Biomedicine & Pharmacotherapy 167 (2023) 115467

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

1,8-cineole (eucalyptol): A versatile phytochemical with therapeutic

applications across multiple diseases
Cosima C. Hoch a, Julie Petry a, Lena Griesbaum a, Tobias Weiser a, Kathrin Werner a,
Michael Ploch b, Admar Verschoor a, Gabriele Multhoff c, Ali Bashiri Dezfouli a, c,
Barbara Wollenberg a, *
a
Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany
b
Cassella-med GmbH & Co. KG, 50670 Cologne, Germany
c
Central Institute for Translational Cancer Research, Technical University of Munich (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, 81675
Munich, Germany

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

Keywords: 1,8-cineole (Eucalyptol), a naturally occurring compound derived from botanical sources such as eucalyptus,
1,8-cineole rosemary, and camphor laurel, has a long history of use in traditional medicine and exhibits an array of biological
Eucalyptol properties, including anti-inflammatory, antioxidant, antimicrobial, bronchodilatory, analgesic, and pro-
Respiratory disorders
apoptotic effects. Recent evidence has also indicated its potential role in managing conditions such as Alz­
Anti-inflammatory activity
Antimicrobial
heimer’s disease, neuropathic pain, and cancer. This review spotlights the health advantages of 1,8-cineole, as
Antioxidant demonstrated in clinical trials involving patients with respiratory disorders, including chronic obstructive pul­
monary disease, asthma, bronchitis, and rhinosinusitis. In addition, we shed light on potential therapeutic ap­
plications of 1,8-cineole in various conditions, such as depression, epilepsy, peptic ulcer disease, diarrhea,
cardiac-related heart diseases, and diabetes mellitus. A comprehensive understanding of 1,8-cineole’s pharma­
codynamics and safety aspects as well as developing effective formulations, might help to leverage its therapeutic
value. This thorough review sets the stage for future research on diverse health benefits and potential uses of 1,8-
cineole in tackling complex medical conditions.

1. Introduction
Plants have long been recognized as a significant reservoir of active
pharmaceutical ingredients for drug discovery, and their naturally
occurring small molecules have emerged as a prominent class of thera­
peutic compounds [1]. Among these, 1,8-cineole (1,3,3-trimethy­
l-2-oxabicyclo[2.2.2]octane), also referred to as Eucalyptol, is a
naturally derived compound found in the essential oil fraction of various
botanical sources, including eucalyptus, rosemary, and camphor laurel
[2].
Eucalyptus nicholii essential oil is renowned for its high 1,8-cineole
concentration, which can reach levels of up to 90% [3]. The oil com­
prises mainly volatile organic compounds, including monoterpenes and
sesquiterpenes [4]. Due to its pleasant flavor and aroma, 1,8-cineole is
frequently used in food, fragrances, and cosmetics [5]. Additionally, it
has been historically used in traditional medicine across different cul­
tures, such as Chinese, Indian, and Australian Aboriginal medicines, for
treating a variety of conditions, including respiratory and digestive is­
sues, fever, and pain [6].
In Germany, Soledum™ enteric-coated capsules, which contain 100
mg or 200 mg (forte) of 1,8-cineole (CNL-1976) per capsule, have been
registered as authorized medicinal products for several years and are
utilized in treating inflammatory respiratory disorders such as the
common cold, bronchitis, sinusitis, bronchial asthma, and chronic
obstructive pulmonary disease (COPD) [7].
After oral administration, 1,8-cineole is absorbed in the small in­
testine and subsequently metabolized in the liver by human cytochrome
P450 enzymes (CYP3A4/5). Its primary metabolites, 2alpha-hydroxy-
and 3alpha-hydroxy-1,8-cineole, are excreted through urine [8]. In
addition to its systemic availability in the bloodstream, 1,8-cineole can

* Correspondence to: Department of Otolaryngology, Head and Neck Surgery. School of Medicine, Technical University of Munich (TUM), Ismaningerstrasse 22,
81675 Munich, Germany.
E-mail address: barbara.wollenberg@tum.de (B. Wollenberg).

