Nigella sativa for the treatment of COVID-19: An open-label randomized controlled clinical trial

Abstract

Background
Effective treatment for Coronavirus Disease-2019 (COVID-19) is under intensive research. Nigella sativa oil (NSO) is a herbal medicine with antiviral and immunomodulatory activities, and has been recommended for the treatment of COVID-19. This study aimed to evaluate the efficacy of NSO treatment in patients with COVID-19.

Methods
All adult patients with mild COVID-19 symptoms presented to King Abdulaziz University Hospital, Jeddah, Saudi Arabia, were recruited for an open label randomized clinical trial (RCT). They were randomly divided into control or treatment groups, with the latter receiving 500 mg NSO (MARNYS® Cuminmar) twice daily for 10 days. Symptoms were daily monitored via telecommunication. The primary outcome focused on the percentage of patients who recovered (symptom-free for 3 days) within 14-days. The trial was registered at clinicaltrials.gov (NCT04401202).

Results
A total of 173 patients were enrolled for RCT. The average age was 36(±11) years, and 53% of patients were males. The control and NSO groups included 87 and 86 patients respectively. The percentage of recovered patients in NSO group (54[62%]) was significantly higher than that in the control group (31[36%]; p = 0.001). The mean duration to recovery was also shorter for patients receiving NSO (10.7 ± 3.2 days) compared with the control group (12.3 ± 2.8 days); p = 0.001.

Conclusions
NSO supplementation was associated with faster recovery of symptoms than usual care alone for patients with mild COVID-19 infection. These potential therapeutic benefits require further exploration with placebo-controlled, double-blinded studies.

Full text

Complementary Therapies in Medicine 61 (2021) 102769
Available online 15 August 2021
0965-2299/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Nigella sativa for the treatment of COVID-19: An open-label randomized
controlled clinical trial
Abdulrahman E. Koshak
a
,
*, Emad A. Koshak
b
, Abdullah F. Mobeireek
c
, Mazen A. Badawi
b
,
Siraj O. Wali
b
, Husam M. Malibary
b
, Ali F. Atwah
d
, Meshari M. Alhamdan
e
, Reem A. Almalki
b
,
Tariq A. Madani
b
a
Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University 80260, Jeddah, 21589, Saudi Arabia
b
Department of Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
c
Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
d
Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia
e
University Medical Services Centre, King Abdulaziz University, Jeddah, Saudi Arabia
ARTICLE INFO
Keywords:
COVID-19
SARS-CoV-2
Herbal medicine
Nigella sativa
ABSTRACT
Background: Effective treatment for Coronavirus Disease-2019 (COVID-19) is under intensive research. Nigella
sativa oil (NSO) is a herbal medicine with antiviral and immunomodulatory activities, and has been recom-
mended for the treatment of COVID-19. This study aimed to evaluate the efcacy of NSO treatment in patients
with COVID-19.
Methods: All adult patients with mild COVID-19 symptoms presented to King Abdulaziz University Hospital,
Jeddah, Saudi Arabia, were recruited for an open label randomized clinical trial (RCT). They were randomly
divided into control or treatment groups, with the latter receiving 500 mg NSO (MARNYS® Cuminmar) twice
daily for 10 days. Symptoms were daily monitored via telecommunication. The primary outcome focused on the
percentage of patients who recovered (symptom-free for 3 days) within 14-days. The trial was registered at
clinicaltrials.gov (NCT04401202).
Results: A total of 173 patients were enrolled for RCT. The average age was 36(±11) years, and 53 % of patients
were males. The control and NSO groups included 87 and 86 patients respectively. The percentage of recovered
patients in NSO group (54[62 %]) was signicantly higher than that in the control group (31[36 %]; p =0.001).
The mean duration to recovery was also shorter for patients receiving NSO (10.7 ±3.2 days) compared with the
control group (12.3 ±2.8 days); p =0.001.
