Herbal Medicine in Three Different Mediterranean Living Areas During the COVID-19 Pandemic: The Role of Polyphenolic-Rich Thyme-like Plants

Abstract

Despite herbal medicine being popular across the Mediterranean basin, there is no evidence in favor of COVID-19 infection. This study investigates the utilization and effects of medicinal plants in Italy, Lebanon, and Tunisia during COVID-19 and its effects on post-COVID-19 pandemics. We used a tailored, web-based “Google Form” questionnaire with the random sampling method. We gathered 812 complete responses (Italy: 116, Lebanon: 557, and Tunisia: 139), revealing diverse demographics and symptom experiences. Fatigue prevailed across all groups (89.0–94.2%), while psychological impacts ranged from 20.1% to 30.9%, with higher rates in Lebanon. Post-COVID-19 symptoms affected 22.4% (Italy), 48.8% (Lebanon), and 31.7% (Tunisia). General use of herbs was consistent (41.4–50.4%), with 23.3% (Italy), 50.2% (Lebanon), and 65.5% (Tunisia) employing herbs for COVID-19 therapy. Notably, in Lebanon, Za’atar, a thyme-like plant, correlated with reduced symptoms, suggesting potential protective effects that are likely due to its polyphenol richness. This study underscores the persistent reliance on traditional medicinal plants remedies in the Mediterranean area, with regional variations. Further exploration of herbal compounds for COVID-19-like symptoms is warranted.

Full text

Citation: Khalil, M.; Abdallah, H.;
Calasso, M.; Khalil, N.; Daher, A.;
Missaoui, J.; Diab, F.; Zeaiter, L.;
Vergani, L.; Di Ciaula, A.; et al.
Herbal Medicine in Three Different
Mediterranean Living Areas During
the COVID-19 Pandemic: The Role of
Polyphenolic-Rich Thyme-like Plants.
Plants 2024,13, 3340. https://doi.org/
10.3390/plants13233340
Academic Editors: Jose M. Soriano del
Castillo, Eimad Dine Tariq Bouhlali
and Mohammed Ajebli
Received: 7 October 2024
Revised: 7 November 2024
Accepted: 26 November 2024
Published: 28 November 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Article
Herbal Medicine in Three Different Mediterranean Living Areas
During the COVID-19 Pandemic: The Role of Polyphenolic-Rich
Thyme-like Plants
Mohamad Khalil 1, * , Hala Abdallah 1, Maria Calasso 2, Nour Khalil 3, Ahmad Daher 3, Jihen Missaoui 4,
Farah Diab 5, Lama Zeaiter 5, Laura Vergani 5, Agostino Di Ciaula 1and Piero Portincasa 1, *
1
Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J),
University of Bari Medical School, 70124 Bari, Italy; halaabdallah18@gmail.com (H.A.);
agodiciaula@gmail.com (A.D.C.)
2Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a,
70126 Bari, Italy; maria.calasso@uniba.it
3Rammal Laboratory, Faculty of Sciences, Lebanese University, Al-Hadath Campus, Beirut 1003, Lebanon;
noorkhalil2498@gmail.com (N.K.); ahmad.daher@ul.edu.lb (A.D.)
4
Research Laboratory of BIORESSOURCES—Integrative Biology & Valorisation BIOLIVAL (LR14 ES06) at ISBM,
Monastir 5000, Tunisia; missaouijihen@outlook.fr
5Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26,
16132 Genova, Italy; diabfarah2@gmail.com (F.D.); lama.zeaiter777@hotmail.com (L.Z.);
lara.vergani@unige.it (L.V.)
*Correspondence: mohamad.khalil@uniba.it (M.K.); piero.portincasa@uniba.it (P.P.)
Abstract: Despite herbal medicine being popular across the Mediterranean basin, there is no evidence
in favor of COVID-19 infection. This study investigates the utilization and effects of medicinal plants
in Italy, Lebanon, and Tunisia during COVID-19 and its effects on post-COVID-19 pandemics. We used
a tailored, web-based “Google Form” questionnaire with the random sampling method. We gathered
812 complete responses (Italy: 116, Lebanon: 557, and Tunisia: 139), revealing diverse demographics
and symptom experiences. Fatigue prevailed across all groups (89.0–94.2%), while psychological
impacts ranged from 20.1% to 30.9%, with higher rates in Lebanon. Post-
COVID-19
symptoms affected
22.4% (Italy), 48.8% (Lebanon), and 31.7% (Tunisia). General use of herbs was consistent (41.4–50.4%),
with 23.3% (Italy), 50.2% (Lebanon), and 65.5% (Tunisia) employing herbs for
COVID-19
therapy.
Notably, in Lebanon, Za’atar, a thyme-like plant, correlated with reduced symptoms, suggesting
potential protective effects that are likely due to its polyphenol richness. This study underscores the
persistent reliance on traditional medicinal plants remedies in the Mediterranean area, with regional
variations. Further exploration of herbal compounds for COVID-19-like symptoms is warranted.
Keywords: COVID-19; medicinal plants; Za’atar; post-COVID-19; Mediterranean
1. Introduction
The World Health Organization (WHO) defines traditional medicine, including medic-
inal plants, as having a long history. It is the total of the knowledge, skills, and practices
used in the maintenance of health, as well as in the prevention, diagnosis, or treatment of
physical and mental disorders [
1
]. Natural products from medicinal plants and their struc-
tural analogs have historically played a significant role in drug development, particularly
in treating cancer and infectious diseases [
2
]. For centuries, natural compounds have been
foundational in medicine, with classic examples including digitalis (derived from foxglove),
ergotamine (from contaminated rye), quinine (from cinchona bark), and salicylates (from
willow bark) [
3
]. Several prescribed and clinical medicines are originally derived from
medicinal plants; however, discovering drugs from natural sources requires a complex
approach, integrating botanical, phytochemical, biological, and molecular methods.
Plants 2024,13, 3340. https://doi.org/10.3390/plants13233340 https://www.mdpi.com/journal/plants

Plants 2024,13, 3340 2 of 21
A panel of preclinical studies including
in vitro
cellular and
in vivo
animal studies, as
well as human clinical trials, showed the efficacy of some medicinal plants and bioactive
compounds for several diseases including metabolic, neoplastic, neurodegenerative, and
infectious diseases [
4
–
7
]. Several medicinal plants are practiced worldwide for respira-
tory diseases such as obstructive lung diseases [
8
] and different infectious respiratory
diseases [
9
]. Specific plants, like Echinacea purpurea and Zingiber officinale, show potential
as supportive treatments for respiratory symptoms. Certain plant leaves, like those of
Acacia torta and Ocimum sanctum, are commonly used for ailments like pneumonia and
bronchitis [10].
The Mediterranean basin differs from other regions in its rich inventory of herbal
medicinal products. The mild climate and the biogeography, geology, and ecological
features make the Mediterranean basin unique in terms of biodiversity and plant species
with medicinal potential [
11
]. The use of herbal medicine in the Mediterranean area is
an integral part of folk culture, where plants and herbs are largely used for the treatment
and/or prevention of a wide spectrum of diseases, including respiratory diseases.
Medicinal plants have long been utilized to treat various infectious diseases, with ap-
proximately 25% of commonly prescribed drugs containing plant-derived compounds [
12
].
Several plants have demonstrated potential in managing viral infections, and advances
in vector-based drug discovery and the separation of bioactive compounds represent
promising avenues for new drug development [13].
In late 2019, a new strain of coronavirus appeared and was named acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy
of Viruses (ICTV) [
14
] when a cluster of patients with pneumonia of unknown cause
was recognized in Wuhan, China [
7
]. SARS-CoV-2 was the cause of the Coronavirus
Disease-19
(
COVID-19
), which has rapidly increased worldwide due to high transmission
rate and severe effects on human health. Since then, around 460 million confirmed cases
and 6 million deaths have occurred (“WHO Coronavirus (COVID-19) Dashboard|WHO
Coronavirus (COVID-19) Dashboard With Vaccination Data”, n.d.) [
15
–
17
]. On 11 March
2020, the World Health Organization (WHO) defined COVID-19 as a global pandemic and
public health emergency of international concern [5].
Patients infected with SARS-CoV-2 show different clinical manifestations, ranging
from an asymptomatic disease to a mild, severe, or fatal illness [
18
]. The most com-
mon symptoms of COVID-19 are fever, cough, and myalgia. Other minor symptoms
include sore throat, headache, chills, nausea or vomiting, diarrhea, and conjunctival con-
gestion [6]. Gastrointestinal and hepatobiliary manifestations are also possible in patients
with
COVID-19 [15,16,19]
. Several studies have shown that this coronavirus can also cause
long-term complications, as it may cause major injuries to the heart, kidneys, gastroin-
testinal tract, brain, and even blood vessels [
20
]. Besides vaccination, various therapeutic
approaches for COVID-19 are being employed for both hospitalized adults and children, as
well as for outpatients at risk of severe disease [
21
]. Current treatments include antiviral
agents, immunomodulators, and supportive therapies aimed at managing symptoms and
preventing complications. However, limitations persist, such as the incomplete under-
standing of COVID-19’s diverse mechanisms of action and the variability in treatment
efficacy across different patient populations. The ongoing emergence of new variants
and the potential for long-term sequelae further highlight gaps in therapeutic knowledge,
underscoring the need for continued research into optimizing COVID-19 therapies [22].
Numerous phytochemicals with antiviral properties, derived from medicinal plants,
are under investigation as potential therapeutic agents for COVID-19 [
23
–
25
]. Given the ex-
periences from past epidemics, researchers suggest that herbal medicines offer advantages
such as lower side effects, affordability, and a reduced likelihood of resistance development.
Traditional medicine has also highlighted the effectiveness of essential oils from plants in
managing viral respiratory infections [
26
]. Multiple studies evaluated the efficacy and possi-
ble applications of phytomedicine against SARS-CoV-2 [
1
,
27
,
28
]. Research on plant-derived
compounds showed that they inhibit virus replication, block viral entry, and modulate

Plants 2024,13, 3340 3 of 21
immune responses, including ACE-2 receptor and TMPRSS2 blockade, inflammation regu-
lation, and TLR/Nrf2 pathway activation. Notable plants with anti-SARS-CoV-2 potential
include Allium sativum,Nigella sativa,Glycyrrhiza glabra, and Withania somnifera, while
compounds like kaempferol, quercetin, and glycyrrhizin show promise [
29
]. However,
the potential preventive effects of medicinal herbs and their impacts on disease severity
following SARS-CoV-2 infection remain largely unexplored and warrant further clinical
and epidemiological investigation.
Za’atar is a full expression of the popular plant-based medicine and food in Lebanon,
Eastern Mediterranean, and North African countries. As a word, the meanings of Za’atar
may differ between regions and cultures. Generally, Za’atar refers to a type of plant, and at
the same time to a combination of different plants and spices blended altogether [30,31].
One of the most common Za’atar species is Origanum syriacum L., which is widely
cultivated across the Mediterranean, Western Asia, and Southern Europe, where it holds
significant economic importance [
32
]. Commonly known as Lebanese oregano, “Za’atar”,
Bible hyssop, or Syrian oregano. Additionally, Za’atar is enjoyed as an herbal tea and used
as a seasoning in cooking. It is available in several commercial forms, including fresh and
dried leaves, as well as essential oil. Particularly in Lebanon and Tunisia, Za’atar refers to
many plants belonging to different families called thyme-like plants, including Origanum,
Thymus,Thymbra, and Satureja. Those plants are rich in carvacrol and thymol, two isomers
of phenolic “monoterpenes” that give the unique smell of these plants [31].
In the present study, we aimed to explore the COVID-19 severity of and the real-life use
and possible effects of different medicinal plants on self-treated COVID-19 patients without
previous vaccination in three different geographical areas in the Mediterranean basin, i.e., Italy,
Lebanon, and Tunisia. In this context, this study explored the general use of medicinal plants in
daily routines, focusing on their roles as preventive measures, and then specifically examined
how participants used medicinal plants in response to the COVID-19 pandemic, investigating
their applications for prevention, treatment, and symptom relief related to COVID-19.
2. Results
2.1. General Characteristics of the Enrolled Subjects and Clinical Presentation
The number of completed questionnaires was 812 and they were returned by 116 Italian
subjects (14.3%), 557 Lebanese subjects (68.6%), and 139 Tunisian subjects (17.1%). Detailed
information on the enrolled subjects according to the living area, sex, age, infection duration,
and N/severity of COVID-19 symptoms are depicted in Table 1.
In the Italian cohort, 66.4% were females (p= 0.0001 vs. males). Overall, the mean age
was 37.5
±
SEM 1.3 years. The mean duration of infection was 11.8
±
0.6 days, the mean
number of COVID-19 symptoms was 7.2
±
0.3, with an overall symptom severity score of
17.9 ±0.9, and no statistical difference between males and females.
In the Lebanese cohort, 58.2% were females (p= 0.02 vs. males). Overall, the mean age
was 32.0
±
0.6 years. The mean duration of infection was 14.7
±
0.2 days, and the mean
number of COVID-19 symptoms was 8.2
±
0.3, with an overall symptom severity score of
23.9
±
0.6. Females were significantly younger and reported more symptoms and higher
severity scores than males (0.00003 < p< 0.0003).
In the Tunisian cohort, 68.3% were females (p= 0.0001 vs. males). Overall, the mean
age was 33.0
±
1.0 years. The mean duration of infection was 11.1
±
0.5 days, and the mean
number of COVID-19 symptoms was 10.3
±
0.3, with an overall symptom severity score of
29.2 ±1.2. Females were significantly younger than males (0.00003 < p< 0.0003).
The comparison between the Italian, Lebanese, and Tunisian cohorts with respect to
age, infection duration, and N/severity of COVID-19 symptoms is depicted in Figure 1A–D.
Italian participants were about five years older (p= 0.0006) than both Lebanese and Tunisian
participants (Figure 1A). The duration of the COVID-19 infection was longer (p< 0.00001)
in Lebanese subjects compared to Italian and Tunisian subjects (Figure 1B). The number
and severity of symptoms increased progressively from the Italian to Lebanese to Tunisian
cohorts (p< 0.00001) (Figure 1C,D).