https://doi.org/10.1016/j.biopha.2023.115467
Received 23 July 2023; Received in revised form 28 August 2023; Accepted 7 September 2023
Available online 9 September 2023
0753-3322/© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
C.C. Hoch et al.
reach the bronchial system and be exhaled through the peripheral air­
ways. This allows its beneficial effects to extend throughout the entire
respiratory system, including the sinuses, which are a key source of
infection-related exacerbations [9,10].
1,8-cineole has gained widespread attention for its array of biolog­
ical properties, such as anti-inflammatory, antioxidant, mucolytic/
secretolytic, bronchodilatory, and antimicrobial effects [11,12]. More­
over, recent studies have highlighted the neuroprotective, analgesic, and
pro-apoptotic properties of 1,8-cineole, underscoring its potential
beneficial role in a broad spectrum of conditions such as Alzheimer’s
disease, neuropathic pain, and cancer [13–15].
Given its extensive range of beneficial effects across multiple dis­
eases, there has been a growing interest in exploring the mechanisms of
action and potential therapeutic applications of 1,8-cineole in various
conditions, including respiratory, neurological, gastrointestinal, and
oncological disorders. Therefore, this review aims to critically evaluate
the available evidence on the effects of 1,8-cineole, mechanisms of ac­
tion, and potential clinical applications, while identifying promising
areas for future research.
2. Pharmacological properties
The pharmacological properties exhibited by 1,8-cineole are of
profound significance, underlining its versatile attributes. At room
temperature, this compound takes the form of a clear liquid, with a
melting point recorded at 1.5 ◦ C and a flash point at 49 ◦ C [16]. Marked
by a logP value of 2.74, 1,8-cineole strikes an optimal equilibrium be­
tween solubility and permeability, hinting at its favorable potential for
oral bioavailability [17]. Emerging from isoprene units (C5H8), mono­
terpenes like 1,8-cineole are synthesized via the activation of iso­
pentenyl pyrophosphate and dimethylallyl pyrophosphate [18]. These
foundational units undergo iterative linkage, culminating in the creation
of diverse terpenes distinguished by their carbon backbones, including
monoterpenes (C10) and sesquiterpenes (C15).
In terms of pharmacokinetics, investigations have shed light on the
behavior of 1,8-cineole. In rabbits, oral administration of 200 mg/kg has
led to rapid attainment of peak plasma concentration within 1 h, indi­
cating efficient absorption [19]. Biotransformation investigations con­
cerning 1,8-cineole have been conducted on brushtail possums and
rabbits [20,21]. These studies have successfully identified a range of
hydroxylated derivatives, among them 7-hydroxy-1,8-cineole and 9-hy­
droxy-1,8-cineole. Rodent models revealed oxidative modifications
yielding metabolites like 2-hydroxy-1,8-cineole and 3-hydroxy-1,
8-cineole, present within 2 h post-oral dosing. Additionally, the corre­
sponding diols, cineolic acids, and hydroxylcineolic acids have been
recognized as phase I metabolites, present in both urine and blood
plasma. Subsequent conjugation formed glucuronide products, a pattern
similarly observed in rat and human liver microsome studies [22].
Addressing the compound’s toxicity profile, the oral acute LD50 value
in rats is documented at 2480 mg/kg body weight [23]. Subacute
toxicity has been observed in rats at dose levels of 600 mg/kg body
weight and beyond. Manifestations of this subacute toxicity included
reduced body weight and the presence of lesions in liver and kidney. No
indications of chronic or genotoxic effects attributed to 1,8-cineole have
been identified [24].
Limited research exists regarding the metabolism of 1,8-cineole in
humans, and as of the present time, the identification of urinary me­
tabolites following a single 100 mg dose of 1,8-cineole has revealed 2-
hydroxy-1,8-cineole and 3-hydroxy-1,8-cineole [8]. Nevertheless,
given the considerably lower doses acquired through the consumption of
1,8-cineole via herbal teas or spices, the significance of dose-dependent
metabolism becomes pivotal in a comprehensive assessment encom­
passing both pharmacological and toxicological dimensions.