Conclusions: NSO supplementation was associated with faster recovery of symptoms than usual care alone for
patients with mild COVID-19 infection. These potential therapeutic benets require further exploration with
placebo-controlled, double-blinded studies.
1. Introduction
Coronavirus disease-2019 (COVID-19) was rst recognized in China
in December 2019. A novel betacoronavirus, designated as Severe Acute
Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)
1
was found to be
the responsible agent for this infection. SARS-CoV-2 has since spread
throughout the world, causing an enormous pandemic and presenting
major challenges to global health systems.
1
In Saudi Arabia, COVID-19
has thus far been responsible for over 300,000 cases and 1500 fatalities.
2
Fortunately, most COVID-19 patients are either asymptomatic or
have a mild disease, which is usually managed by relieving constitu-
tional symptoms through analgesics, antipyretics, hydration, and close
Abbreviations: COVID-19, Coronavirus Disease-2019; HCV, Hepatitis C Virus; HIV, Human Immunodeciency Virus; IFNγ, Interferon-gamma; IL, Interleukin;
ISARIC, International Severe Acute Respiratory and Emerging Infection Consortium; ITT, Intention-to-treat; KAUH, King Abdulaziz University Hospital; NSO, Nigella
sativa L. oil; RCT, Randomized Controlled Trial; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus-2; TNF, Tumour Necrosis Factor; WHO, World Health
Organization.
* Corresponding author.
E-mail address: aekoshak@kau.edu.sa (A.E. Koshak).
Contents lists available at ScienceDirect
Complementary Therapies in Medicine
journal homepage: www.elsevier.com/locate/ctim
https://doi.org/10.1016/j.ctim.2021.102769
Received 24 April 2021; Received in revised form 10 August 2021; Accepted 12 August 2021

Complementary Therapies in Medicine 61 (2021) 102769
2
monitoring for clinical deterioration.
3
The most commonly reported
symptoms include fever, cough, fatigue, anorexia, shortness of breath,
myalgia, sore throat, nasal congestion, headache, diarrhea, nausea,
vomiting, and loss of smell (anosmia).
4
According to symptoms, disease
severity is classied into mild, moderate, and severe.
4
While about 80 %
of COVID-19 patients develop mild to moderate disease, approximately
15 % develop a severe disease that requires oxygen support, and 5%
develop a critical disease with complications.
4
Several global studies
have reported high mortality rates exceeding 20 % in hospitalized
patients.
5–7
As this pandemic continues, the search for an effective treatment has
become a priority of scientic medical research.
3
Currently, there are
limited pharmacotherapeutic drugs effective against COVID-19. There-
fore, complementary herbal medicines with their wealth of biologically
active molecules are being considered for treatment against coronavirus
infection.
8
These therapies are widely used against respiratory ailments,
and their efcacy towards u symptoms has been reported.
9
Particu-
larly, Nigella sativa L is suggested as a potential phytomedicine owing to
its several pharmacological activities such as anti-inammatory, anti--
viral, and immunomodulatory effects.
10
,
11
N. sativa L., a well-known food spice with a high medicinal value,
originates from different historical backgrounds.
9,12
Several active
compounds have been identied in N. sativa L. including thymoqui-
none.
12
The safety prole, of thymoquinone has been documented in
many clinical trials, including our previous trial with asthmatic pa-
tients.
13
A recent systematic review of randomized clinical trials (RCTs)
that used N. sativa L. showed no serious adverse effects on hepatic and
renal function.
14
Several preclinical and clinical studies have docu-
mented the antiviral activities of N. sativa L. against several viruses.
15–23
An in vitro study showed that the coronavirus load decreased with
N. sativa L.
17
Some N. sativa L. compounds demonstrated potential in-
hibition of coronavirus replication in in silico models.
24
The immune system comprises a complex cellular arrangement that
defend against undesired intruders. However, well-coordinated action
between its elements is essential for proper function.
