxicity and is contraindicated [183]. Excessive consumption causes vomiting, nausea, anorexia, and drowsiness. A. millefolium
should not be used simultaneously with antiplatelet drugs, blood pressure medications, analgesics and sedatives, and barbiturates.

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Fig. 10. Mechanism of Antihypertensive and vasorelaxant effect of Leucodin and Achillin. A. millefolium hexanic extract has a significant relaxant
effect by calcium channel blockade and NO release. The main bioactive compounds responsible for the relaxant action are Leucodin and Achillin.

However, the pollen of A. millefolium is highly allergic [184,185].

5.3. Coagulating effect

Although A. millefolium has anticoagulant effects, concomitant use of immunosuppressants with anticoagulants such as Warfarin
and A. millefolium due to decreased international normalized ratio may cause the plant in the environment in vivo to have a coagulating
effect [186]. Consuming large amounts of A. millefolium can reduce the rate of blood clotting. Taking A. millefolium with medicines that
slow down blood clotting may increase the chance of bruising and bleeding, drugs such as Aspirin, Clopidogrel, Diclofenac, Ibuprofen,
Naproxen, Dalteparin, Enoxaparin [187].

5.4. Interaction with CYP

Natural compounds can also act as triggers for modifications in CYP activity. Therefore, interactions are not just confined to
synthetic medications. The main enzymes for the oxidative metabolism of pharmaceuticals and other xenobiotics are members of the
CYP P450 protein family, which consists of more than 50 distinct proteins. The metabolism of medicines with clinical importance
seems to be most relevant for a few isoforms, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. One study looked into how cha­
mazulene inhibits four specific human cytochromes P450 enzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A4). Then, it was discovered
that CYP1A2 was active toward CYP3A4 and more sensitive than the other isoforms. The inhibition of CYP2C9 and CYP2D6 was lower.
so, chamazulene in A. millefolium inhibits the activities of major human drug metabolizing enzymes and interacts with drugs that
metabolize to these enzymes such as Estrogens, Estradiol, Acetaminophen, Codeine, Erythromycin, Diazepam, Cyclosporine [188,
189].
Quercetin is a plant pigment (flavonoid). Quercetin increases xanthine oxidase and N-acetyltransferase activity while decreasing
CYP3A4 and CYP1A2 activity in vivo. To a similar extent, quercetin inhibits the P-glycoprotein (Pgp) activity in vivo. Pgp is a drug

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Table 2
Quercetin drug interaction severity (based on Medscape online database [194]).
Drug classification Example of drugs Type of drug Mechanism
interaction

Antibiotics Ciprofloxacin Minor Quercetin decreases effects of mentioned antibiotics by pharmacodynamic antagonism
Fleroxacin
Gemifloxacin
Levofloxacin
Ofloxacin
Moxifloxacin
Antihistamines Fexofenadine Minor Quercetin will decrease the level or effects of these antihistamines by P-glycoprotein
Loratadine (MDR1) efflux transporter
Antidepressants Amitriptyline Monitor Closely Quercetin will decrease the level or effects of these antidepressants by P-glycoprotein
Nortriptyline (MDR1) efflux transporter. Also Quercetin can also exert antidepressant effects by
inhibiting the hyperactivity of the hypothalamic-pituitary-adrenal axis [195]
Cardiovascular Atorvastatin Monitor Closely Quercetin will decrease the level or effects of these cardiovascular drugs by P-glycoprotein
Digoxin (MDR1) efflux transporter
Lovastatin
Corticosteroids Budesonide Monitor Closely Quercetin will decrease the level or effects of Corticosteroids drugs by P-glycoprotein
Cortisone (MDR1) efflux transporter
Deflazacort
Dexamethasone
Fludrocortisone
Methylprednisolone
Prednisolone
Antigout Drugs Colchicine Monitor Closely Quercetin will decrease the level or effects of Colchicine by P-glycoprotein (MDR1) efflux
transporter
Sex Hormones Conjugated- Monitor Closely Quercetin will decrease the level or effects of these drugs by P-glycoprotein (MDR1) efflux
Estrogens transporter
Estradiol
Mestranol
Immunosuppressants Ciclosporin Monitor Closely Quercetin will decrease the level or effects of these drugs by P-glycoprotein (MDR1) efflux
Sirolimus transporter
Tacrolimus
Anti-cancer Imatinib Monitor Closely Quercetin can reverse the resistance mechanisms of anticancer drugs through the inhibition
Nilotinib of group P function and ABCB1 gene expression in many cell lines. Also it will decrease the
Paclitaxel level or effects of these drugs by P-glycoprotein (MDR1) efflux transporter
Vincristine
Vinblastine
Antivirals Saquinavir Monitor Closely Quercetin will decrease the level or effects of these drugs by P-glycoprotein (MDR1) efflux
Indinavir transporter
Maraviroc
Nelfinavir
Ritonavir
Anti-cancer Topotecan Serious Topotecan: Quercetin will increase the level or effects of topotecan by P-glycoprotein
Everolimus (MDR1) efflux. So, avoid concomitant use of P-glycoprotein inhibitors. The interaction with
IV topotecan may be less severe.
Everolimus: Quercetin will decrease the level or effects of Everolimus by P-glycoprotein
(MDR1) efflux transporter