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Biomedicine & Pharmacotherapy 167 (2023) 115467
3. Mechanisms of action
3.1. Anti-inflammatory mechanisms of 1,8-cineole
3.1.1. Regulation of inflammatory mediators and cytokines
Pro-inflammatory cytokines are small proteins secreted by immune
cells, which play a crucial role in mediating and regulating inflammation
in the body. Dysregulated production of these cytokines contributes to
the development and progression of various inflammatory diseases [25].
Venkataraman et al. identified the anti-inflammatory effects of 1,8-
cineole on colonic inflammation using a dextran sodium sulfate (DSS)-
induced mouse model of colitis [26]. 1,8-cineole effectively prevented
colonic shortening, reduced myeloperoxidase (MPO) enzyme activity,
and decreased pro-inflammatory cytokine levels, such as interleukin
(IL)− 6, IL-1β, tumor necrosis factor (TNF)-α, and IL-17A. In addition, 1,
8-cineole reduced the DSS-induced expression of pro-inflammatory
mediators, including cyclooxygenase-2 (COX2) and inducible nitric
oxide synthase (iNOS), at both the protein and mRNA levels [26].
Moreover, in an acute pancreatitis mouse model, it has been shown that
treatment with 1,8-cineole resulted in decreased cytokine levels of
TNF-α, IL-1β, and IL-6, mirroring the effects seen with thalidomide, a
TNF-α inhibitor. Of note, the anti-inflammatory cytokine IL-10 increased
upon 1,8-cineole treatment [27]. A study investigating trinitrobenzene
sulfonic acid-induced colitis in rats also demonstrated similar protective
effects of 1,8-cineole, particularly in relation to reduced cytokine levels
[28].
In a guinea pig model of ovalbumin (OVA)-induced asthma, Bastos
et al. found that inhalation of 1,8-cineole mitigated tracheal contrac­
tions, reduced TNF-α and IL-1β levels, and inhibited eosinophil and
neutrophil aggregation in bronchoalveolar lavage fluid (BALF) samples
[29]. Juergens et al. documented that 1,8-cineole decreased the release
of prostaglandin E2 and leukotriene B4 (LTB4) from peripheral blood
mononuclear cells in asthmatic patients, and reduced TNF-α, IL-1β,
LTB4, and thromboxane B2 in lipopolysaccharide (LPS)-stimulated pe­
ripheral blood monocytes of healthy individuals [30].
Furthermore, treatment with 1,8-cineole resulted in a reduction in
vascular endothelial inflammation mediated by pro-inflammatory cy­
tokines in LPS-induced systemic inflammation in mice [31] and
decreased the expression of TNF-α and IL-1β mRNA expression in human
umbilical vein endothelial cells (HUVECs) after LPS stimulation in vitro
[32].
1,8-cineole has also been shown to effectively reduce Dermatopha­
goides pteronyssinus (Der p)-triggered cytokine production and intra­
cellular toll-like receptor (TLR)− 4 expression in human bronchial
epithelial cells [33]. Moreover, in a Der p-induced mouse model, 1,
8-cineole treatment significantly decreased airway hyper­
responsiveness and the number of eosinophils in BALF, as well as the
production of IL-4, IL-13, and IL-17A [33].
The effectiveness of 1,8-cineole in suppressing pro-inflammatory
cytokines in LPS-induced lung inflammation, human mononuclear
cells, and lung macrophages has been further confirmed in other studies
[34–36]. For instance, 1,8-cineole has demonstrated inhibitory proper­
ties in both monocytes and lymphocytes, specifically targeting chemo­
tactic cytokines like IL-8 and IL-5 [37]. As a matter of note, 1,8-cineole
has shown promising potential as an anti-allergic agent by inhibiting the
production of IL-4. In the context of respiratory disorders, the observed
decrease in cytokine production indicates that 1,8-cineole operates via
an anti-inflammatory mechanism, effectively inhibiting
cytokine-induced airway mucus hypersecretion rather than solely
functioning as a secretolytic agent. These findings are consistent with
previous studies and highlight the potential of 1,8-cineole as an alter­
native medication with anti-inflammatory properties which are com­
parable to those of steroids [7].
Finally, 1,8-cineole significantly influenced the phosphorylation and
activation of endothelial nitric oxide synthase 3 in tissue samples from
nasal polyps of chronic rhinosinusitis patients [38]. This effect is
C.C. Hoch et al. Biomedicine & Pharmacotherapy 167 (2023) 115467