25
In several
studies, N. sativa L. has been shown to exhibit immunostimulant effects
through the induction of multiple cellular mediators and immune re-
sponses to eradicate infections.
26–29
Contrariwise, in studies on inam-
matory conditions, N. sativa L. has demonstrated anti-inammatory and
immunomodulatory activities by reducing pro-inammatory media-
tors.
29,30
Moreover, analgesic, antipyretic, and bronchodilatation
properties of N. sativa L. have also been reported.
31–33
Based on these observations on the pharmacological activities of
N. sativa, the potential therapeutic efcacy of N. sativa L. was proposed
in COVID-19. This study aimed to explore the impact of N. sativa L. oil
(NSO) supplementation in reducing the duration of symptoms and
complications in symptomatic patients with mild COVID-19.
2. Methods
2.1. Trial design
The study was a prospective, two-arm, parallel-group, randomized,
controlled, open-label, phase II clinical trial using oral NSO in adult
patients with mild COVID-19. The trial was approved by the ethical
committee of King Abdulaziz University Hospital (KAUH), Jeddah,
Saudi Arabia (reference number 266-20). It was registered online at
ClinicalTrials.gov Identier: NCT04401202, https://clinicaltrials.gov/c
t2/show/NCT04401202.
2.2. Participants
Consecutive adult patients aged 18 and above with mild COVID-19,
presented to the emergency department and outpatient clinics at KAUH
between May 1 and September 31, 2020, were recruited. Participants
were isolated in the KAUH dorm or their homes. SARS-CoV-2 infection
was conrmed in all patients via polymerase chain reaction test within
one week of the onset of symptoms. Mild COVID-19 was dened as
upper respiratory tract infection symptoms in the absence of clinical or
radiological signs of pneumonia or hypoxia.
4
All participants under-
stood and agreed to comply with the planned study procedures. Baseline
characteristics were recorded for participants, including age, sex, body
mass index, smoking status, pre-enrollment days, and comorbidities.
Exclusion criteria included current history of pneumonia, severe
illness requiring admission to the intensive care unit, severe chronic
kidney disease (estimated glomerular ltration rate <30 mL/min), end-
stage renal disease requiring dialysis, elevated alanine transaminase or
aspartate transaminase (>5 times the upper limit of normal), pregnancy
or breastfeeding, anticipated transfer within 72 h to another hospital
from the study site, previous N. sativa L. treatment, or allergy to the
study medication. Due to infection control policies, participants (or le-
gally authorized representatives) provided verbal informed consent
before randomization. The study followed the guidelines of the Decla-
ration of Helsinki and Tokyo for humans.
2.3. Interventions and randomization
The web-based program (http://www.randomization.com) was used
to generate a random allocation sequence. Centralized randomization
was used to ensure allocation concealment. Participants were random-
ized in a 1:1 ratio to standard of care (control group) or standard of care
with oral NSO (500 mg twice daily postprandial for 10 days; treatment
group). This dose was recommended by the manufacturing company,
and based on previous clinical trial on asthmatic patients.
13
The dura-
tion was proposed based on several registered clinical trials on
COVID-19 treatments.
34
The NSO product was previously characterized
with 0.7 % thymoquinone by high-performance liquid chromatography
analysis at the UCL School of Pharmacy, London, UK.
13
It is manufac-
tured by the Good Manufacturing Practice (GMP) certied facility
Marnys® (Cartagena, Spain; brand name: CUMINMAR; batch number:
E365). Product quality assurance and licensing were performed by the
Saudi Food and Drug Authority (26.861/MU). The NSO product was
stored in a cool and dry place.