Plants 2024,13, 3340 4 of 21
Table 1. Demographic characteristics of the 812 participants according to gender, age, infection
duration, number of symptoms, and symptom severity score in the three cohorts.
Total Males Females p(M vs. F)
ITALIAN COHORT
N (%) 116 (100%) 39 (33.6%) 77 (66.4%) 0.0001
Age (years) 37.5 ±1.3 39.4 ±2.5 36.5 ±1.5 0.29
Infection duration (days) 11.8 ±0.6 11.4 ±0.7 11.9 ±0.8 0.64
N of COVID-19 symptoms 7.2 ±0.3 7.3 ±0.5 7.2 ±0.3 0.94
Symptom severity score 17.9 ±0.9 17.9 ±1.7 17.9 ±1.2 0.97
LEBANESE COHORT
N (%) 557 (100%) 233 (41.8%) 324 (58.2%) 0.02
Age (years) 32.0 ±0.6 34.7 ±1.0 30.0 ±0.7 0.00008
Infection duration (days) 14.7 ±0.2 14.9 ±0.3 14.5 ±0.3 0.41
N of COVID-19 symptoms 8.2 ±0.1 7.6 ±0.2 8.6 ±0.2 0.00003
Symptom severity score 23.9 ±0.6 21.2 ±0.9 25.9 ±0.7 0.0003
TUNISIAN COHORT
N (%) 139 44 (31.7%) 95 (68.3%) 0.0001
Age (years) 33.3 ±1.0 37.3 ±2.0 31.5 ±1.2 0.009
Infection duration (days) 11.1 ±0.5 10.7 ±0.5 11.8 ±1.0 0.27
N of COVID-19 symptoms 10.3 ±0.3 9.8 ±0.5 10.5 ±0.3 0.22
Symptom severity score 29.2 ±1.2 25.7 ±1.8 30.8 ±1.6 0.054
Data are expressed as means
±
SEMs. N: number of subjects. The difference between genders was tested by a
t-test. M = males; F = females.
Plants 2024, 13, x FOR PEER REVIEW 5 of 22
Figure 1. Comparison between the Italian, Lebanese, and Tunisian cohorts with respect to (A) age,
(B) infection duration, (C) number of COVID-19 symptoms, and (D) the severity of COVID-19
symptoms. Significant differences were tested by ANOVA with post hoc tests.
2.2. Age Classes
Adult subjects (i.e., ≥18 years) represented the most patients in the three cohorts, i.e.,
92.2% in Italy, 89.4% in Lebanon, and 93.5% in Tunisia. Details about the three age classes,
i.e., pediatric, adult, and geriatric, are reported in Supplementary Table S1. Due to the
scant number of cases in the pediatric and geriatric age groups in both the Italian and
Tunisian cohorts, however, the most meaningful results belonged to the Lebanese cohort.
Here, both the number and severity of COVID-19 symptoms were significantly less in
pediatric participants (7.2%) compared to adults (0.001 ≤ p ≤ 0.001) but not the elderly.
2.3. Smoking
The classification of participating subjects according to cohorts and smoking status
is depicted in Supplementary Table S2. In each cohort, the prevalence of smokers was
significantly lower than non-smokers (0.0001 ≤ p ≤ 0.004). The number of smokers in the
cohorts tended to increase from 30.2% in Italy to 36.3% in Tunisia and to 39.9% in Lebanon
(p = n.s.). The percentage of smoking females was comparable between the cohorts. No
differences existed between the infection duration and N/severity of symptoms between
smokers and non-smokers in all cohorts.
Figure 1. Comparison between the Italian, Lebanese, and Tunisian cohorts with respect to (A) age,
(B) infection duration, (C) number of COVID-19 symptoms, and (D) the severity of COVID-19
symptoms. Significant differences were tested by ANOVA with post hoc tests.

Plants 2024,13, 3340 5 of 21
2.2. Age Classes
Adult subjects (i.e.,
≥
18 years) represented the most patients in the three cohorts, i.e.,
92.2% in Italy, 89.4% in Lebanon, and 93.5% in Tunisia. Details about the three age classes,
i.e., pediatric, adult, and geriatric, are reported in Supplementary Table S1. Due to the scant
number of cases in the pediatric and geriatric age groups in both the Italian and Tunisian
cohorts, however, the most meaningful results belonged to the Lebanese cohort. Here,
both the number and severity of COVID-19 symptoms were significantly less in pediatric
participants (7.2%) compared to adults (0.001 ≤p≤0.001) but not the elderly.
2.3. Smoking
The classification of participating subjects according to cohorts and smoking status
is depicted in Supplementary Table S2. In each cohort, the prevalence of smokers was
significantly lower than non-smokers (0.0001
≤
p
≤
0.004). The number of smokers in the
cohorts tended to increase from 30.2% in Italy to 36.3% in Tunisia and to 39.9% in Lebanon
(p= n.s.). The percentage of smoking females was comparable between the cohorts. No
differences existed between the infection duration and N/severity of symptoms between
smokers and non-smokers in all cohorts.
2.4. Prevalence, Management, and Psychological Consequences of COVID-19 Symptoms and
Post-COVID-19 Symptoms in the Three Cohorts
Table 2compares the three cohorts according to the prevalence of the 13 COVID-19
symptoms, their management, psychological consequences, post-COVID-19 symptoms,
and use of herbs.
Table 2. Prevalence, management, and psychological consequences of COVID-19 symptoms, post-
COVID-19 symptoms, and use of herbs in the three cohorts.
ITALIAN
COHORT
(N = 116)
LEBANESE
COHORT
(N = 557)
TUNISIAN
COHORT
(N = 139)
p
ITA vs. LEB
p
ITA vs. TUN
p
LEB vs. TUN
COVID-19 Symptoms
Abdominal pain * 48 (41.4%) 245 (44.0%) 89 (64.0%) 0.60 <0.00001 <0.00001
Chest pain 46 (39.7%) 288 (51.7%) 100 (71.9%) 0.02 <0.00001 <0.00001
Cough 91 (78.4%) 431 (77.4%) 127 (91.4%) 0.80 0.003 0.0002
Diarrhea * 19 (16.4%) 212 (38.1%) 78 (56.1%) <0.00001 <0.00001 <0.00001
Dyspnea 60 (51.7%) 291 (52.2%) 105 (75.5%) 0.92 0.0001 <0.00001
Fatigue 105 (90.5%) 496 (89.0%) 131 (94.2%) 0.64 0.25 0.06
Fever 98 (84.5%) 362 (65.0%) 123 (88.5%) <0.00001 0.19 <0.00001
Headache 108 (93.1%) 467 (83.8%) 131 (94.2%) 0.01 0.53 0.0007
Joint pain 73 (62.9%) 414 (74.3%) 122 (87.8%) 0.01 <0.00001 0.0008
Loss of taste 51 (44.0%) 381 (68.4%) 121 (87.1%) <0.00001 <0.00001 <0.00001
Loss of smell 47 (40.5%) 447 (80.3%) 118 (84.9%) <0.00001 <0.00001 0.1
Muscle pain 85 (73.3%) 414 (74.3%) 120 (86.3%) 0.81 0.009 0.003
Vomiting * 10 (8.6%) 115 (20.6%) 60 (43.2%) 0.002 <0.00001 <0.00001
Management of symptoms
Recourse to a doctor 93 (80.2%) 413 (74.2%) 104 (74.8%) 0.17 0.3 0.87
Medication for COVID-19 81 (69.8%) 419 (75.2%) 125 (89.9%) 0.22 <0.00001 0.0002
Hospitalization 2 (1.7%) 43 (7.7%) 10 (7.2%) 0.02 0.04 0.83
Psychological consequences 30 (25.9%) 172 (30.9%) 28 (20.1%) 0.28 0.27 0.01
Post-COVID-19 symptoms 26 (22.4%) 272 (48.8%) 44 (31.7%) <0.00001 0.1 0.0003

Plants 2024,13, 3340 6 of 21
Table 2. Cont.
ITALIAN
COHORT
(N = 116)
LEBANESE
COHORT
(N = 557)
TUNISIAN
COHORT
(N = 139)
p
ITA vs. LEB
p
ITA vs. TUN
p
LEB vs. TUN
General use of herbs
Regular 48 (41.4%) 274 (49.2%) 70 (50.4%) 0.12 0.15 0.80
Occasional 36 (31.0%) 190 (34.1%) 55 (39.6%) 0.52 0.16 0.23
Non-user 32 (27.6%) 93 (16.7%) 14 (10.0%) 0.006 0.0003 0.053
Believe that the use of herbs can
cure or prevent 40 (34.7%) 336 (64.1%) 101 (72.4%) <0.00001 <0.00001 0.007
Use of herbs for COVID-19
For prevention 3 (2.6%) 168 (30.2%) 82 (59.0%) <0.00001 <0.00001 <0.00001
For therapy 27 (23.3%) 283 (50.8%) 91 (65.5%) <0.00001 <0.00001 0.0002
Effects on symptoms 17 (14.7%) 219 (39.3%) 100 (71.9%) <0.00001 <0.00001 <0.00001
Data are expressed as numbers and percentages (%). Differences between cohorts were tested by the chi-square
test. The asterisk (*) indicates gastrointestinal symptoms.
The Tunisian cohort reported a consistently higher prevalence of almost all symptoms
compared to the Italian and Lebanese cohorts, except for fatigue. In addition, fever and
headache were comparable between the Tunisian and Italian cohorts, while loss of smell
was comparable between the Tunisian and Lebanese cohorts. The three most recorded
symptoms in the Italian cohort were headache (93.1%), fatigue (90.5%), and fever (84.5%);
in the Lebanese cohort were fatigue (89.0%), headache (83.8%), and anosmia (80.3%); and
in the Tunisian cohort were fatigue (94.2%), headache (94.2%), and fever (88.5%).
Most participants recorded a similar recourse to the doctor (Italy 80.2%, Lebanon
74.2%, and Tunisia 74.8%, p= n.s.) during the COVID-19 infection period. The percentage
of participants who took medication in an attempt to decrease symptoms was significantly
higher in the Tunisian cohort (89.9%) compared to the Italian (69.8%) and Lebanese (75.2%)
cohorts. The percentage of hospitalized subjects was small and significantly lower in the
Italian cohort (1.7%) than in the Lebanese (7.7%) and Tunisian (7.2%) cohorts. Aspects of
the psychological consequences of COVID-19’s effects were reported by 25.9% in the Italian
cohort, 30.9% in the Lebanese cohort, and 20.1% in the Tunisian cohort. Post-COVID-19
symptoms were significantly higher in Lebanese participants (48.8%) compared to Italian
(22.4%) and Tunisian (31.7%) participants.
2.5. Use of Herbal Medicines
Table 3shows that in general, the prevalence of regular
(41–50%)
and occasional
(31–40%)
use of herbs was comparable between the three cohorts. The prevalence of non-
users decreased significantly across the Italian, Lebanese, and Tunisian cohorts. Notably,
the prevalence of subjects believing that herbs can cure or prevent, and the prevalence of
subjects using herbs for COVID-19 prevention and therapy, and those reporting effects on
symptoms increased significantly from the Italian to the Lebanese to the Tunisian cohorts
(0.00001 ≤p≤0.007).
The prevalence of specific herbs used for COVID-19 in the three cohorts is detailed
in Table 3. Only 27 out of 116 (23.3%) of Italian subjects reported the use of herbs dur-
ing COVID-19. The herbal tea, known in Italy as a “tisane”, a mix of mainly Matricaria
chamomilla,Mentha piperita,Melissa officinalis, and Foeniculum vulgare, was the most used
herbal product (37.1%), followed by Matricaria chamomilla (22.2%) and Camellia sinensis
(14.8%). A quarter of subjects (25.9%) reported the use of other herbs.
In the Lebanese cohort, 50.8% reported the use of herbs during COVID-19 infection.
The popular Lebanese herbal tea known as “zhourat”, a mixture of mainly Rosa damascen’,
Matricaria chamomilla, and Micromeria spp., was the most used herbal product (55.8%),
followed by Za’atar plants (Origanum syriacum,Thymbra spicata, and Satureja thymbra)