particularly noteworthy since it suggests that 1,8-cineole may reduce
inflammation and edema by regulating the vascular permeability. As
nasal nitric oxide (nNO) is a known mediator of ongoing sinus inflam­
mation, the use of 1,8-cineole to reduce nNO levels presents a promising
therapeutic approach for airway diseases, particularly chronic rhinosi­
nusitis with nasal polyps (CRSwNP).
3.1.2. Modulation of immune cells
Macrophages are phagocytic cells primarily responsible for engulfing
and digesting foreign particles, debris, and pathogens, in helping to
maintain tissue homeostasis and promoting tissue repair [39]. Rui et al.
have shown that treatment with 1,8-cineole suppressed IL-13-induced
polarization of M2 macrophage and mitigated pathological alterations
associated with lung fibrosis in mice [40]. 1,8-cineole appeared to alter
M2 macrophage polarization by inhibiting the phosphorylation of
signaling molecules such as STAT6 and p38 MAPK, and the expression of
transcription factors such as KLF4 and PPAR-γ [40]. Moreover, 1,
8-cineole hindered LPS-induced nitric oxide (NO) production in mouse
macrophage cell lines [34], facilitated acute lung injury in a mouse
model [41], and mitigated active oxygen release by cultured alveolar
macrophages of COPD patients [42].
There is also evidence that 1,8-cineole is capable of influencing
neutrophils. In an in vivo experiment on Bleomycin-induced pulmonary
inflammation it was shown that 1,8-cineole can inhibit neutrophils
pulmonary infiltration, suggesting a potential role for 1,8-cineole in
regulating neutrophil migration and activation [40]. It has been
demonstrated that 1,8-cineole inhibits basophil activation mediated by
IgE, which is involved in allergic reactions [43]. In a study involving an
IgE-mediated local allergic model, Nakamura et al. confirmed that the
anti-inflammatory effect of 1,8-cineole in wild-type mice was attribut­
able to the suppression of mast cell activation when compared to mast
cell-deficient mice [44]. The mechanism of action was further examined
in an in vitro cell system using bone-marrow-derived mast cells, which
revealed that 1,8-cineole not only repressed mast cell degranulation but
also mitigated allergic dermatitis. According to the findings, the authors
suggested that 1,8-cineole may have a direct or indirect impact on the
phosphorylation of PLCγ and p38 MAPK, contributing to its ability to
suppress degranulation in mast cells.

Fig. 1. The anti-inflammatory mechanisms of 1,8-cineole involve the inhibition of nuclear translocation of NF-κB p65 and PPARγ, leading to the suppression of
immune response genes. This regulatory process effectively modulates the expression of key inflammatory mediators, including TNF-alpha, IL-6, IL-8, VCAM-1, and
E-selectin. By targeting these crucial pathways, 1,8-cineole demonstrates its potential to mitigate inflammation and associated effects (Figure created using Bio­
Render, Toronto, ON, Canada).