Prof. Tariq Madani generated the allocation sequence; Dr. Ali Atwah,
Dr. Mazen Badawib, Dr. Meshari Alhamdane, and Dr. Reem Almalki
enrolled participants; and Dr. Abdulrahman Koshak assigned partici-
pants to their respective groups. Subsequently, NSO was delivered to
each patient of the treatment group at their isolation place. Compliance
was monitored by the patients self-reporting their treatment intake
through daily telecommunication and recorded in the follow-up ques-
tionnaire (Appendix 1). Symptoms and any potential side effects during
the study were also monitored by daily telephone communication (Ap-
pendix 1). The standard of care was decided by the treating physicians
and included antipyretics, antihistamines, and other drugs as per the
Saudi Ministry of Health and the KAUH protocol.
2.4. Outcomes and follow-up
The primary outcome was the percentage of participants with clin-
ical recovery within 14 days after randomization. Clinical recovery was
dened as the absence of symptoms for three days. The secondary out-
comes included the number of days for recovery, duration of each
symptom, adverse drug reactions, and hospital admission due to disease
complications.
35
All outcomes were assessed by on-site investigators
who were aware of the trial-group assignments. From the day of
randomization, data were collected every day for 14 days in an elec-
tronic case report form including a pre-dened list of monitored symp-
toms (Appendix 1) via a structured telephone call to the participants or
their legal representatives. The same investigator was responsible for
data collection from all patients during the follow-up.
A.E. Koshak et al.

Complementary Therapies in Medicine 61 (2021) 102769
3
2.5. Sample-size calculation
To achieve a power of 80 % and a two-tailed p-value of <0.05 of an
assumed 40 % difference between the proportion of patients with clin-
ical cure among the NSO group in comparison with the control group,
the sample size was estimated to be 200 patients assigned randomly into
the two arms (i.e., 100 patients per arm) as calculated using G*Power
version 3.1.9.2 (Heinrich-Heine-University Düsseldorf, Düsseldorf,
Germany).
2.6. Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics 23. The
data normality was tested using the Shapiro–Wilk test and Q–Q plot.
Means ±standard deviations of the normally distributed data were
compared using an independent t-test. Non-normally distributed data
were described as medians ±interquartile range and compared using
the Mann–Whitney U test Intention-to-treat (ITT) analysis was used for
the outcome analysis. Multiple regression substitution was used to
impute missing outcome data, considering baseline values.
3. Results
A total of 233 patients with conrmed COVID-19 were assessed for
eligibility from May 1 to September 30, 2020 (Fig. 1). Fifty patients were
excluded for the reasons described in Fig. 1. The remaining 183 patients
were randomized into the NSO (91) and control groups (92). Subse-
quently, four patients from the NSO group and six patients from the
control group were lost to follow-up for reasons shown in Fig. 1.
A total of 183 patients with conrmed mild COVID-19 were included
in the analysis. Their mean age was 36 ±11 years. Ninety-seven (53 %)
patients were male and 86 (47 %) were female. Their mean body mass
index was 27.1 ±5.6 kg/m
2
. Baseline characteristics of randomized
patients are shown in Table 1.
Of the total study patients (n =183), 85 (46 %) patients recovered
within the 14-day study period. The percentage of patients recovered in
the NSO group was signicantly higher than that in the control group
(57 patients [63 %] versus 32 patients [35 %], respectively; P <0.01)
(Fig. 2). Additionally, the average number of days required for recovery
in the NSO group was signicantly less compared with those in the
control group (10.7 ±3.3 days versus 12.4 ±2.9 days, respectively; P <
Fig. 1. Flow diagram of patient’s enrollment.
Table 1
Baseline characteristics of randomized patients.