Plants 2024,13, 3340 7 of 21
(12.0%), Pimpinella anisum (6.0%), and Zingiber officinale (5.7%). The other 12.7% of subjects
reported the use of other herbs.
Table 3. Use of specific medicinal plants for COVID-19 infection in the three cohorts.
ITALIAN COHORT
(N = 116) Common Name Scientific Name N (%)
Non-users 89 (76.7%)
Users 27 (23.3%)
Plants used
Herbal tea (tisane)
Mixture of Matricaria chamomilla,Mentha piperita,
Melissa officinalis,Foeniculum vulgare,Rosmarinus officinalis,
Lavandula angustifolia, and Thymus vulgaris
10/27 (37.1%)
Chamomile Matricaria chamomilla 6/27 (22.2%)
Green tea Camellia sinensis 4/27 (14.8%)
Others 7/27 (25.9%)
LEBANESE COHORT
(N = 557) N. (%)
Non-users 274 (49.2%)
Users 283 (50.8%)
Plants used
Herbal tea (zhourat)
Mixture of mainly Rosa damascen’,Matricaria chamomilla,
Micromeria sp., and Crataegus monogyna 158/283 (55.8%)
Za’atar Origanum syriacum,Thymbra spicata, and Satureja thymbra 34/283 (12.0%)
Anise Pimpinella anisum 17/283 (6.0%)
Ginger Zingiber officinale 16/283 (5.7%)
Green tea Camellia sinensis 13/283 (4.6%)
Chamomile Matricaria chamomilla 9/283 (3.2%)
Others 36/283 (12.7%)
TUNISIAN COHORT
(N = 139) N. (%)
Non-users 48 (34.5%)
Users 91 (65.5%)
Plants used
Za’atar Thymbra capitata 48/91 (52.7%)
Tisane (verveine) Verbena officinalis 9/91 (9.9%)
Eucalyptus Eucalyptus sp. 6/91 (6.6%)
Cloves Syzygium aromaticum 5/91 (5.5%)
Herbal tea Camellia sinensis, Rosmarinus officinalis, and Mentha piperita 5/91 (5.5%)
Others 18/91 (19.8%)
Data are expressed as numbers and percentages, N (%).
In the Tunisian cohort, 65.5% of subjects reported the use of herbs during COVID-19.
Za’atar (Thymbra capitata) was the most used herbal product (52.7%), followed by Verbena
officinalis (9.9%) and Eucalyptus sp. (6.6%). The other 19.8% of enrolled subjects reported the
use of other herbs. The use of herbs was well tolerated and none of the subjects reported
adverse effects, independently from the specific herb used.
2.6. Reported Effects of Herbal Medicine on COVID-19 Symptom Severity
The clinical presentation of COVID-19 in terms of the infection duration, severity
of the 13 symptoms, number of symptoms, and severity of symptoms score, as well as
COVID-19 management, were compared between subgroups of subjects taking the most
employed herbal products and non-users of herbal products (Table 4).

Plants 2024,13, 3340 8 of 21
Table 4. Symptoms reported during the COVID-19 infection according to the use of herbs in the
three cohorts.
ITALIAN COHORT
(N = 116)
No Herbs
(N = 89)
Tisane
(N = 10)
Chamomile
(N = 6) p
Age 38.4 ±1.6 35.8 ±3.3 33.8 ±4.4 0.90
Infection duration 11.6 ±0.6 10.6 ±1.7 14.3 ±1.5 0.11
Symptoms
Abdominal pain 1.0 ±0.1 0.3 ±0.2 1.3 ±0.6 0.22
Chest pain 1.0 ±0.1 0.4 ±0.2 0.5 ±0.3 0.46
Cough 1.9 ±0.2 2.9 ±0.4 2.0 ±0.3 0.15
Diarrhea 0.2 ±0.1 0.2 ±0.1 0.3 ±0.2 0.71
Dyspnea 1.1 ±0.1 0.7 ±0.3 0.5 ±0.5 0.23
Fatigue 2.5 ±0.2 2.1 ±0.5 2.5 ±0.4 0.79
Fever 2.1 ±0.2 * 3.5 ±0.6 * 3.2 ±0.3 0.01
Headache 2.7 ±0.2 2.4 ±0.3 2.3 ±0.5 0.67
Joint pain 1.5 ±0.2 0.4 ±0.2 1.3 ±0.5 0.05
Loss of smell 1.1 ±0.2 1.0 ±0.4 1.0 ±0.4 0.88
Loss of taste 1.0 ±0.2 1.1 ±0.4 1.0 ±0.4 0.83
Muscle pain 1.9 ±0.2 1.7 ±0.4 2.3 ±0.3 0.71
Vomiting 0.2 ±0.1 0.2 ±0.2 0.0 ±0.0 0.93
N of symptoms 7.2 ±0.3 6.8 ±0.7 8.5 ±0.7 0.48
Symptom score 18.1 ±1.1 16.9 ±2.0 18.3 ±3.0 0.90
Management
Recourse to doctor 78 (87.7%) *# 5 (50.0%) * 3 (50.0%) # <0.05
Medication for COVID-19 59 (66.3%) 7 (70.0%) 6 (100%) n.s.
Hospitalization 2 (2.3%) 0 (0.0%) 0 (0.0%) n.a.
LEBANESE COHORT
(N = 557)
No herbs
(N = 274)
Zhourat
(N = 158)
Za’atar
(N = 34) p
Age 31.2 ±0.8 31.5 ±1.0 33.8 ±3.0 0.82
Infection duration 14.8 ±0.3 15.1 ±0.5 13.3 ±0.5 0.10
Symptoms
Abdominal pain 1.0 ±0.1 * 1.3 ±0.1 * 0.3 ±0.1 * 0.0008
Chest pain 1.3 ±0.1 * 1.7 ±0.1 * 0.5 ±0.2 * 0.0001
Cough 1.9 ±0.1 * 2.4 ±0.1 *# 1.5 ±0.2 # 0.0005
Dyspnea 1.4 ±0.1 * 1.5 ±0.1 # 0.5 ±0.2 *# 0.003
Diarrhea 1.0 ±0.1 1.0 ±0.1 0.4 ±0.1 0.06
Fatigue 2.9 ±0.1 * 3.2 ±0.1 * 2.3 ±0.2 * 0.001
Fever 1.8 ±0.1 1.7 ±0.1 1.1 ±0.2 0.15
Headache 2.4 ±0.1 * 2.8 ±0.1 *# 2.1 ±0.3 # 0.02
Joint pain 2.3 ±0.1 * 2.7 ±0.1 * 1.2 ±0.3 * 0.00004
Loss of smell 2.6 ±0.1 2.5 ±0.1 1.9 ±0.3 0.19
Loss of taste 2.2 ±0.1 2.0 ±0.1 1.8 ±0.3 0.67
Muscle pain 2.2 ±0.1 * 2.6 ±0.1 * 1.3 ±0.3 * 0.0002
Vomiting 0.6 ±0.1 0.6 ±0.1 0.0 ±0.0 0.15
N of symptoms 8.0 ±0.2 * 8.9 ±0.2 * 6.3 ±0.5 * 0.0007
Symptom score 23.6 ±0.8 * 26.1 ±1.0 # 14.9 ±2.2 *# 0.00005

Plants 2024,13, 3340 9 of 21
Table 4. Cont.
ITALIAN COHORT
(N = 116)
No Herbs
(N = 89)
Tisane
(N = 10)
Chamomile
(N = 6) p
Management
Recourse to doctor 206 (75.2%) * 124 (78.5%) # 20 (58.8%) *# <0.05
Medication for COVID-19 197 (71.9%) * 138 (87.3%) # 18 (52.9%) *# <0.05
Hospitalization 26 (9.5%) * 12 (7.6%) 1 (2.9%) * <0.05
TUNISIAN COHORT
(N = 139)
No herbs
(N = 48)
Za’atar
(N = 48)
Tisane
(N = 9) p
Age 30.3 ±1.2 35.2 ±2.3 26.3 ±2.4 0.15
Infection duration 11.0 ±1.0 11.5 ±0.3 11.0 ±1.3 0.18
Symptoms
Abdominal pain 1.4 ±0.2 * 1.8 ±0.2 2.6 ±0.5 * 0.04
Chest pain 2.0 ±0.2 1.9 ±0.2 3.0 ±0.6 0.15
Cough 2.2 ±0.2 *# 2.8 ±0.2 * 3.4 ±0.2 # 0.01
Diarrhea 1.3 ±0.2 1.6 ±0.2 1.4 ±0.4 0.31
Dyspnea 1.6 ±0.2 *# 2.4 ±0.1 * 2.8 ±0.5 # 0.01
Fatigue 2.9 ±0.2 * 2.7 ±0.2 # 4.1 ±0.3 *# 0.02
Fever 2.4 ±0.2 2.9 ±0.2 3.6 ±0.3 0.07
Headache 2.8 ±0.2 * 2.5 ±0.2 # 4.1 ±0.3 *# 0.01
Joint pain 2.5 ±0.3 * 2.4 ±0.2 # 4.1 ±0.3 *# 0.006
Loss of smell 2.3 ±0.3 2.4 ±0.2 3.7 ±0.6 0.06
Loss of taste 2.3 ±0.3 * 2.4 ±0.2 # 3.9 ±0.4 *# 0.02
Muscle pain 2.4 ±0.3 * 2.4 ±0.2 # 3.8 ±0.4 *# 0.048
Vomiting 0.6 ±0.2 1.2 ±0.2 0.9 ±0.5 0.052
N of symptoms 9.0 ±0.6 * 11.6 ±0.3 * 11.3 ±0.7 0.002
Symptom score 26.6 ±2.4 * 29.4 ±1.6 # 41.3 ±4.5 *# 0.02
Management
Recourse to doctor 30 (62.6) *# 43 (89.6%) * 8 (88.9%) # <0.05
Medication for COVID-19 39 (81.3%) * 47 (97.9%) * 8 (88.9%) <0.05
Hospitalization 4 (8.3%) 4 (8.3%) 0 (0.0%) n.a
Age, infection duration, and the 13 symptoms are expressed as averages
±
SEMs derived from a 0–5 semiquanti-
tative scale. Management is expressed as numbers and percentages (N, %). Differences between percentages were
tested by the chi-square test; differences between averages were tested by the Kruskal–Wallis multiple comparison
Z-value test. N, number of subjects. n.s., Not significant; n.a.; not applicable. Similar symbols (*, #) indicate a
significant difference (p< 0.05).
In the Italian cohort, age and the duration of infection were comparable irrespective
of herbal use. Data for symptoms showed variability mostly due to the scant number of
observations since patients reported that, as compared to the no herb group, fever was in-
creased in the tisane group (p= 0.01). Similarly, the management of the COVID-19 infection,
including doctor visits and medication, displayed high variability with either increased or
decreased effects in the “no herb” group and groups using herbs. In the Lebanese cohort,
age and the duration of infection were comparable irrespective of herbal use. Regarding
symptoms, no significant changes were observed between groups regarding diarrhea, fever,
loss of smell, loss of taste, and vomiting. For abdominal pain, chest pain, cough, dyspnea,
fatigue, headache, joint pain, and muscle pain, subjects in the zhourat group reported a
significantly higher symptom severity compared to the control group, while subjects in the
Za’atar group reported a significantly lower symptom severity (
0.00005 ≤p≤0.02
). The
number of symptoms and symptom severity scores were significantly lower in the Za’atar