3
C.C. Hoch et al.
3.1.3. PPARγ and NF-κB signaling pathways
Peroxisome proliferator-activated receptor-gamma (PPARγ) and
nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)
are two important cellular signaling molecules involved in inflammation
which can be regulated by 1,8-cineole (Fig. 1).
PPARγ is a member of the nuclear receptor superfamily and a ligand-
inducible transcription factor that plays a significant role in adipocyte
function. Recent research has demonstrated that PPARγ is also crucial in
regulating immune cells, cell proliferation, and in stimulating the anti-
inflammatory activity of PPARγ [45]. Treatment with 1,8-cineole has
been shown to restore PPARγ protein activity in DSS-induced colitis
[26]. In addition, an increase in PPARγ expression has been observed in
1,8-cineole-treated vascular endothelium dysfunction induced by LPS
[46]. Both 1,8-cineole and PPAR-γ agonists had comparable effects on
blocking the protein and mRNA levels of VCAM-1, E-selectin, IL-6, and
IL-8 triggered by LPS. The authors confirmed that the anti-inflammatory
activity of 1,8-cineole can be reversed by PPAR-γ inhibitors [46].
Therefore, it is assumed that 1,8-cineole mediates its anti-inflammatory
effects, at least in part by PPARγ activation.
NF-κB is a crucial transcription factor in inflammation and immune
response regulation. Inflammatory stimuli such as LPS or TNF-α can
activate the NF-κB pathway that increases the expression of pro-
inflammatory genes [47]. 1,8-cineole inhibited NF-κB-mediated
signaling events by preventing the dissociation of the inhibitory subunit
IκBa and the translocation of the NF-κB subunit P65 into the nucleus [26,
48]. These findings are consistent with a study demonstrating
anti-inflammatory properties of 1,8-cineole in mice with acute lung
inflammation induced by cigarette smoke [49]. Specifically, 1,8-cineole
reduced the activation of the NF-κB p65 subunit, decreasing both in­
flammatory cells and the cytokine secretion, including TNF-α. Moreover,
1,8-cineole has been shown to improve the inflammatory phenotype in
HUVECs by modulating the NF-κB expression in vitro [50]. 1,8-cineole
has been found to impede UVB-induced COX-2 protein and mRNA
production in HaCaT cells [51]. The suppression of the aryl hydrocarbon
receptor (AhR) led to decreased COX-2 expression and diminished
ERK1/2 phosphorylation in these cells. Additionally, the topical appli­
cation of 1,8-cineole to the mouse skin effectively postponed tumor
formation, reduced the tumor growth, concurrently with obstructing the
COX-2 expression in vivo. The bioinformatics application, TFactsS,
postulated the possibility of 1,8-cineole being able to regulate NF-κB in
HaCaT cells [52]. However, deeper exploration is required to elucidate
the transcription factors involved in the UVB-induced COX-2 expression
through the AhR/c-Src/EGFR/ERK pathway. 1,8-cineole’s inhibition of
COX2 may contribute to reducing inflammation by reducing the NF-κB
expression.
3.2. Antioxidant properties of 1,8-cineole: mechanisms and cellular
effects
3.2.1. Scavenging of free radicals
1,8-cineole’s antioxidant properties play a crucial role in its thera­
peutic potential, as it is effective in neutralizing reactive oxygen species
(ROS) and enhancing cellular defense mechanisms. Oxidative stress,
caused by ROS accumulation, is involved in the developing and pro­
gression of various pathological conditions, including inflammation,
aging, and neurodegenerative diseases [53].
1,8-cineole has demonstrated potent free radical scavenging activity
in a variety of in vitro assays, highlighting its ability to neutralize ROS
and protect cells from oxidative damage [54,55]. In grass carp hepato­
cytes, 1,8-cineole treatment enhanced antioxidant enzymes activities,
such as superoxide dismutase (SOD) and catalase (CAT), increased total
antioxidant capacity, and decreased ROS and malondialdehyde (MDA)
content, effectively attenuating oxidative stress caused by di
(2-ethylhexyl)phthalate [56].
Various models have demonstrated similar antioxidant effects,
including RAW264.7 cells and ankle tissues [57]. In these studies, 1,
4
Biomedicine & Pharmacotherapy 167 (2023) 115467
8-cineole has been found to enhance the activities of antioxidant en­
zymes while reducing ROS levels, effectively alleviating the oxidative
stress induced by monosodium urate. 1,8-cineole co-administered with
bisphenol A (BPA) significantly increased the activities of antioxidant
enzymes like SOD, glutathione peroxidase (GPx), and CAT, while
reducing high levels of oxidative parameters, including MDA, iNOS, and
NO in chickens [58].
The antioxidant capacity of 1,8-cineole extends beyond its ability to
scavenge ROS directly. It has also been shown to chelate metal ions,
contributing to ROS production [59]. By sequestering these ions, 1,
8-cineole can limit ROS formation and protect cells from oxidative
damage.
3.2.2. Inhibition of lipid peroxidation
Lipid peroxidation (LP) is a detrimental process that can cause sig­
nificant cellular damage and has been implicated in the pathogenesis of
various diseases, including rheumatoid arthritis, atherosclerosis,
ischemia, carcinogenesis, and aging [60].
1,8-cineole has demonstrated the ability to inhibit LP [61]. In a study
examining the protective effect of 1,8-cineole against LP in rat liver
microsomes, 1,8-cineole successfully inhibited the formation of thio­
barbituric acid reactive substances, commonly used markers of LP [62].
This finding indicates that 1,8-cineole can protect cellular components,
such as membranes and lipids, from oxidative damage.
Furthermore, 1,8-cineole exhibited a dose-dependent protective ef­
fect on linoleic acid oxidation [63], an essential fatty acid that plays a
critical role in cellular function and is a primary target of LP. By pre­
venting the oxidation of linoleic acid, 1,8-cineole may help maintain
cellular homeostasis and protect against the development and progres­
sion of diseases associated with LP.
3.2.3. Nrf2/Keap1 signaling pathway
The antioxidant activity of 1,8-cineole is mediated, in part, by acti­
vating the Nrf2/Keap1 system, a critical regulator of cellular protective
responses to oxidative stress and inflammation [64]. This pathway is
essential for maintaining cellular redox balance and promoting cell
survival under stress conditions (Fig. 2).
Treatment with 1,8-cineole promoted the nuclear translocation of
Nrf2, a transcription factor that binds to antioxidant response elements
in the promoter regions of target genes, leading to increased expression
of phase II detoxifying enzymes and antioxidant proteins, such as heme
oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 (NOQ1) [26].
Additional studies have demonstrated the protective effects of 1,8-
cineole on liver cells and pheochromocytoma cells through activating
the Nrf2/Keap1 system and increasing SOD expression [65–67]. In
various cellular and tissue models, 1,8-cineole treatment has been
shown to enhance the activities of antioxidant enzymes, such as SOD,
GPx, and CAT, while reducing the levels of oxidative parameters
generated by different ROS inducers, such as LPS, hydrogen peroxide,
and cigarette smoke [68–70].
3.3. Broad-spectrum antimicrobial properties of 1,8-cineole
3.3.1. Antibacterial properties: activity, synergy with antibiotics, and
impact on biofilm formation and cell morphology
Antimicrobial resistance is a pressing global health concern, and the
formation of biofilms by bacteria is a potential cause of resistance.
Biofilms are structured communities of microorganisms that produce a
protective extracellular matrix that reduces the efficacy of antibiotics
[71,72]. To address this issue, natural compounds derived from plants,
such as the monoterpene 1,8-cineole, have gained significant attention
for their potential to decrease antibiotic resistance (Table 1).
1,8-cineole has demonstrated antibacterial activity against various
Gram-positive pathogenic strains, including Staphylococcus aureus, Ba­
cillus subtilis, Streptococcus pyogenes, Bacillus cereus, Micrococcus flavus,
and Staphylococcus epidermidis, as well as Gram-negative strains, such as
C.C. Hoch et al. Biomedicine & Pharmacotherapy 167 (2023) 115467