Variable Total (n =
183)
NSO group (n
=91)
Control group (n
=92)
Age, mean ±SD 36 ±11 35 ±10 36 ±12
Male, n (%) 97 (53 %) 48 (53 %) 49 (53 %)
Female, n (%) 86 (47 %) 43 (47 %) 43 (47 %)
BMI, mean ±SD 27.1 ±5.6 27 ±5.9 27.2 ±5.4
Smoking, n (%) 21 (11 %) 12 (13 %) 9 (10 %)
Pre-enrollment days, mean ±
SD
3.7 ±2.6 3.5 ±2.1 4 ±2.9
Comorbidities
Obesity, n (%) 45 (25 %) 20 (22 %) 25 (27 %)
Allergic rhinitis, n (%) 28 (15 %) 13 (14 %) 15 (16 %)
Hypertension, n (%) 16 (9%) 13 (14 %) 3 (3%)
Diabetes, n (%) 14 (8%) 11 (12 %) 3 (3%)
Asthma, n (%) 7 (4%) 3 (3%) 4 (4%)
Allergic Conjunctivitis, n (%) 7 (4%) 1 (1%) 6 (6%)
Hypothyroidism, n (%) 5 (3%) 4 (4%) 1 (1%)
Ezcema, n (%) 4 (2%) 3 (3%) 1 (1%)
Food Allergy, n (%) 4 (2%) 1 (1%) 3 (3%)
Allergic Sinusitis, n (%) 3 (2%) 1 (1%) 2 (2%)
Migraine, n (%) 2 (1%) 2 (2%) 0
Hypercholesterolemia, n (%) 1 (0.5 %) 0 1 (1%)
Psoriasis, n (%) 1 (0.5 %) 1 (1%) 0
Ischemic heart disease, n (%) 1 (0.5 %) 0 1 (1%)
Osteoarthritis, n (%) 1 (0.5 %) 1 (1%) 0
A.E. Koshak et al.

Complementary Therapies in Medicine 61 (2021) 102769
4
0.01).
Table 2 shows the types and durations of COVID-19 symptoms re-
ported by the participants. The most predominant symptoms were
anosmia (56 %), cough (55 %), lethargy/fatigue (46 %), headache (46
%), myalgia (43 %), loss of appetite (34 %), and fever (34 %). NSO
treated patients had a signicantly shorter mean duration of chills (2.1
±1.0 versus 4.9 ±3.4; P =0.02), anosmia (8.5 ±3.9 versus 10.4 ±3.6;
P <0.01), runny nose (2.5 ±1.6 versus 3.7 ±2.5; P =0.02), and loss of
appetite (3.5 ±2.9 versus 5.5 ±3.1; P =0.01) as compared to the
control group. However, there were no signicant changes found in the
rest of symptoms’ duration between groups.
Adverse events occurred in three patients with mild gastrointestinal
symptoms of NSO group (3.4 %). Furthermore, four patients from the
control group (4.6 %) were hospitalized during the study period due to
disease complications (pneumonia [n =1] and hypoxemia [n =3]).
However, only one patient from the NSO group (1.1 %) was hospitalized
due to severe nausea and vomiting; these were suspected to be the
aggravated adverse effects of NSO. Nearly all of the patients in the NSO
group showed good compliance with the NSO treatment (consumed
more than 90 % of their NSO capsules).
4. Discussion
In this study, NSO was found to be signicantly associated with a
higher likelihood of recovery from mild COVID-19 on day 14th. Almost
62 % of the patients with mild COVID-19 treated with NSO recovered
compared to only 36 % of the patients in the control group. Further-
more, the average recovery time was signicantly shorter in the NSO-
treated group than in the control group by approximately 2 days.
The most common COVID-19 symptoms observed here include
anosmia, cough, fatigue, lethargy, and headache, whereas the most
common symptoms in the ISARIC Global COVID-19 report are fever,
shortness of breath, cough, and fatigue/malaise.
36
In this study, chills,
anosmia, runny nose, and loss of appetite were signicantly reduced in
the NSO group in comparison with the control group after the treatment.
This might be attributed to the anti-inammatory effects of N. sativa L.
Fig. 2. The number of patients who recovered within the study period.
Table 2
Frequency and duration of symptoms in 173 patients with mild COVID-19.