Plants 2024,13, 3340 10 of 21
group compared to the zhourat and no herb groups. In addition, the percentage of subjects
who reported recourse to a doctor and medication use for COVID-19 were significantly
lower in the “Za’atar” group compared to the other groups.
In the Tunisian cohort, age and the duration of infection were comparable irrespective
of herbal use. Subjects in the tisane group reported a significantly higher severity of
abdominal pain, cough, dyspnea, fatigue, headache, joint pain, and muscle pain compared
to the no herb group (0.04
≤
p
≤
0.006). The N/symptoms were higher in the tisane
group compared to the no herb group (0.02
≤
p
≤
0.002). Regarding management, a higher
percentage of subjects in the Za’atar and tisane groups used recourse to the doctor (
p< 0.05
),
while the number of subjects who took medications for COVID-19 were significantly higher
in the tisane group compared to the no herb group (p< 0.05).
2.7. Emergence of Post-COVID-19 Symptoms and Possible Effects of Herbs
The emergence of post(long)-COVID-19 symptoms within 12 months in all subjects
and according to the herb groups in the three cohorts are depicted in Table 5.
Table 5. Post-COVID-19 symptoms according to the use of herbs in the three cohorts.
ITALIAN COHORT
(N = 116)
Total
(N = 116)
No Herbs
(N = 89)
Tisane
(N = 10)
Chamomile
(N = 6)
N of subjects (%) 26 (22.4%) 15 (16.9%) *# 6 (60.0%) * 5 (83.3%) #
Fatigue 5 (19.2%) 3 (20.0%) 1 (16.7%) 1 (16.7%)
Muscle pain 3 (11.5%) 1 (6.7%) 1 (10.0%) 1 (16.7%)
Headache 9 (34.6%) 5 (33.3%) 2 (20.0%) 2 (33.3%)
Dyspnea 3 (11.5%) 2 (13.3%) 0 (0.0%) 1(16.7%)
Gastrointestinal symptoms 2 (7.7%) 2 (13.3%) 0 (0.0%) 0 (0.0%)
Others 4 (15.4%) 2 (13.3%) 2 (20.0%) 0 (0.0%)
LEBANESE COHORT
(N = 557)
Total
(N = 557)
No herbs
(N = 274)
Zhourat
(N = 158)
Zaatar
(N = 34)
N of subjects (%) 272 (48.8%) 158 (57.7%) * 103 (65.2%) # 11 (32.4%) *#
Fatigue 76 (27.9%) 34 (21.5%) 35 (34.0%) 4 (36.7%)
Muscle pain 47(17.3%) 27 (17.1%) 17 (16.5%) 1 (9.1%)
Headache 66 (24.3%) 43 (27.2%) 26 (25.2%) 5 (45.5%)
Dyspnea 45 (16.5%) 25 (15.8%) 18 (17.5%) 0 (0.0%)
Gastrointestinal symptoms 11 (4.0%) 9 (5.7%) 2 (1.9%) 0 (0.0%)
Others 27 (9.9%) 20 (12.7%) 5 (4.9%) 1 (9.1%)
TUNISIAN COHORT
(N = 139)
Total
(N = 139)
No herbs
(N = 48)
Zaatar
(N = 48)
Tisane
(N = 9)
N of subjects (%) 44 (31.7%) 28 (58.3%) * 11 (22.9%) *# 5 (55.6%) #
Fatigue 11 (25.0%) 7 (25.0%) 2 (18.2%) 1 (20.0%)
Muscle pain 5 (11.4%) 3 (10.7%) 2 (18.2%) 0 (11.1%)
Headache 10 (22.7%) 6 (21.4%) 4 (36.4%) 1 (20.0%)
Dyspnea 5 (11.4%) 3 (10.7%) 0 (0.0%) 1 (20.0%)
Gastrointestinal symptoms 2 (4.5%) 1 (3.6%) 2 (18.2%) 0 (0.0%)
Others 11 (25.0%) 8 (28.6%) 1(9.1%) 2 (40.0%)
Data are expressed as numbers and percentages; N (%). Difference between percentages tested by chi-square test.
Similar symbols (*, #) indicate a significant difference (p< 0.05). GI, gastrointestinal; N, Number of subjects.

Plants 2024,13, 3340 11 of 21
In the Italian cohort, 26 subjects (22.4%) reported post-COVID-19 symptoms. The
most reported symptoms were headache (34.6%) and fatigue (19.2%). Gastrointestinal (GI)
symptoms, including recurrent abdominal pain associated with changes in the frequency
and shape of stool, were reported by 2 subjects (7.7%). The prevalence of post-COVID-19
symptoms was significantly lower in the no herb group (16.9%) compared to the tisane
group (60.0%) and chamomile group (83.3%), with the results likely influenced by the
limited number of cases in this group.
In the Lebanese cohort, 272 subjects (48.8%) reported post-COVID-19 symptoms. The
most reported symptoms were fatigue (27.9%), headache (24.3%), and muscle pain (17.3%).
The prevalence of post-COVID-19 was significantly lower in the Za’atar group (32.4%)
compared to the zhourat (65.2%) and no herb groups (57.7%). Gastrointestinal symptoms
were reported by 11 subjects (4.0%) and were comparable irrespective of herb use. In the
Tunisian cohort, 44 subjects (31.7%) reported post-COVID-19 symptoms. The most reported
post-COVID-19 symptoms were fatigue (25.0%) and headache (22.7%). The prevalence of
post-COVID-19 was significantly lower in the Za’atar group (22.9%) compared to the tisane
(55.6%) and no herb groups (58.3%). GI symptoms were reported by 2 subjects (4.5%).
3. Discussion
Generally, the use of medicinal plants in the Mediterranean area is popular and well-
documented [
11
,
33
]. This is the first systematic study dealing with herbal use during the 1st
wave of the COVID-19 pandemic in three different geographical areas in the Mediterranean
basin, i.e., Italy, Lebanon, and Tunisia. We also extended the study to the post-COVID-19
period. In addition, the survey paves the way for several considerations, which include
geographical, cultural, and scientific aspects.
In general, the three cohorts consisted of relatively young adults, and the Lebanese
cohort was the most represented one. Some gender aspects emerged, since the number
of females was higher than males in all countries, with a slightly younger age for females
than males in Lebanon and Tunisia. The smoking status was comparable in both genders
throughout the cohorts and did not influence the symptom characteristics. Whether the
most prevalent manifestations of symptoms in the Tunisian cohort represent a true phe-
nomenon remains to be investigated, although more participants used medications for
COVID-19 than participants in the Italian and Lebanese cohorts.
The prevalence of COVID-19 symptoms was different between symptoms, and vari-
ability was recorded between cohorts. The highest prevalence was recorded for headache
(83–94%), and the lowest prevalence was for vomiting (8–43%). Post-COVID-19 com-
plications within 12 months after recovery (post(long)-COVID-19) were experienced by
around one-quarter in the Italian cohorts, half in the Lebanese cohort, and one-third in the
Tunisian cohort. These results are in line with other studies suggesting that the prevalence
of post-COVID-19 syndrome varies widely between 8% and 70%, depending on the defini-
tion, living area, assessment method, and time points [
34
,
35
]. These complications were
mainly in terms of fatigue, muscle pain, headache, and dyspnea. Here, we additionally
observed an emergence of a few cases (7.7% in Italy, 4.0% in Lebanon, and 4.5% in Tunisia)
of gastrointestinal symptoms, most likely associated with the diagnostic criteria of irritable
bowel syndrome. The gastrointestinal involvement in post(long)- COVID-19 syndrome, its
frequency, and its pathophysiology are still not completely understood. These results are in
line with two recent international studies [19,36,37].
During the last few years, a considerable amount of population-based and ethnob-
otanical studies have documented the use of medicinal plants for COVID-19. These studies
collectively explored the impact of the COVID-19 pandemic on herbal medicine practices
across different regions, highlighting a range of medicinal plants traditionally used to
manage COVID-19 symptoms. In the UK, practitioners adapted by prescribing plants like
Glycyrrhiza glabra and Echinacea spp. for mild to moderate symptoms, with a noted need for
consistent approaches in remote consultations [
10
]. Lithuania’s study raised concerns about
the safe use of locally popular plants for respiratory health, especially when lacking formal

Plants 2024,13, 3340 12 of 21
approval or evidence-based guidelines [
38
]. In Morocco and Tanzania, ethnopharmacologi-
cal research identified common medicinal plants like Eucalyptus globulus and Azadirachta
indica, valued for their antiviral compounds, emphasizing the need for phytochemical vali-
dation [
39
,
40
]. Zimbabwe’s and Nigeria’s analyses highlighted the potential for integrating
traditional African herbal knowledge with modern research to address COVID-19’s broader
health impacts and explore phytochemicals with antiviral potential [
41
,
42
]. Together, these
findings underscore the global interest in local herbal remedies as complementary or sup-
portive treatments for COVID-19, with calls for systematic validation, safety evaluations,
and culturally informed health governance.
Despite the possible socioeconomic and educational differences between the three
cohorts, in Italy, the adherence to herbal medicine use was moderate. However, herbal
remedies are deeply embedded in cultural practices in Lebanon and Tunisia, with different
preferences for a broader range of herbs. This highlights how herbal remedies are not only
influenced by the individual’s socioeconomic status or educational background but also by
the rich local traditions and regional health practices prevalent in each country [43].
Such evident differences within the Mediterranean basin existed along with the in-
creased use of a variety of medicinal plants for COVID-19, as reported in Table 3. In Italy,
nearly one-quarter (23.3%) of participants used herbs for COVID-19 therapy, while half of
the Lebanese participants (50.8%) reported herbal medicine use, and the majority (65.5%) of
the Tunisian participants used herbs during COVID-19. In Italy, most herbal users reported
herbal tea (tisane) as the most used, followed by chamomile and green tea. Tisane is a
popular hot drink in Italy, which is usually made by steeping fresh or dried herbs in boiled
water, and it can vary depending on the desired flavour and health benefits.
The Lebanese population uses medicinal plants as natural remedies against different
disorders, including infective, acute, or chronic diseases. Indeed, in this study, half of the
Lebanese participants (49%) reported the regular use of herbs, 34.2% occasional use, and
most subjects (65%) agreed with the statement “Do you believe herbs can cure or prevent
diseases?”. This confirms that the use of herbal medicine in Lebanon remains diffused and
popular. Half of the Tunisian cohort (50%) reported the regular use of herbs, 40% occasional
use, and most subjects (72%) agreed with the statement “Do you believe herbs can cure or
prevent diseases?”.
In the Lebanese cohort, many patients relied on taking a group of herbs, which
included zhourat, Za’atar, ginger, anise, green tea, chamomile, and other herbs, as they
thought that taking them would heal them from the virus or at least alleviate the severity
of the symptoms.
Za’atar is the most used herb since it is used in Tunisia as a hot drink or as a spicy herb
for breakfast and dinner. Za’atar or Thymbra capitata L. is widely used in folk medicine as a
stomachic, antispasmodic, or diaphoretic, and specifically against cough since it stimulates
blood circulation [44].
The results of the current study revealed a distinct feature between different living
areas regarding the use of herbs during the COVID-19 acute phase and the effects on
COVID-19 and post-COVID-19 symptoms.
Our results apparently point to Za’atar as the most effective herbal product, in terms of
beneficial effects on the COVID-19 symptom prevalence and severity in the Lebanese cohort.
In fact, subjects in the Za’atar group reported lower overall symptom scores than subjects
using no herbs or other herbal products. Interestingly, the prevalence of post-COVID-19
complications was significantly lower in the Za’atar group.
These effects might be explained, at least in part, by previous observations showing a
broad spectrum of beneficial effects of Za’atar plants, such as an anti-inflammatory
[45–49]
,
antioxidant [
50
,
51
], antidiabetic [
52
–
54
], and hypolipidemic [
51
,
55
] agent. In detail, Za’atar
plants such as Origanum syriacum L., Thymbra spicata L., and Satureja thymbra L. are perennial
aromatic species belonging to the Lamiaceae family, and are popular as fresh or dried culinary
herbs and food seasonings [
56
]. Essential oils of these plants are rich in volatile compounds,
including thymol, p-cymene, and
γ
- terpinene, but most notably carvacrol [
57
]. Remarkably,