efflux transporter that plays an important role in the intestinal and biliary transport and elimination of a wide variety of drugs and their
metabolites. Quercetin may change the blood levels of all medications processed by these enzymes due to these interactions [190,191].
However, quercetin, especially in the case of “Minor severity,” reduces the effect(s) of the drug by means of pharmacodynamic
antagonism. Quercetin inhibits P-glycoprotein, which is responsible for the majority of drug interactions (MDR1) carriers of efflux. As
predicted, the dosage of quercetin may potentially impact drug-nutrient interactions. Consequently, a pig study revealed a fatal
interaction between quercetin and digoxin, a P-glycoprotein substrate with a very limited therapeutic range; in fact, the co-
administration of quercetin and digoxin (50 mg/kg and 0.02 mg/kg, respectively) led to the sudden death of two out of the three
pigs within 30 min of administration [192]. Surprisingly, even though the co-administration of quercetin at a lesser dose (40 mg/kg)
significantly increased the Cmax (highest concentration) of digoxin by 413 %, it had no fatal side effects [193].
In Table 2 most of the drug-plant interactions has been mentioned classified due to the drugs’ classification. Type of drug inter­
action and mechanism of action also has been mentioned.

5.5. Photosensitivity interactions

It is also mentioned in many investigations that A. millefolium interferes with photodermatitis drugs, that these drugs increase
photosensitivity [196]. In other words, one of the most significant causes of airborne contact dermatitis appears to be due to
A. millefolium. Although this species has been shown to have higher concentrations of ten distinct alkaloids and three polyenes, none is
likely to be powerful contact sensitizers. Because they lack the crucial a-methylene group that is exocyclic to the α-lactone, as well as

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cyclopentenone and epoxy groups [197]. A. millefolium was reexamined, namely its flowers, which indicated the existence of five novel
unsaturated guaianolides with peroxide property that had not been discovered before in Compositae species. The primary sensitizer
must be considered a-peroxyachifolid [198].

6. Discussion and future perspectives

Herbal remedies continue to be an accepted complementary medical opinion throughout the world. There are more than 80 species
of A. millefolium, each with its unique constituents. This review summarizes the safety, efficacy, pharmacodynamics, pharmacokinetics
and herb-drug interactions of A. millefolium. A. millefolium is prescribed as a supplement for anti-inflammatory cases, liver disorders,
bleeding disorders, dyspepsia and many other cases. A considerable point about this medicinal herb is that the polar portion of the
extract has an antioxidant role and the oil showed antimicrobial effects. Therefore, it can have both antioxidant and antimicrobial
effects. Two risk factors of kidney stone can be low volume of urine and also bacterial infections [199]. This plant increases diuresis by
25 % from initial volume without changing of urine pH in the patients with calcium type of urolithiasis. So A. milefolium has diuretic
effects in addition to antimicrobial effect as mentioned [200]. So, these mechanisms can be possible for preventive and curative effects
of A. millefolium [201]. Traditional and widespread beliefs hold that the herb A. millefolium is helpful for treating wounds, inflam­
mation, and digestive issues. It may be helpful for these objectives due to its anti-inflammatory and perhaps anti-pathogenic properties,
and its hemostyptic properties would independently assist ailments including skin injuries and hemorrhoids. Its less frequent usage for
liver illness is consistent with its proven hepatoprotective effect. Additionally, A. millefolium is safe and well tolerated by people who
are not allergic to it, according to animal research and a wealth of human experience. We have mentioned different types of in­
teractions between A. millefolium and chemical drugs. Some of them are serious interactions like Topotecan-A. millefolium and some of
them are minor ones such as antihistamines-A. millefolium. Coagulating or anticoagulating effects of A. millefolium are unreliable and
can increase the risk of bleeding and bruising when taking other antiplatelet or anticoagulant medicines. As mentioned previously,
there are many anticancer components in this plant. There are different mechanisms for this property, such asdifferent mechanisms for
this property, for example, arresting the cell cycle at the G2/M phase in Kaempferol. Many other components have anti-inflammatory
properties such as Camphene, a prostaglandin E2 inhibitor. A. millefolium by effecting on CYP450 can increase the concentration of
certain drugs, which are a prostaglandin E2 inhibitor. A. millefolium by effecting on CYP450 can increase the concentration of certain
drugs sensitive to hepatic enzymes. For example, increasing the concentration of Estradiol, Acetaminophen, Codein, and etc. Also, the
leaf and flower extracts of A. millefolium were assumed to promote acid production in the stomach, lowering the efficiency of
gastrointestinal tract medicines, but not due to CYP inhibition. The A. millefolium-CYP inhibition demonstrated here implies
nonspecific activity against various human drug-metabolizing enzymes, which might result in a larger than predicted in vivo or clinical
herb-drug interaction.
Also, as effective antioxidant, A. millefolium EO is suggested as a new potential source of natural additives for the food and
pharmaceutical industries. Moreover, there is a link between the antioxidant activity of phenolic substances. The comparatively high
concentrations of the phenolic chemicals carvacrol and thymol in EO may be responsible for its antioxidant action. However, the
results showed that thymol and carvacrol are primarily responsible for the EO’s antioxidant activity. On the other Nature’s abundant
anti-inflammatory phenol, salicylic acid (aka salicin), can be found in A. millefolium.
Also, A. millefolium has been utilized as an appetite stimulant for dyspeptic disorders and circulatory conditions such as hyper­
tension. The active components in A. millefolium, Acillin and Leucodin were shown to lower blood pressure by relaxing blood vessels. In
addition, the NO/cGMP pathway is involved in the relaxation of blood vessels. The process of the most likely by causing the endo­
thelium to release NO and make more cGMP and by blocking calcium channels. Obviously, it is vital to evaluate the pharmacological
interactions between this plant and blood pressure-lowering medications. A. millefolium hexane-ether-methanol extract exhibited
antibacterial action against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella
enteritidis. Essential oil of A. millefolium is considered effective against Streptococcus pneumoniae, Clostridium perfringens, Acetinobacter
lawoffii, and Mycobacterium smegmatis. People also utilize it for its antipyretic properties and to struggle the common cold. According
to the notable pharmacological effects of p-cymene of A. millefolium essential oil in the treatment of colds, and its antibacterial
properties, this extract can be used to treat fever, colds, influenza and to control SARS-COVID. To influence nuclear translocation and
viral proliferation, p-cymene binds to a nuclear localization signal (NLS) in the C-terminal structural domain of SARS-CoV with low
micromolar affinity. P-cymene changes the NLS sites of influenza virus nucleoproteins, reducing their ability to bind with importin A.
Because it works against viruses via this same mechanism, p-cymene can be used effectively in alone or in tandem with other antiviral
drugs. Also, A. millefolium expands blood vessels and promotes sweating to eliminate toxins. Antibiotic properties of A. millefolium
eliminate cold infections and act as a potent antimicrobial with a synergistic effect. This is why this plant is recommended for reducing
cold-related coughing and sneezing.