Table 1
A comprehensive summary of 1,8-cineole’s diverse antimicrobial properties,
including antibacterial, antifungal, and antiviral effects. HSV: herpes simplex
virus; IBV: infectious bronchitis virus; SARS-CoV-2: severe acute respiratory
syndrome coronavirus 2; IRF3: interferon regulatory factor 3.
Properties Details Potential References
Applications

Antibacterial • Effective against Gram- Development of [71,73–75,

positive strains (e.g., new antibacterial 78,80,84,
S. aureus, B. subtilis) and agents to eliminate 86–88,90,92,
Gram-negative strains antibiotic 95,96]
(e.g., E. coli, resistance and
P. aeruginosa), biofilm-associated
• Synergistic with infections
antibiotics like
gentamicin,
amoxicillin/clavulanic
acid, and penicillin G,
• Inhibits quorum sensing
and biofilm formation,
affecting bacterial
growth and motility,
• Modifies shape and size
of bacterial cells,
particularly in E. coli
and S. aureus
Antifungal • Inhibits growth of Development of [97–101]
various fungi, including new antifungal
F. oxysporum, agents to address
F. sporotrichioides, and limited efficacy and
A. tubingensis, toxicity risks of
• Disrupts fungal biofilm current antifungal
formation in F. solani medications
species complex,
Fig. 2. Molecular mechanisms of 1,8-cineole’s antioxidant activity via Nrf2/ C. albicans, and
Keap1 pathway activation. ARE: antioxidant response element; HO-1: heme C. glabrata,
oxygenase-1; NQO1: NAD(P)H: quinone oxidoreductase 1 (Figure created using • Inhibitory effect on
BioRender, Toronto, ON, Canada). dermatophytes using
1,8-cineole nano­
emulsion gel,
Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis, Entero­ • Affects cell wall
bacter cloacae, Proteus mirabilis, and Salmonella typhimurium [73–79]. biogenesis,
mitochondrial activity,
The antimicrobial properties of 1,8-cineole can be mainly attributed to
and adhesion
its ability to cause cell membrane permeabilization [80,81]. Sun and Antiviral • Antiviral efficacy Development of [102–107]
colleagues demonstrated that treating Salmonella with 1,8-cineole against HSV-1, HSV-2, new antiviral
resulted in the downregulation of genes related to carbohydrate meta­ IBV, and influenza A agents targeting
bolism and membrane proteins at the mRNA level [82]. Similar results virus, viral replication
• Potential for SARS-CoV- and enhancing
have been reported for carbapenemase-producing Klebsiella pneumoniae 2 treatment by inhibit­ antiviral responses
isolates [83]. The antimicrobial activity of 1,8-cineole against bacteria ing Mpro enzyme crucial
possessing an outer LPS membrane is attributed to its hydrophobic na­ for viral replication,
ture [78]. • Stimulates antiviral
response by increasing
Although 1,8-cineole exhibited weaker bactericidal activity than
activity of IRF3 and
commonly used antibiotics such as gentamicin and amoxicillin (AMX)/ reducing
clavulanic acid, it significantly reduced the minimum inhibitory con­ proinflammatory
centration of antibiotics when used in combination with other drugs [84, activity of NF-kB,
85]. These findings align with a study that reported synergistic effects • Synergistic with
oseltamivir in treating
between 1,8-cineole and nisin against S. aureus [73]. Moreover, a
influenza A, enhancing
combination of AMX and 1,8-cineole has been noted to reduce the af­ immune response and
finity of the β-lactam antibiotic, AMX, for the β-lactamase enzyme as vaccine co-
well as to improve the bioavailability of AMX partly by enhancing in­ administration effects
testinal absorption and mainly by prolonging its half-time [86,87].
Accordingly, in vitro assays indicated that combining 1,8-cineole and
et al., who noted the inhibition of biofilm formation by S. pyogenes and
beta-lactam antibiotics, such as penicillin G and AMX, displayed a syn­
its mediated virulence factors [77]. Importantly, 1,8-cineole inhibited
ergistic effect against MRSA strains [88].
virulence production and biofilm formation in P. aeruginosa mediated by
At non-inhibitory doses, 1,8-cineole has been found to substantially
QS without detrimental effects on their growth [91]. In addition, a
inhibit the expression of Quorum sensing (QS), which plays a crucial role
decrease in biomass and cell viability of biofilms formed by MDR
in the formation and structure of bacterial biofilms [89], and virulence
ESBL-producing E. coli and K. pneumoniae isolates following treatment
genes in E. coli O101, particularly the luxS gene [90]. Furthermore,
with 1,8-cineole was documented [92,93]. Interestingly, S. aureus, the
non-inhibitory concentrations of 1,8-cineole and the absence of the luxS
most prevalent germ in chronic rhinosinusitis, demonstrated a reduction
gene led to a significant reduction in bacterial biofilm formation and
in biofilm formation [94]. Real-time quantitative polymerase chain re­
motility, indicating that 1,8-cineole can target both bacterial biofilm
action analysis verified that this phenomenon resulted from the
and motility. This finding agrees with a study conducted by Vijayakumar