Total frequency n
(%)
NSO group Control group P-value of the symptom’s duration
between groups
Frequency n
(%)
Duration (days) Mean
±SD
Frequency n
(%)
Duration (days) Mean
±SD
Anosmia 123 (71) 57 (66) 8.5 ±3.9 66 (77) 10.4 ±3.6 <0.01
Lethargy/Fatigue 118 (68) 62 (71) 6.3 ±4.1 56 (65) 5.4 ±3.2 0.18
Cough 116 (67) 64 (74) 7.3 ±4.8 52 (60) 8.2 ±4.3 0.3
Headache 107 (62) 57 (66) 4.2 ±3.4 50 (58) 4.6 ±3.3 0.55
Myalgia 99 (57) 55 (63) 5.2 ±3.5 44 (51) 4.6 ±2.8 0.41
Nasal congestion 88 (51) 44 (51) 3.9 ±2.8 44 (51) 5.2 ±3.6 0.06
Fever 85 (49) 50 (57) 2.8 ±1.8 35 (41) 3.6 ±2.2 0.07
Sore throat 70 (40) 40 (46) 3.9 ±2.8 30 (35) 4.2 ±3.2 0.73
Runny nose 68 (39) 37 (43) 2.5 ±1.6 31 (36) 3.7 ±2.5 0.02
Loss of appetite 62 (36) 35 (40) 3.5 ±2.9 27 (31) 5.5 ±3.1 0.01
Arthralgia 55 (31) 34 (39) 4.5 ±3.5 21 (24) 4.2 ±3.4 0.74
Sputum 51 (29) 27 (31) 5.0 ±4.0 24 (28) 6.2 ±4.4 0.30
Sneezing 48 (27) 24 (28) 2.9 ±2.6 24 (28) 3.5 ±2.0 0.39
Diarrhea 46 (26) 21 (24) 2.8 ±2.4 25 (29) 2.7 ±2.2 0.94
Nausea 41 (23) 21 (24) 3.3 ±2.7 20 (23) 4.5 ±3.9 0.29
Chest tightness 36 (21) 24 (28) 5.2 ±3.8 12 (14) 3.6 ±3.6 0.25
Chills 27 (16) 16 (18) 2.1 ±1.0 11 (13) 4.9 ±3.4 0.02
Shortness of
breath
26 (15) 16 (18) 2.9 ±1.8 10 (12) 3.4 ±2.8 0.62
Abdominal pain 26 (15) 13 (15) 2.8 ±3.4 13 (15) 4.0 ±2.7 0.32
Chest pain 17 (10) 10 (11) 2.9 ±1.6 7 (8) 4.7 ±2.9 0.12
Vomiting 10 (6) 6 (7) 1.5 ±1.2 4 (5) 2.7 ±1.7 0.21
A.E. Koshak et al.

Complementary Therapies in Medicine 61 (2021) 102769
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Corticosteroids, potent anti-inammatory drugs, have been used to
eliminate inammation in patients with post-infectious olfactory
dysfunction.
37
Some trials have been conducted to evaluate a specic therapeutic
intervention to treat patients with mild COVID-19. However, high-
quality data supporting interventions are limited. Additionally, there
are concerns about the potential toxicity of experimental novel or
repurposed medications.
38
Hence, it was proposed that specic thera-
pies for COVID-19 in the ambulatory setting should be limited to clinical
trials.
39
To our knowledge, this is the rst RCT where the effects of NSO in
patients with mild COVID-19 were observed. In contrast to the previ-
ously reported trials evaluating specic medications for mild COVID-19,
our study revealed a signicant benet of NSO treatment for mild
COVID-19 as it increased the likelihood of recovery and reduced the
duration of illness. For example, hydroxychloroquine has received
considerable attention with potential for COVID-19 treatment; however,
it failed to demonstrate consistent benets for patients with mild
COVID-19.
40,41
Bromhexine, a mucolytic agent used primarily for
bronchopulmonary infections, likewise, failed to demonstrate thera-
peutic benets for COVID-19 treatment.
42
In comparison with other
N. sativa L. studies pertaining to COVID-19, a retrospective study
showed some benets of using N. sativa L. in combination with other
natural products.