Plants 2024,13, 3340 13 of 21
those plants are also rich in phenolic compounds, including phenolic acids (rosmarinic
acid) and flavonoids (both glycosides and aglycones) [58,59].
Studies on the effects of thyme-like plants and their primary compounds, carvacrol and
thymol, suggest these components may offer antiviral, anti-inflammatory, and antioxidant
benefits in the context of COVID-19 and SARS-CoV-2. Thymus vulgaris has traditionally been
recognized for its antimicrobial and antiviral properties. Research shows that thyme and its
bioactive compounds can suppress pro-inflammatory cytokines (e.g., TNF-
α
, and
IL-6
) and
boost anti-inflammatory cytokines like IL-10, which may help manage inflammation linked
to COVID-19 [
60
]. Carvacrol and thymol, two major constituents in thyme essential oil,
have shown potential in inhibiting SARS-CoV-2 pathways. For example, in silico studies
indicate that these compounds can bind to the catalytic domain of TMPRSS2 (a host enzyme
facilitating viral entry), showing stability and potentially preventing SARS-CoV-2 from
entering host cells [
61
]. Additionally, these compounds demonstrate binding affinities to
the viral spike protein’s receptor-binding domain, potentially disrupting viral attachment
and replication processes [
62
]. Further studies highlight that carvacrol and thymol can
reduce oxidative stress and enhance antioxidant defenses, which may protect against virus-
induced tissue damage [
63
]. Molecular docking analyses suggest that these compounds
act as viral inhibitors by modulating immune responses and controlling CoV-induced
lung inflammation, potentially making them valuable in alternative or complementary
COVID-19
therapies [
64
]. A study on the ethanol and water extracts of thyme (Thymus
vulgaris) showed its effects on the inhibition of the SARS-CoV-2 spike protein–ACE2 binding
by 82.6 and 86.4%, respectively, which proved that thyme can be used to prevent SARS-
CoV-2 infection and reduce the complications from the infection [41].
Carvacrol, one of the well-known bioactive compounds widely found in Lamiaceae
plants, was proven to exhibit different beneficial effects [
30
]. A wide array of
in vivo
and
in vitro
studies have demonstrated the therapeutic potential and clinical significance of car-
vacrol as an anticancer [
65
], antibacterial [
66
,
67
], antioxidant [
68
], anti-inflammatory
[69–71]
,
and hepatoprotective [
72
] natural agent. A recent
in vitro
study on the inhibitory activity
of Origanum essential oils and carvacrol against angiotensin-converting enzyme 2 (ACE2)
and lipoxygenase (LOX), showed that carvacrol has 90.7% inhibitory activity against ACE2
in vitro
[
73
]. In fact, many recent studies suggested that the selection of various FDA-
approved antiviral compounds might yield promising results against COVID-19 infection.
In this sense, Kumar et al. proved that CVL possesses a binding capacity to Mpro, a
protease in the SARS-CoV-2 viral genome with a considerable role in the replication and
maturation of the virus [
74
]. On the other hand, carvacrol exerts a potent suppressive
activity against COX-2 expression and NF
κ
B activation, and modulates the Nrf2/HO-1
signaling pathway, minimizing the acute inflammatory process and decreasing the re-
lease of some pro-inflammatory mediators such as IL-1
β
, TNF-
α
, and PGE2 [
53
,
75
], and
it could down-regulate the activation of NF-
κ
B signaling in lipopolysaccharide-treated
macrophages [
69
]. Interestingly, different clinical studies showed that CVL consump-
tion reduced the inflammatory status in pulmonary and respiratory diseases. In detail,
CVL reduced serum pro-inflammatory cytokine and chemokine levels while increasing
anti-inflammatory cytokine levels, improve respiratory symptoms [
20
], and reduced in-
flammatory cells and oxidant biomarkers, whereas it increased antioxidant biomarkers
and improved pulmonary function [
76
]. In addition, in asthmatic patients, CVL increased
pulmonary function tests, but respiratory symptoms, inflammatory cells, and hs-CRP levels
were reduced [77,78].
Rosmarinic acid (RA), well-known as an “anti-inflammatory agent” [
56
], is present
in high amounts in Za’atar plants [
68
]. RA possesses a significant activity as a radical
scavenger in physiological environments [
79
] and has a wide range of pharmacological
and biological activities, including antiviral, antibacterial, antioxidant, antimutagenic, and
anti-inflammatory activities [
53
]. Many
in vitro
and
in vivo
studies have reported the
anti-inflammatory effects of RA in inflammatory diseases such as asthma and respiratory

Plants 2024,13, 3340 14 of 21
diseases [
80
,
81
]. Recently, RA showed an antiviral effect against COVID-19 through a
significant inhibition of the main protease (Mpro) of SARS-CoV-2 [82].
However, these results were not observed in subjects who took Za’atar plants in
the Tunisian cohort. This could be attributed to the huge variety of Za’atar plants that
vary from the Thymus,Origanum,Thymbra, and Satureja plant families. People recognized
Za’atar plants according to the culture and geographical area. Za’atar plants are known
as the carvacrol- and thymol-containing plants. Those essential oils give the plants their
favorable aroma and smell. Additionally, different plants of those families have different
phytochemical compositions, especially in terms of the polyphenol content, which is
mainly responsible for the possible antioxidant and anti-inflammatory properties. Za’atar
in Lebanon mainly includes Origanum syriacum L. and Thymbra spicata L., with higher
amounts of polyphenols that could reach 350 mg GAE/g of dry plant extract [
83
]. While in
Tunisia, Za’atar plants include mainly Thymbra capitata L. and thymus vulgaris L., with a
moderate polyphenol content ranging between 23 and 126 mg GAE/g dry extract [84,85].
Thus, the possible effects of Lebanese Za’atar plants on reducing COVID-19 symptom
severity may be explained by their high number of polyphenols and essential oils with
considerable antioxidant and anti-inflammatory effects. To give examples, Shen et al.
revealed the anti-inflammatory role of Origanum syriacum, as it has the potential to decrease
the LPS-induced iNOS and COX-2 enzyme levels [
56
]. Thymbra spicata was also shown
to possess an antioxidant effect by decreasing ROS production, NO release, and lipid
peroxidation [68,86].
Our study has some limitations. The sample size in our study was limited due to
several factors. Our study was conducted during the first wave of the COVID-19 pandemic,
prior to the availability of vaccines, when the number of individuals infected with the
virus was relatively low. As a result, the sample size may not be fully representative of
the broader population. We additionally recognize the importance of isolating the effects
of plant use from other factors. While some overlap in symptom management might
occur between herbal and allopathic treatments for similar conditions (such as influenza
or pneumonia), our data collection specifically focused on the use of medicinal plants in
general for COVID-19 prevention and for COVID-19 treatment. To ensure that the results
reflected the actions of the plants to the best extent possible, we analyzed aspects related
to the management of COVID-19. Our findings suggest that the users of Za’atar plants
in Lebanon have a lower prevalence of conventional medication use and recourse to a
doctor, which could strengthen our findings on the possible beneficial effects of Za’atar on
COVID-19. Another limitation is that the cultural familiarity and daily use of plants and
mixing or interaction of other plants in the Middle East and North Africa may influence
perceptions of their efficacy. The cultural factor could impact the generalizability of our
findings. Detailed explorations of how acute and regular exposure to these plants might
shape health outcomes or perceived benefits in ways that may differ in populations without
this background are needed.
Strongly emerging from this survey is the idea that at least in some geographical
areas within the Mediterranean area, herbal medicines are considered options to tackle
COVID-19 symptoms. This popular view stems from doubts about the effectiveness and
toxicity of chemical drugs compared to the safety and efficiency of plants and plant-based
drugs. Several herbal products have been clinically examined for COVID-19 treatment with
promising results [
16
,
87
,
88
]. In this context, our study provides new information about the
possible use of Za’atar plants or bioactive components as adjuvants for COVID-19 therapy.
4. Materials and Methods
4.1. Subjects
We conducted a web-based survey in three different free-living target populations
in Italy, Lebanon, and Tunisia concerning the first wave of COVID-19 before vaccination
in 2020 and throughout the 12 months after an acute COVID-19 infection. Participation
was on a voluntary basis. The inclusion criteria encompassed individuals of all ages and

Plants 2024,13, 3340 15 of 21
genders who had been infected with SARS-CoV-2 at least once. We excluded participants
with incomplete responses and those who had not undergone a PCR test.
The three cohorts consisted of 116 Italian, 557 Lebanese, and 139 Tunisian individuals.
The protocol was approved by the local Ethics Committee at the Hospital Policlinico and
University of Bari ‘Aldo Moro’ (study number 6558, protocol number 0085284).
4.2. Questionnaire
We used a tailored, anonymous, web-based “Google Form” questionnaire (Supple-
mentary Text S1) designed in the English language and subsequently translated into Italian
and Arabic (validated similarly to our previous study [
89
]). Sampling was conducted
using random methods. We employed a simple and clear questionnaire to be distributed
using social media (the link to the questionnaire was shared by the social media platforms
WhatsApp, Email, and Facebook) or during face-to-face interviews with people without
web access to have a simple random sample. This method was chosen to minimize bias
and ensure that every individual in the target population had an equal chance of being
selected, thereby supporting the study’s validity.
4.2.1. COVID-19 Clinical Manifestations
The questionnaire consisted of 26 items investigating demographic characteristics,
smoking status, and features of a COVID-19 infection, including the presence of
13 COVID-19
-
related symptoms (i.e., abdominal pain, chest pain, cough, diarrhea, dyspnea, fatigue, fever,
headache, joint pain, loss of taste, loss of smell, muscle pain, and vomiting). The intensity of
each symptom was scored using a semi-quantitative scale that ranges from 0 to 5, with each
level representing a distinct degree of severity. Specifically, 0 indicates the absence of the
symptom, 1 represents a very mild intensity, 2 corresponds to mild, 3 to moderate, 4 to high,
and 5 signifies the maximal intensity. This type of scale is commonly used in clinical research
to assess symptom severity across various conditions. A symptom score for each participant
was therefore calculated by the sum of each score (maximal possible score 65). We included a
section regarding the management of
COVID-19
, including allopathic treatments (i.e., use of
conventional medications), recourse to the doctor, or hospitalization. The following aspects
were also evaluated: psychological consequences (i.e., appearance of at least one of the
following: stress, anxiety, and fear), and major post-
COVID-19
symptoms, namely, fatigue,
muscle pain, headache, dyspnea, and others. Besides a few gastrointestinal symptoms
during
COVID-19
, we investigated specific post-COVID-19 gastrointestinal (GI) symptoms,
including recurrent abdominal pain associated with changes in the frequency and form of
stool, using the Rome IV Diagnostic Questionnaire for Functional Gastrointestinal Disorders
in Adults (R4DQ) [90].
4.2.2. Use of Medicinal Plants
The methodology used in this section consisted of a structured survey aimed at assess-
ing both the general and COVID-19-specific use of medicinal herbs among participants. The
survey was administered to capture self-reported data, allowing participants to describe
their habits and beliefs in their own words, where applicable. The mixed response types
(multiple choice and open ended) allowed for both a quantitative analysis (e.g., frequency
of use and beliefs about efficacy) and qualitative insights (e.g., types of herbs, preparation
methods, and symptom relief). Quantitative responses were analyzed to determine us-
age patterns and belief prevalence, while qualitative data provided deeper insights into
individual practices and perceptions.
To establish baseline information on general usage, participants were asked if they
used medicinal herbs (e.g., in the form of teas, infusions, or other natural products) with
the options to select “Yes”, “No”, or “Once in a while”. This question sought to gauge
the frequency of regular herb usage in daily life. Their beliefs regarding the effectiveness
of medicinal herbs for general health purposes were specifically assessed by asking if
they thought herbs could cure or prevent diseases. The responses available were “Yes”,