7. Conclusion

Herb-drug interactions associated with A. millefolium were completely explained previously. Also, the pharmacokinetics and
pharmacodynamics of this herb were discussed. As A. millefolium CYP the greatest interactions are for drugs with a narrow therapeutic
index. No serious adverse effect was seen toward using this herb except contact dermatitis. As mentioned in this review, A. millefolium
is traditionally believed to be a useful medicine for respiratory infections, digestive diseases, injuries, and inflammatory conditions.
Anti-inflammatory and possibly anti-pathogenic activities can actually be beneficial in these cases. As reviewed, It has been shown to
protect the liver. Activity is also compatible with its less common use. In addition, animal studies and extensive human experience

18
B. Farasati Far et al. Heliyon 9 (2023) e22841

have shown that yarrow is safe for those who are not allergic to it and is well tolerated. There is evidence that A. millefolium can play a
significant role as a strong antioxidant source and positively affects gastrointestinal inflammations. Inflammation, cancer, dyspepsia,
bacterial, viral, parasitic, helminth infections, and other pathological illnesses are only a few of the diseases and pathological con­
ditions that the pharmacological qualities of A. millefolium suggest they be used as natural drugs in clinical settings. To determine the
precise mechanism underlying, more study is required to determine the full scope of their pharmacological effects, particularly
regarding their use as an antifertility agent, their ability to promote gastric motility and treat gastric ulcers, their potential to cause
cytotoxic and genotoxic effects, to cardiovascular diseases, and their toxicity as a fumigant for the management. Additionally, many of
the plant’s pharmacological effects have neither been scientifically established nor linked to specific plant components. In addition to
the uses and effects mentioned for this plant and its extract, other new studies also show new uses for it, such as the encapsulation of
yarrow extract in nanoautosomal vesicles followed by encapsulation in a gel for topical delivery.

Data availability statement

Data in this study has not associated or deposited into a publicly available repository. All data in this study included in article and
there’s no other available data.

CRediT authorship contribution statement

Bahareh Farasati Far: Writing - review & editing, Writing - original draft, Software, Conceptualization. Golnaz Behzad: Writing -
review & editing, Writing - original draft, Methodology, Investigation. Hasti Khalili: Writing - review & editing, Writing - original
draft, Visualization, Software, Investigation.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to
influence the work reported in this paper.

Acknowledgement

The authors would like to express their gratitude to BioRender.com for providing an invaluable platform that significantly
contributed to the creation of visual elements and illustrations in this manuscript. The user-friendly interface and diverse library of
scientific icons and templates offered by BioRender.com played a crucial role in enhancing the visual representation of complex
concepts. The ability to seamlessly design high-quality figures greatly facilitated the communication of our research findings. We
acknowledge BioRender.com for their commitment to supporting scientific communication and visualization, empowering researchers
to convey their ideas with clarity and impact.

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