5
C.C. Hoch et al.
downregulation of essential components in biofilm production (AgrA,
SarA, and σB) which is supported by 1,8-cineole.
Research findings by Li et al. indicated that 1,8-cineole can modify
the shape and size of bacterial cells, including Gram-negative and Gram-
positive bacteria [95]. The antimicrobial activity of 1,8-cineole might be
more pronounced against E. coli due to its susceptibility, compared to
S. aureus, which possesses a more robust cell wall and membrane. These
observations are highly relevant in the clinical setting, given the ease
with which virulence factors spread among Gram-negative bacteria and
the limited efficacy of conventional antibiotics in such cases.
3.3.2. Antifungal properties: inhibition of fungal growth and disruption of
biofilm formation
Despite the availability of specific antifungal medications like
amphotericin B and voriconazole for treating fusariosis, their efficacy in
clinical trials is limited, and they bear some serious toxicity risks
[108–110]. 1,8-cineole has shown potential as an alternative antifungal
agent with significant inhibitory effects on various fungi, including
Fusarium oxysporum, Fusarium sporotrichioides, and Aspergillus tubingensis
(Table 1) [97].
1,8-cineole nanoemulsion gel demonstrated a significant inhibitory
effect on dermatophytes [101]. It is noteworthy that 1,8-cineole can
penetrate the cell membranes and damage organelles without altering
the membrane potential [98].
In vitro studies have demonstrated that 1,8-cineole can effectively
inhibit biofilm formation in the Fusarium solani species complex by
downregulating ergosterol biosynthetic genes, inhibiting adhesion,
interfering with mitochondrial activity, and hindering extracellular
matrix synthesis [99]. Furthermore, 1,8-cineole exhibited anti-biofilm
activity against mature and developing of Candida albicans and
Candida glabrata biofilms, including their clinical isolates [100]. Treat­
ment with 1,8-cineole generated ROS and caused cell cycle arrest at the
G1/S phase in both species and altered the mitochondrial membrane
potential in C. glabrata. Transcriptional analysis revealed differential
gene expression patterns of selected ABC transporters, secreted hydro­
lytic enzymes, and cell wall biogenesis in C. albicans and C. glabrata
when treated with 1,8-cineole [100].
3.3.3. Antiviral properties: inhibition of viral replication and enhancement
of antiviral responses
1,8-cineole has been reported to exhibit antiviral efficacy against a
range of viruses, including herpes simplex virus (HSV)− 1, HSV-2, in­
fectious bronchitis virus (IBV), influenza A virus, and potentially, severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Table 1).
In vitro studies have shown that 1,8-cineole moderately inhibited
HSV-1 replication, with rates close to 40% [103]. An in vivo study
revealed that 1,8-cineole provided significant protection against genital
HSV-2 infection in a mouse model, with a 44% response rate [102].
Furthermore, 1,8-cineole demonstrated antiviral activity against IBV in
vitro [111] and alleviated pathological viral pneumonia changes in mice
inoculated with influenza A virus (H1N1) by decreasing the levels of
inflammatory cytokines (IL-4, IL-5, IL-10, and MCP-1) in nasal lavage
fluids and IL-1β, IL-6, TNF-α, and IFN-γ in lung tissues [104]. It also
restored the expression of proinflammatory NF-kB p65, intercellular
adhesion molecule (ICAM)− 1, and vascular cell adhesion molecule
(VCAM)− 1 in lung tissue after H1N1 virus infection. In silico molecular
docking assays have suggested the potential efficacy of 1,8-cineole
against SARS-CoV-2 Mpro, an enzyme crucial for viral replication [112,
113]. 1,8-cineole showed efficient binding to the active site of Mpro,
forming hydrophobic interactions, and may thus represent a potential
treatment for COVID-19 as an inhibitor of Mpro.
Noteworthy, 1,8-cineole potentiated an antiviral response in human
stem cells by increasing the activity of the antiviral transcription factor,
interferon regulatory factor 3, while reducing the NF-κB proin­
flammatory activity [105]. In mice, 1,8-cineole exhibited synergistic
effects with oseltamivir in the treatment of influenza A [106] and
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Biomedicine & Pharmacotherapy 167 (2023) 115467
provided cross-protection against the virus when co-administered with a
vaccination [114]. The combination increased the production of specific
antibodies (IgG2a), the secretory response of IgA in nasal cavity mucosa,
the expression of intraepithelial lymphocytes, the maturation of den­
dritic cells, and the expression of costimulatory proteins (CD40, CD80,
and CD86) in the peripheral blood [114].
Based on the behavior of similar monoterpenes, it can be inferred
that 1,8-cineole may act directly on viruses, whereas commonly used
antivirals drugs like acyclovir target viral enzymes such as DNA poly­
merase or RNA polymerase, as in the case of remdesivir.
3.4. The role of 1,8-cineole in bronchodilation, mucus reduction, and
airway clearance
Potential therapeutic applications of 1,8-cineole in respiratory dis­
eases are underpinned by its ability to act as a bronchodilator, enhance
mucociliary clearance, and reduce mucus production [115]. Based on a
study using a rat model exposed to cigarette smoke, 1,8-cineole has been
shown to decrease mucus accumulation in the airways and alleviate lung
damage [116]. 1,8-cineole may also protect the lungs from reduced
mucociliary clearance and bacterial infections associated with cigarette
smoking-induced cilia damage [117].
A plethora of studies has revealed that 1,8-cineole exhibits myor­
elaxant effects on isolated tracheal smooth muscle from guinea pigs and
Wistar rats, suggesting its bronchodilatory activity [118–120].
Sagortchev et al. investigated the impact of 1,8-cineole on spontaneous
contractile behavior in guinea pig stomach smooth muscle tissue, sug­
gesting that 1,8-cineole functions as a reversible competitive antagonist
at histamine receptors [121]. Therefore, 1,8-cineole is likely to possess
spasmolytic and secretolytic properties.
An experimental rhinosinusitis model using ex vivo cultured human
nasal slices co-incubated with LPS and 1,8-cineole showed a significant