Plants 2024,13, 3340 16 of 21
“No”, and “I don’t know” to capture not only beliefs but also any uncertainty regarding
herbal efficacy.
To explore the application of medicinal herbs specifically for COVID-19, the survey
included targeted questions. Participants were asked if they used medicinal herbs as a
preventive measure before infection, with “Yes” or “No” responses, to understand if herbs
were used proactively. During the COVID-19 infection phase, participants were questioned
on whether they used medicinal herbs, also with a “Yes” or “No” response. This was
followed by a series of questions if they responded “Yes”: type of herbs used—participants
could specify which herbs they used through a short-answer response, allowing for detailed
data on specific plants or combinations. In addition, the survey provided options for regular
use (one or more times daily), occasional use (once every 2–3 days), or rare use (once a week)
to determine usage patterns and intensity during the infection. An open-ended question
asked participants to describe the method of preparation (e.g., herb infusion in water or
use as a food ingredient) and the quantity consumed to capture detailed information on
herbal administration methods and doses. Finally, participants were asked whether they
believed the herbs alleviated their symptoms (“Yes”, “No”, or “I don’t know”) to assess
perceived outcomes. If participants reported symptom relief, they were asked to specify
which symptoms were alleviated through a short-answer response. This question aimed to
link specific symptoms with potential herbal benefits.
This methodology enabled a thorough understanding of medicinal herb use, both
in general and within the specific context of the COVID-19 pandemic. The structured
questions ensured comparability, while open-ended responses provided detailed insights,
which were particularly valuable for identifying traditional or region-specific practices.
4.3. Statistical Analysis
Data are expressed as the means and standard errors (SEMs) for continuous variables
or as proportions and percentages for categorical variables. The chi-square test (propor-
tions), the t-test (unpaired data), and the Kruskal–Wallis multiple comparison Z-value
test were employed to evaluate intra- or inter-group differences. All statistical analyses
were performed using NCSS software (NCSS LLC, Kaysville, UT, USA), and statistical
significance was declared if a two-sided p-value was <0.05 [91].
5. Conclusions
This study provides valuable insights into the use of herbal medicine, particularly
polyphenolic-rich thyme-like plants, during the COVID-19 pandemic across three Mediter-
ranean regions: Italy, Lebanon, and Tunisia. The use of herbal remedies varies significantly
across the Italian, Lebanese, and Tunisian cohorts, reflecting cultural preferences and local
plant availability. In Italy, herbal remedy use is relatively low (23.3%), with a preference
for mixed herbal teas containing chamomile (Matricaria chamomilla), peppermint (Mentha
piperita), and lavender (Lavandula angustifolia). In contrast, Lebanon shows higher usage
(50.8%) and a strong preference for “zhourat”, a blend of herbs like damask rose (Rosa
damascena), Chamomile, linden flowers (Tilia cordata), and Za’atar plants (Origanum,Thymbra,
and Satureja plants). Tunisia has the highest proportion of users (65.5%), with Za’atar
(Thymbra capitata) as the predominant choice, alongside other herbs like verveine (Verbena
officinalis) and Eucalyptus. These differences highlight the role of regional traditions and
the local flora in shaping herbal remedy practices across cultures. In Lebanon, the use of
Za’atar, a thyme-like plant, was particularly prominent and correlated with a reduction in
COVID-19 symptoms. This suggests that the polyphenolic compounds present in Za’atar,
such as thymol and carvacrol, may offer protective effects against COVID-19. Despite
the widespread use of herbal medicine, there remains a lack of robust scientific evidence
supporting their efficacy in treating COVID-19. This study highlights the need for further
research to explore the therapeutic potential of these herbal compounds. Clinical trials
and in-depth studies are essential to validate the observed benefits and understand the
mechanisms through which these plants may exert their effects.

Plants 2024,13, 3340 17 of 21
Supplementary Materials: The following supporting information can be downloaded at https://
www.mdpi.com/article/10.3390/plants13233340/s1, Supplementary Text S1; Table S1: Classification
of participating subjects according to cohorts and age classes. Table S2: Classification of participating
subjects according to cohorts and smoking status
Author Contributions: Conceptualization, P.P. and M.K.; methodology, H.A., N.K., J.M., F.D., L.Z.,
formal analysis, A.D.C. and M.C.; investigation, A.D. and L.V.; writing—original draft preparation,
M.K.; writing—review and editing, P.P. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Data Availability Statement: The raw data supporting the conclusions of this article will be made
available by the authors on request.
Acknowledgments: P.P. is the coordinator of B4HT projects “Box for Health by Tradition & In-
novation: Promoting Sustainable Mediterranean Diet by Healthy Foods” funded by the PRIMA
project, Section 2—Multi-topic 2022. Project partners include the University of Bari Aldo Moro
(Italy), University of Genoa (Italy), Lebanese University (Lebanon), and University of Monastir
(Tunisia). PP is a grant recipient and MK is an assistant researcher (RTDA) in a project funded
under the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment
1.3—Call for tender No. 341 of 15/03/2022 of Italian Ministry of University and Research funded
by the European Union—NextGenerationEU Award Number: Project code PE0000003, Concession
Decree No. 1550 of 11/10/2022 adopted by the Italian Ministry of University and Research, CUP
D93C22000890001, Project title “Research and Innovation Network on Food and Nutrition Sustain-
ability, Safety and Security—Working ON Foods” (ONFoods). The authors are indebted to the
Consortium of Mediterranean Universities (CMU), Bari (www.cmungo.eu), for helpful discussions.
The authors acknowledge the longstanding technical and secretarial support of Paola De Benedictis
and Rosa De Venuto.
Conflicts of Interest: The authors declare no conflicts of interest.
References
1. World Health Organisation. Traditional, Complementary and Integrative Medicine; WHO: Geneva, Switzerland, 2024.
2.
Atanasov, A.G.; Zotchev, S.B.; Dirsch, V.M.; Orhan, I.E.; Banach, M.; Rollinger, J.M.; Barreca, D.; Weckwerth, W.; Bauer, R.;
Bayer, E.A.; et al. Natural products in drug discovery: Advances and opportunities. Nat. Rev. Drug Discov. 2021,20, 200–216.
[CrossRef] [PubMed]
3.
Sen, T.; Samanta, S.K. Medicinal plants, human health and biodiversity: A broad review. Adv. Biochem. Eng. Biotechnol. 2015,
147, 59–110. [CrossRef]
4.
Baloch, S.; Baloch, M.A.; Zheng, T.; Pei, X. The Coronavirus Disease 2019 (COVID-19) Pandemic. Tohoku J. Exp. Med. 2020,
250, 271–278. [CrossRef]
5.
Li, X.; Wang, W.; Zhao, X.; Zai, J.; Zhao, Q.; Li, Y.; Chaillon, A. Transmission dynamics and evolutionary history of 2019-nCoV.
J. Med. Virol. 2020,92, 501–511. [CrossRef]
6.
Umakanthan, S.; Sahu, P.; Ranade, A.V.; Bukelo, M.M.; Rao, J.S.; Abrahao-Machado, L.F.; Dahal, S.; Kumar, H.; Kv, D. Origin,
transmission, diagnosis and management of coronavirus disease 2019 (COVID-19). Postgrad. Med. J. 2020,96, 753–758. [PubMed]
7.
Wiersinga, W.J.; Rhodes, A.; Cheng, A.C.; Peacock, S.J.; Prescott, H.C. Pathophysiology, Transmission, Diagnosis, and Treatment
of Coronavirus Disease 2019 (COVID-19): A Review. JAMA 2020,324, 782–793. [CrossRef]
8.
Ram, A.; Balachandar, S.; Vijayananth, P.; Singh, V.P. Medicinal plants useful for treating chronic obstructive pulmonary disease
(COPD): Current status and future perspectives. Fitoterapia 2011,82, 141–151. [CrossRef] [PubMed]
9.
Cock, I.E.; Van Vuuren, S.F. The traditional use of southern African medicinal plants for the treatment of bacterial respiratory
diseases: A review of the ethnobotany and scientific evaluations. J. Ethnopharmacol. 2020,263, 113204. [CrossRef]
10.
Firdaus, A.; Yunus, M.H.; Izhar, S.K.; Afaq, U. Medicinal Plants in the Treatment of Respiratory Diseases and their Future Aspects.
Recent Pat. Biotechnol. 2024,19, 2–18. [CrossRef] [PubMed]
11.
Leonti, M.; Verpoorte, R. Traditional Mediterranean and European herbal medicines. J. Ethnopharmacol. 2017,199, 161–167.
[CrossRef] [PubMed]
12.
Mukhtar, M.; Arshad, M.; Ahmad, M.; Pomerantz, R.J.; Wigdahl, B.; Parveen, Z. Antiviral potentials of medicinal plants. Virus Res.
2008,131, 111–120. [CrossRef] [PubMed]
13.
Nawrot, J.; Gornowicz-Porowska, J.; Budzianowski, J.; Nowak, G.; Schroeder, G.; Kurczewska, J. Medicinal Herbs in the Relief of
Neurological, Cardiovascular, and Respiratory Symptoms after COVID-19 Infection A Literature Review. Cells 2022,11, 1897.
[CrossRef] [PubMed]