43
The study of Ashraf et al. has also reported promising
therapeutic outcomes; however, they used a different treatment product:
honey combined with whole N. sativa L seeds.
44
Previous studies reported that in different grades of COVID-19
severity, there were changes in release of leukocytes and pro-
inammatory cytokines
45,46
Therefore, therapies targeting the im-
mune system and restricting the cytokine storm are worth investigating
in COVID-19 patients.
47
N. sativa L. has immunoregulatory and
anti-inammatory effects via decreasing many pro-inammatory cyto-
kine responses.
11,29,48
In addition, N. sativa L. may have therapeutic
effects against immune disturbance, autophagy dysfunction, oxidative
stress, ischemia, and inammation in the COVID-19 associated comor-
bidities such as diabetes, cardiovascular disorders, and co-infections
with bacterial and viral pathogens.
47
The most common comorbidities
found in this study were obesity, allergic disorders, smoking, hyper-
tension, diabetes, and asthma. The signicance of these diseases and
treatment outcomes should be assessed in further studies.
Limitations of this study include restricting outcomes to clinical
symptoms. Serological biomarkers (such as biochemical or hematolog-
ical parameters) were not considered herein because of the regulations
imposed by isolation policies and lack of sufcient funding. All symptom
reports were based on a subjective assessment via telephone commu-
nication between the patient and the investigator. Moreover, the open
design of the study may have introduced biases in assessing the response
towards the treatment. The estimated sample size in the power calcu-
lation was not reached because the number of eligible cases decreased
towards the end of the rst pandemic wave. Although clinical symptoms
showed that early administration of NSO did not worsen the immune
response, the potential to aggravate the cytokine storm should be taken
into consideration if NSO is administered at the later stages of the
infection. The importance of timeframe towards the administrating of
such immunomodulatory/anti-inammatory agent in COVID-19 and its
paradoxical effects require further analysis in future trials. Finally, the
ndings of present study cannot be generalized to other disease sever-
ities, age categories, treatment doses, or formulations.
5. Conclusion
Oral NSO dosage supplementation at 500 mg twice daily for 10 days
in a sample of adult patients with mild symptoms of COVID-119 was
associated with a higher percentage of recovery than usual care alone at
day 14 of the illness. Additionally, faster recovery from COVID-19
symptoms and a lower hospitalization rate were observed with a low
adverse effect prole. Specically, NSO treatment had a pronounced
effect on the duration of anosmia and runny nose. To our knowledge,
this is the rst RCT to demonstrate the effects of NSO on COVID-19
symptoms. Future larger double-blinded placebo-controlled studies
using objective laboratory outcomes and including more patients with
severe illness are required to verify the benets of NSO for COVID-19
treatment.
Funding
This research did not receive any specic grant from funding
agencies in the public, commercial, or not-for-prot sectors.
CRediT authorship contribution statement
Abdulrahman E. Koshak: Conceptualization, Project administra-
tion, Writing - original draft, Writing - review & editing. Emad A.
Koshak: Conceptualization, Methodology, Writing - original draft,
Writing - review & editing. Abdullah F. Mobeireek: Methodology,
Validation, Writing - review & editing. Mazen A. Badawi: Data cura-
tion. Siraj O. Wali: Methodology, Writing - review & editing. Husam M.
Malibary: Data curation. Ali F. Atwah: Data curation, Writing - review
& editing. Meshari M. Alhamdan: Data curation. Reem A. Almalki:
Data curation. Tariq A. Madani: Conceptualization, Methodology, Re-
sources, Supervision, Writing - original draft, Writing - review & editing.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
We acknowledge Marnys® for trial drug donation with no role in the
conduct of the trial, the analysis, or the decision to submit the manu-
script for publication. We thank Dr. Md Dilshad Manzar for the statistical
consultation. We thank Editage (www.editage.com) for English lan-
guage editing.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.ctim.2021.102769.
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