Plants 2024,13, 3340 18 of 21
14.
Habas, K.; Nganwuchu, C.; Shahzad, F.; Gopalan, R.; Haque, M.; Rahman, S.; Majumder, A.A.; Nasim, T. Resolution of coronavirus
disease 2019 (COVID-19). Expert Rev. Anti-Infect. Ther. 2020,18, 1201–1211. [CrossRef]
15.
Smyk, W.; Janik, M.K.; Portincasa, P.; Milkiewicz, P.; Lammert, F.; Krawczyk, M. COVID-19: Focus on the lungs but do not forget
the gastrointestinal tract. Eur. J. Clin. Investig. 2020,50, e13276. [CrossRef] [PubMed]
16.
Portincasa, P.; Krawczyk, M.; Machill, A.; Lammert, F.; Di Ciaula, A. Hepatic consequences of COVID-19 infection. Lapping or
biting? Eur. J. Intern. Med. 2020,77, 18–24. [CrossRef] [PubMed]
17.
Di Ciaula, A.; Palmieri, V.O.; Migliore, G.; Portincasa, P.; Group, I.M.C. COVID-19, internists and resilience: The north-south Italy
outbreak. Eur. J. Clin. Investig. 2020,50, e13299. [CrossRef] [PubMed]
18.
Baj, J.; Karakuła-Juchnowicz, H.; Teresi´nski, G.; Buszewicz, G.; Ciesielka, M.; Sitarz, R.; Forma, A.; Karakuła, K.; Flieger, W.;
Portincasa, P.; et al. COVID-19: Specific and Non-Specific Clinical Manifestations and Symptoms: The Current State of Knowledge.
J. Clin. Med. 2020,9, 1753. [CrossRef]
19.
Marasco, G.; Cremon, C.; Barbaro, M.R.; Salvi, D.; Cacciari, G.; Kagramanova, A.; Bordin, D.; Drug, V.; Miftode, E.; Fusaroli, P.;
et al. Prevalence of Gastrointestinal Symptoms in Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Results of the
Prospective Controlled Multinational GI-COVID-19 Study. Am. J. Gastroenterol. 2022,117, 147–157. [CrossRef] [PubMed]
20.
Wang, X.; Fang, X.; Cai, Z.; Wu, X.; Gao, X.; Min, J.; Wang, F. Comorbid Chronic Diseases and Acute Organ Injuries Are Strongly
Correlated with Disease Severity and Mortality among COVID-19 Patients: A Systemic Review and Meta-Analysis. Research 2020,
2020, 2402961. [CrossRef]
21.
Li, G.; Hilgenfeld, R.; Whitley, R.; De Clercq, E. Therapeutic strategies for COVID-19: Progress and lessons learned. Nat. Rev.
Drug Discov. 2023,22, 449–475. [CrossRef]
22.
Zhou, Y.-W.; Xie, Y.; Tang, L.-S.; Pu, D.; Zhu, Y.-J.; Liu, J.-Y.; Ma, X.-L. Therapeutic targets and interventional strategies in
COVID-19: Mechanisms and clinical studies. Signal Transduct. Target. Ther. 2021,6, 317. [CrossRef] [PubMed]
23.
Zaman, W.; Saqib, S.; Ullah, F.; Ayaz, A.; Ye, J. COVID-19: Phylogenetic approaches may help in finding resources for natural cure.
Phytother. Res. PTR 2020,34, 2783–2785. [CrossRef] [PubMed]
24.
Ebenezer, O.; Bodede, O.; Awolade, P.; Jordaan, M.A.; Ogunsakin, R.E.; Shapi, M. Medicinal plants with anti-SARS-CoV activity
repurposing for treatment of COVID-19 infection: A systematic review and meta-analysis. Acta Pharm. 2022,72, 199–224.
[CrossRef] [PubMed]
25.
Sadeek, A.; Abdallah, E. Medicinal Plants with Antiviral Properties to Tackle Covid-19 Pandemic: A Short-Review. Antivirals
2021,2, 122–127.
26.
Salem, M.A.; Ezzat, S.M. The use of aromatic plants and their therapeutic potential as antiviral agents: A hope for finding
anti-COVID 19 essential oils. J. Essent. Oil Res. 2021,33, 105–113. [CrossRef]
27.
Khan, T.; Khan, M.A.; Mashwani, Z.-u.-R.; Ullah, N.; Nadhman, A. Therapeutic potential of medicinal plants against COVID-19:
The role of antiviral medicinal metabolites. Biocatal. Agric. Biotechnol. 2021,31, 101890. [CrossRef] [PubMed]
28.
Bachar, S.C.; Mazumder, K.; Bachar, R.; Aktar, A.; Al Mahtab, M. A review of medicinal plants with antiviral activity available
in Bangladesh and mechanistic insight into their bioactive metabolites on SARS-CoV-2, HIV and HBV. Front. Pharmacol. 2021,
12, 732891. [CrossRef] [PubMed]
29.
Malekmohammad, K.; Rafieian-Kopaei, M. Mechanistic Aspects of Medicinal Plants and Secondary Metabolites against Severe
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Curr. Pharm. Des. 2021,27, 3996–4007. [CrossRef] [PubMed]
30.
Khalil, M.; Rita Caponio, G.; Diab, F.; Shanmugam, H.; Di Ciaula, A.; Khalifeh, H.; Vergani, L.; Calasso, M.; De Angelis, M.;
Portincasa, P. Unraveling the beneficial effects of herbal Lebanese mixture “Za’atar”. History, studies, and properties of a potential
healthy food ingredient. J. Funct. Foods 2022,90, 104993. [CrossRef]
31.
Khalil, M.; Abdallah, H.; Razuka-Ebela, D.; Calasso, M.; De Angelis, M.; Portincasa, P. The Impact of Za’atar Antioxidant
Compounds on the Gut Microbiota and Gastrointestinal Disorders: Insights for Future Clinical Applications. Antioxidants 2023,
12, 426. [CrossRef]
32.
Alwafa, R.A.; Mudalal, S.; Shraim, F.; Mauriello, G. Comparison between Quality Traits of Solar-Dried and Freeze-Dried Origanum
syriacum L. (Za’atar). Plants 2022,11, 1110. [CrossRef] [PubMed]
33.
Obon, C.; Rivera, D.; Fonolla, E.; Alcaraz, F.; Attieh, L. A Comparison Study on Traditional Mixtures of Herbal Teas Used in
Eastern Mediterranean Area. Front. Pharmacol. 2021,12, 632692. [CrossRef] [PubMed]
34.
Nalbandian, A.; Sehgal, K.; Gupta, A.; Madhavan, M.V.; McGroder, C.; Stevens, J.S.; Cook, J.R.; Nordvig, A.S.; Shalev, D.;
Sehrawat, T.S.; et al. Post-acute COVID-19 syndrome. Nat. Med. 2021,27, 601–615. [CrossRef] [PubMed]
35.
Gentilotti, E.; Gorska, A.; Tami, A.; Gusinow, R.; Mirandola, M.; Rodriguez Bano, J.; Palacios Baena, Z.R.; Rossi, E.; Hasenauer, J.;
Lopes-Rafegas, I.; et al. Clinical phenotypes and quality of life to define post-COVID-19 syndrome: A cluster analysis of the
multinational, prospective ORCHESTRA cohort. EClinicalMedicine 2023,62, 102107. [CrossRef] [PubMed]
36.
Di Ciaula, A.; Liberale, L.; Portincasa, P.; Khalil, M.; Galerati, I.; Farella, I.; Noto, A.; JohnBritto, S.; Moriero, M.; Michelauz, C.;
et al. Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients. Eur. J. Clin.
Investig. 2024,54, e14155. [CrossRef] [PubMed]
37.
Marasco, G.; Cremon, C.; Barbaro, M.R.; Cacciari, G.; Falangone, F.; Kagramanova, A.; Bordin, D.; Drug, V.; Miftode, E.; Fusaroli, P.;
et al. Post COVID-19 irritable bowel syndrome. Gut 2022,72, 484–492. [CrossRef]

Plants 2024,13, 3340 19 of 21
38.
Pranskuniene, Z.; Balciunaite, R.; Simaitiene, Z.; Bernatoniene, J. Herbal Medicine Uses for Respiratory System Disorders and
Possible Trends in New Herbal Medicinal Recipes during COVID-19 in Pasvalys District, Lithuania. Int. J. Environ. Res. Public
Health 2022,19, 8905. [CrossRef]
39.
Chaachouay, N.; Douira, A.; Zidane, L. COVID-19, prevention and treatment with herbal medicine in the herbal markets of Salé
Prefecture, North-Western Morocco. Eur. J. Integr. Med. 2021,42, 101285. [CrossRef]
40.
Mlozi, S.H. The role of natural products from medicinal plants against COVID-19: Traditional medicine practice in Tanzania.
Heliyon 2022,8, e09739. [CrossRef]
41.
Dandara, C.; Dzobo, K.; Chirikure, S. COVID-19 Pandemic and Africa: From the Situation in Zimbabwe to a Case for Precision
Herbal Medicine. Omics 2021,25, 209–212. [CrossRef]
42.
Odebunmi, C.A.; Adetunji, T.L.; Adetunji, A.E.; Olatunde, A.; Oluwole, O.E.; Adewale, I.A.; Ejiwumi, A.O.; Iheme, C.E.;
Aremu, T.O. Ethnobotanical Survey of Medicinal Plants Used in the Treatment of COVID-19 and Related Respiratory Infections
in Ogbomosho South and North Local Government Areas, Oyo State, Nigeria. Plants 2022,11, 2667. [CrossRef] [PubMed]
43.
Pathak, A.; Gupta, A.P.; Pandey, P. Herbal Medicine and Sustainable Development Challenges and Opportunities. In Herbal
Medicine Phytochemistry: Applications and Trends; Izah, S.C., Ogwu, M.C., Akram, M., Eds.; Springer International Publishing:
Cham, Switzerland, 2023; pp. 1–26.
44.
Bounatirou, S.; Smiti, S.; Miguel, M.; Faleiro, L.; Rejeb, M.; Neffati, M.; Costa, M.; Figueiredo, A.; Barroso, J.; Pedro, L. Chemical
composition, antioxidant and antibacterial activities of the essential oils isolated from Tunisian Thymus capitatus Hoff. et Link.
Food Chem. 2007,105, 146–155. [CrossRef]
45.
Ahmad, S.; Yousuf, S.; Ishrat, T.; Khan, M.B.; Bhatia, K.; Fazli, I.S.; Khan, J.S.; Ansari, N.H.; Islam, F. Effect of dietary sesame oil as
antioxidant on brain hippocampus of rat in focal cerebral ischemia. Life Sci. 2006,79, 1921–1928. [CrossRef] [PubMed]
46.
Chiang, H.M.; Chang, H.; Yao, P.W.; Chen, Y.S.; Jeng, K.C.; Wang, J.S.; Hou, C.W. Sesamin reduces acute hepatic injury induced by
lead coupled with lipopolysaccharide. J. Chin. Med. Assoc. 2014,77, 227–233. [CrossRef] [PubMed]
47.
Cho, S.; Choi, Y.; Park, S.; Park, T. Carvacrol prevents diet-induced obesity by modulating gene expressions involved in
adipogenesis and inflammation in mice fed with high-fat diet. J. Nutr. Biochem. 2012,23, 192–201. [CrossRef] [PubMed]
48.
Deme, P.; Narasimhulu, C.A.; Parthasarathy, S. Identification and evaluation of anti-inflammatory properties of aqueous
components extracted from sesame (Sesamum indicum) oil. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2018,1087–1088, 61–69.
[CrossRef] [PubMed]
49.
Narasimhulu, C.A.; Riad, A.; Parthasarathy, S. Sesame Oil and an Aqueous Extract Derived from Sesame Oil Enhance Regression
of Preexisting Atherosclerotic Lesions in Low-Density Lipoprotein Receptor Knockout Mice. J. Med. Food 2018,21, 641–646.
[CrossRef]
50.
Slamenová, D.; Horváthová, E.; Sramková, M.; Marsálková, L. DNA-protective effects of two components of essential plant oils
carvacrol and thymol on mammalian cells cultured in vitro. Neoplasma 2007,54, 108–112.
51.
Zych, M.; Kaczmarczyk-Sedlak, I.; Wojnar, W.; Folwarczna, J. Effect of Rosmarinic Acid on the Serum Parameters of Glucose and
Lipid Metabolism and Oxidative Stress in Estrogen-Deficient Rats. Nutrients 2019,11, 267. [CrossRef]
52.
Anwer, T.; Sharma, M.; Khan, G.; Iqbal, M.; Ali, M.S.; Alam, M.S.; Safhi, M.M.; Gupta, N. Rhus coriaria ameliorates insulin
resistance in non-insulin-dependent diabetes mellitus (NIDDM) rats. Acta Pol. Pharm. 2013,70, 861–867.
53.
Arkali, G.; Aksakal, M.; Kaya, S.O. Protective effects of carvacrol against diabetes-induced reproductive damage in male
rats: Modulation of Nrf2/HO-1 signalling pathway and inhibition of Nf-kB-mediated testicular apoptosis and inflammation.
Andrologia 2021,53, e13899. [CrossRef] [PubMed]
54.
Dogan, A.; Celik, I. Healing effects of sumac (Rhus coriaria) in streptozotocin-induced diabetic rats. Pharm. Biol. 2016,
54, 2092–2102. [CrossRef] [PubMed]
55.
Wang, S.J.; Chen, Q.; Liu, M.Y.; Yu, H.Y.; Xu, J.Q.; Wu, J.Q.; Zhang, Y.; Wang, T. Regulation effects of rosemary (Rosmarinus
officinalis Linn.) on hepatic lipid metabolism in OA induced NAFLD rats. Food Funct. 2019,10, 7356–7365. [CrossRef] [PubMed]
56.
Shen, D.; Pan, M.H.; Wu, Q.L.; Park, C.H.; Juliani, H.R.; Ho, C.T.; Simon, J.E. LC-MS method for the simultaneous quantitation of
the anti-inflammatory constituents in oregano (Origanum species). J. Agric. Food Chem. 2010,58, 7119–7125. [CrossRef] [PubMed]
57.
El-Alam, I.; Zgheib, R.; Iriti, M.; El Beyrouthy, M.; Hattouny, P.; Verdin, A.; Fontaine, J.; Chahine, R.; Lounès-Hadj Sahraoui, A.;
Makhlouf, H. Origanum syriacum Essential Oil Chemical Polymorphism According to Soil Type. Foods 2019,8, 90. [CrossRef]
[PubMed]
58.
Dorman, H.J.; Bachmayer, O.; Kosar, M.; Hiltunen, R. Antioxidant properties of aqueous extracts from selected lamiaceae species
grown in Turkey. J. Agric. Food Chem. 2004,52, 762–770. [CrossRef]
59.
Hanci, S.; Sahin, S.; Yilmaz, L. Isolation of volatile oil from thyme (Thymbra spicata) by steam distillation. Nahrung 2003,
47, 252–255
.
[CrossRef]
60.
Nadi, A.; Shiravi, A.A.; Mohammadi, Z.; Aslani, A.; Zeinalian, M. Thymus vulgaris, a natural pharmacy against COVID-19:
A molecular review. J. Herb. Med. 2023,38, 100635. [CrossRef]
61.
Yadav, P.K.; Jaiswal, A.; Singh, R.K. In silico study on spice-derived antiviral phytochemicals against SARS-CoV-2 TMPRSS2
target. J. Biomol. Struct. Dyn. 2022,40, 11874–11884. [CrossRef]
62.
Rolta, R.; Salaria, D.; Sharma, P.; Sharma, B.; Kumar, V.; Rathi, B.; Verma, M.; Sourirajan, A.; Baumler, D.J.; Dev, K. Phytocom-
pounds of Rheum emodi,Thymus serpyllum, and Artemisia annua Inhibit Spike Protein of SARS-CoV-2 Binding to ACE2 Receptor:
In Silico Approach. Curr. Pharmacol. Rep. 2021,7, 135–149. [CrossRef]

Plants 2024,13, 3340 20 of 21
63.
Kianmehr, M.; Khazdair, M.R.; Abbasnezhad, A.; Akram, M. Effects of Lamiaceae family plants and their bioactive ingredients on
coronavirus-induced lung inflammation. Food Sci. Nutr. 2024,12, 1528–1544. [CrossRef] [PubMed]
64.
Kulkarni, S.A.; Nagarajan, S.K.; Ramesh, V.; Palaniyandi, V.; Selvam, S.P.; Madhavan, T. Computational evaluation of major
components from plant essential oils as potent inhibitors of SARS-CoV-2 spike protein. J. Mol. Struct. 2020,1221, 128823.
[CrossRef] [PubMed]
65.
Khalil, M.; Khalifeh, H.; Baldini, F.; Serale, N.; Parodi, A.; Voci, A.; Vergani, L.; Daher, A. Antitumor Activity of Ethanolic Extract
from Thymbra spicata L. aerial Parts: Effects on Cell Viability and Proliferation, Apoptosis Induction, STAT3, and NF-kB Signaling.
Nutr. Cancer 2021,73, 1193–1206. [CrossRef] [PubMed]
66.
Knowles, J.R.; Roller, S.; Murray, D.B.; Naidu, A.S. Antimicrobial action of carvacrol at different stages of dual-species biofilm
development by Staphylococcus aureus and Salmonella enterica serovar Typhimurium. Appl. Environ. Microbiol. 2005,71, 797–803.
[CrossRef] [PubMed]
67.
Ultee, A.; Bennik, M.H.; Moezelaar, R. The phenolic hydroxyl group of carvacrol is essential for action against the food-borne
pathogen Bacillus cereus.Appl. Environ. Microbiol. 2002,68, 1561–1568. [CrossRef]
68.
Khalil, M.; Khalifeh, H.; Baldini, F.; Salis, A.; Damonte, G.; Daher, A.; Voci, A.; Vergani, L. Antisteatotic and antioxidant activities of
Thymbra spicata L. extracts in hepatic and endothelial cells as
in vitro
models of non-alcoholic fatty liver disease. J. Ethnopharmacol.
2019,239, 111919. [CrossRef]
69.
Gholijani, N.; Amirghofran, Z. Effects of thymol and carvacrol on T-helper cell subset cytokines and their main transcription
factors in ovalbumin-immunized mice. J. Immunotoxicol. 2016,13, 729–737. [CrossRef]
70.
Lima Mda, S.; Quintans-Junior, L.J.; de Santana, W.A.; Martins Kaneto, C.; Pereira Soares, M.B.; Villarreal, C.F. Anti-inflammatory
effects of carvacrol: Evidence for a key role of interleukin-10. Eur. J. Pharmacol. 2013,699, 112–117. [CrossRef]
71.
Somensi, N.; Rabelo, T.K.; Guimaraes, A.G.; Quintans-Junior, L.J.; de Souza Araujo, A.A.; Moreira, J.C.F.; Gelain, D.P.
Carvacrol
suppresses LPS-induced pro-inflammatory activation in RAW 264.7 macrophages through ERK1/2 and NF-kB pathway.
Int. Immunopharmacol. 2019,75, 105743. [CrossRef] [PubMed]
72.
Aristatile, B.; Al-Assaf, A.H.; Pugalendi, K.V. Carvacrol ameliorates the PPAR-A and cytochrome P450 expression on D-
galactosamine induced hepatotoxicity rats. Afr. J. Tradit. Complement. Altern. Med. 2014,11, 118–123. [CrossRef]
73.
Demirci, F.; Teralı, K.; Karada˘g, A.E.; Biltekin, S.N.; Ak Sakallı, E.; Demirci, B.; Ko¸sar, M.; Ba¸ser, K.H.C. In Vitro and In Silico
Evaluation of ACE2 and LOX Inhibitory Activity of Origanum Essential Oils and Carvacrol. Planta Med. 2023,89, 790–799.
[CrossRef] [PubMed]
74.
Kumar, A.; Choudhir, G.; Shukla, S.K.; Sharma, M.; Tyagi, P.; Bhushan, A.; Rathore, M. Identification of phytochemical inhibitors
against main protease of COVID-19 using molecular modeling approaches. J. Biomol. Struct. Dyn. 2021,39, 3760–3770. [CrossRef]
[PubMed]
75.
de Carvalho, F.O.; Silva, J.P.R.; Silva, E.R.; de Albuquerque Junior, R.L.C.; Nunes, P.S.; de Souza Araujo, A.A. Would carvacrol be a
supporting treatment option effective in minimizing the deleterious effects of COVID-19? Naunyn-Schmiedeberg’s Arch. Pharmacol.
2021,394, 2471–2474. [CrossRef] [PubMed]
76.
Wang, B.; Li, R.; Lu, Z.; Huang, Y. Does comorbidity increase the risk of patients with COVID-19: Evidence from meta-analysis.
Aging 2020,12, 6049. [CrossRef] [PubMed]
77.
Klok, F.A.; Kruip, M.; van der Meer, N.J.M.; Arbous, M.S.; Gommers, D.; Kant, K.M.; Kaptein, F.H.J.; van Paassen, J.;
Stals, M.A.M.
;
Huisman, M.V.; et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res. 2020,
191, 145–147. [CrossRef]
78. Landi, A.; De Servi, S. The burden of thrombotic complications in critically ill patients with COVID-19: Charting the uncharted.
Intern. Emerg. Med. 2020,15, 893–895. [CrossRef] [PubMed]
79.
Vo, Q.V.; Hoa, N.T.; Flavel, M.; Thong, N.M.; Boulebd, H.; Nam, P.C.; Quang, D.T.; Mechler, A. A Comprehensive Study of the
Radical Scavenging Activity of Rosmarinic Acid. J. Org. Chem. 2023,88, 17237–17248. [CrossRef]
80.
El Beyrouthy, M.; Arnold, N.; Delelis-Dusollier, A.; Dupont, F. Plants used as remedies antirheumatic and antineuralgic in the
traditional medicine of Lebanon. J. Ethnopharmacol. 2008,120, 315–334. [CrossRef]
81.
Zou, X.; Chen, K.; Zou, J.; Han, P.; Hao, J.; Han, Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the
potential risk of different human organs vulnerable to 2019-nCoV infection. Front. Med. 2020,14, 185–192. [CrossRef]
82.
Li, Q.; Zhou, X.; Wang, W.; Xu, Q.; Wang, Q.; Li, J. Structural basis of rosmarinic acid inhibitory mechanism on SARS-CoV-2 main
protease. Biochem. Biophys. Res. Commun. 2024,724, 150230. [CrossRef]
83.
Diab, F.; Zbeeb, H.; Baldini, F.; Portincasa, P.; Khalil, M.; Vergani, L. The Potential of Lamiaceae Herbs for Mitigation of Overweight,
Obesity, and Fatty Liver: Studies and Perspectives. Molecules 2022,27, 5043. [CrossRef] [PubMed]
84.
Adhar, M.; HadjKacem, B.; Périno-Issartier, S.; Ben Amor, I.; Feki, A.; Gargouri, J.; Gargouri, A.; Tounsi, S.; Chemat, F.; Allouche, N.
Thymol-enriched extract from Thymus vulgaris L leaves: Green extraction processes and antiaggregant effects on human platelets.
Bioorganic Chem. 2022,125, 105858. [CrossRef] [PubMed]
85.
Hcini, K.; Bahi, A.; Zarroug, M.B.; Farhat, M.B.; Lozano-Pérez, A.A.; Cenis, J.L.; Quílez, M.; Stambouli-Essassi, S.; Jordán, M.J.
Polyphenolic Profile of Tunisian Thyme (Thymbra capitata L.) Post-Distilled Residues: Evaluation of Total Phenolic Content and
Phenolic Compounds and Their Contribution to Antioxidant Activity. Molecules 2022,27, 8791. [CrossRef] [PubMed]

Plants 2024,13, 3340 21 of 21
86.
Khalil, M.; Piccapane, F.; Vacca, M.; Celano, G.; Mahdi, L.; Perniola, V.; Apa, C.A.; Annunziato, A.; Iacobellis, I.; Procino, G.; et al.
Nutritional and Physiological Properties of Thymbra spicata: In Vitro Study Using Fecal Fermentation and Intestinal Integrity
Models. Nutrients 2024,16, 588. [CrossRef]
87.
Mrityunjaya, M.; Pavithra, V.; Neelam, R.; Janhavi, P.; Halami, P.M.; Ravindra, P.V. Immune-Boosting, Antioxidant and Anti-
inflammatory Food Supplements Targeting Pathogenesis of COVID-19. Front. Immunol. 2020,11, 570122. [CrossRef]
88.
Qi, F.; Qian, S.; Zhang, S.; Zhang, Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human
coronaviruses. Biochem. Biophys. Res. Commun. 2020,526, 135–140. [CrossRef] [PubMed]
89.
Khalil, M.; Bonfrate, L.; Di Ciaula, A.; Portincasa, P.; Abdallah, H.; Capurso, M.; Galerati, I.; Hayek, S.; Khalifeh, H.; Mastandrea, E.;
et al. Self-reported symptoms after COVID-19 vaccination. Distinct sex, age, and geographical outcomes in Lebanese and Italian
cohorts. Intern. Emerg. Med. 2023,18, 1463–1475. [CrossRef]
90.
Palsson, O.S.; Whitehead, W.E.; van Tilburg, M.A.; Chang, L.; Chey, W.; Crowell, M.D.; Keefer, L.; Lembo, A.J.;
Parkman, H.P.
;
Rao, S.S.; et al. Rome IV Diagnostic Questionnaires and Tables for Investigators and Clinicians. Gastroenterology 2016,
150, 1481–1491. [CrossRef] [PubMed]
91. Hintze, J. NCSS 2023 Statistical Software; Number Cruncher Statistical System (NCSS): Kaysville, UT, USA, 2023.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.