reduction in mucin-filled goblet cells, supporting the ability of this
monoterpene to control mucus hypersecretion through cytokine inhi­
bition [122]. A similar outcome was observed in OVA-challenged guinea
pigs treated with 1,8-cineole [29].
Further evidence of 1,8-cineole’s potential benefits includes its
ability to decrease MUC5AC protein and mRNA expression in BALF and
lungs exposed to tobacco smoke [116]. Additionally, 1,8-cineole
significantly reduced LPS-induced gene expression of MUC2 and
MUC19 as well as NF-κB activity [122]. This downregulation may be
attributed to the inhibition of the NF-κB signaling pathway, which
regulates MUC5AC, MUC2, and MUC19 expression [48,123].
3.5. 1,8-cineole: a promising analgesic agent targeting TRP channels and
P2X receptors
A number of studies have provided evidence supporting the analgesic
properties of 1,8-cineole. Santos et al. conducted a study revealing the
independent analgesic effects of 1,8-cineole, distinct from opioids [124].
Notably, the analgesic effect of 1,8-cineole remained unaffected by
naloxone, a mu-opioid receptor antagonist.
Furthermore, 1,8-cineole has been found to exhibit analgesic prop­
erties by activating cool temperature-sensing thermosensitive transient
receptor (TRP) cation channels (TRPM8) [125]. The authors also re­
ported that 1,8-cineole inhibits a well-known sensor of painful cold
called the human transient receptor potential cation channel, subfamily
A, member 1 (TRPA1). Interestingly, using patch clamp techniques, it
was observed that 1,8-cineole could activate TRPA1 channels in the
dorsal root ganglia (DRG), resulting in an increase in spontaneous
excitatory postsynaptic currents in substantia gelatinosa neurons [126].
Although the ability of 1,8-cineole to activate TRPM8 is lower compared
to menthol, it effectively inhibited menthol-induced skin irritation
[125], indicating that its inhibitory effects are likely due to the inhibi­
tion of TRPA1 rather than the activation of TRPM8.
Another study investigated the antinociceptive properties of 1,8-
C.C. Hoch et al.
cineole in acute and neuropathic orofacial pain using rodent models
[127]. The results showed that pretreatment with 1,8-cineole signifi­
cantly reduced formalin-induced nociceptive behaviors in all mouse
strains. 1,8-cineole demonstrated antinociceptive effects and its effect
was sensitive to capsazepine, suggesting the involvement of transient
receptor potential vanilloid 1 (TRPV1) receptors. Molecular docking
analysis supported the interaction between 1,8-cineole and TRPV1.
Wang et al. demonstrated that 1,8-cineole treatment reduced the
downregulation of P2X3 receptor expressions in the L4 and L5 DRG of
rats with chronic constriction injury (CCI) [128]. The P2X2 and P2X3
receptors play a role in transmitting information related to pain and
nociception through primary sensory neurons [129]. Additionally,
Zheng et al. showed that oral administration of 1,8-cineole inhibited the
overexpression of P2X2 receptor protein and mRNA in the spinal cord
and dorsal horn of rats with CCI [14].
3.6. Janus face of 1,8-cineole in apoptosis modulation
1,8-cineole has demonstrated potential therapeutic applications
through both anti-apoptotic and pro-apoptotic effects. On the one hand,
1,8-cineole has shown potential for inhibiting apoptosis and promoting
cell survival in various models. For instance, 1,8-cineole decreased the
protein expression of pro-apoptotic markers (Bax, Cyt-c, cleaved
caspase-3, and cleaved caspase-9) while increasing the levels of the anti-
apoptotic protein Bcl-2, resulting in the inhibition of retinal apoptosis in
diabetic eyes [130]. Additionally, 1,8-cineole reduced
isoprenaline-induced apoptosis, by decreasing the Bax/Bcl-2 ratio and
the expression of cleaved caspase-3 in both H9c2 cardiomyocytes and
rat heart tissue [131]. Co-administration of 1,8-cineole and BPA led to a
significant reduction in apoptosis-positive cells, as well as a decrease in
mRNA and protein levels of pro-apoptotic genes (Cyt-c, cleaved
caspase-3, Bax, and p53) stimulated by BPA, while promoting the
expression of the anti-apoptotic gene Bcl-2 [58]. 1,8-cineole also alle­
viated BPA-induced necrotic injury in the bursa of Fabricius (BF) by
modulating RIPK1, RIPK3, FADD, MLKL, and caspase-8 expression [58].
The combined use of 1,8-cineole and BPA activated the PI3K/AKT
signaling pathway, suggesting a potential mechanism for the
anti-apoptotic and anti-necroptotic effects of 1,8-cineole in vitro.
On the other hand, recent studies have demonstrated the pro-
apoptotic properties of 1,8-cineole in cancer cells. 1,8-cineole stimu­
lated apoptosis in A2780 cancer cells, triggering a dose-dependent surge
in pre-G1 events [132]. It also inhibited A549 lung adenocarcinoma cell
migration and, when combined with simvastatin, increased G0/G1 cell
cycle arrest and sensitized cells to apoptosis [15]. 1,8-cineole induced
G0/G1 arrest and senescence in HepG2 cells through oxidative stress
and various signaling pathways such as MAPK, AMPK, and Akt/mTOR
[133]. In HCT116 and RKO human colon cancer cell lines, 1,8-cineole
selectively promoted apoptosis rather than necrosis [134]. This pro­
cess was linked to survivin and Akt inactivation, along with p38 acti­
vation. These molecules triggered subsequent cleavage of PARP and
caspase-3, resulting in apoptosis. Similarly, 1,8-cineole induced
apoptosis and G2/M phase arrest in A431 cells by increasing p53
expression, as well as the expression of apoptotic proteins (Bax/Bcl-2,
Cyt-c, caspase-9, and caspase-3) [135]. Molecular docking simulations
indicated hydrophobic interactions between 1,8-cineole, Bcl-2, and
PARP1 receptors, supporting its pro-apoptotic properties.
The seemingly contradictory findings regarding the anti-apoptotic
and pro-apoptotic effects of 1,8-cineole could stem from the varying
dosages administered to the treated cells. The efficacious concentrations
of 1,8-cineole reported for inhibiting in vitro cancer cell proliferation
range from micromolar [135,136] to millimolar (mM) [133,134,137]
levels. This variable sensitivity can depend not only on the type of cancer
cell but also on the individual cell line assessed. For instance, leukemia
cells are among those most responsive to 1,8-cineole [136]. In a study
where 1,8-cineole was used at millimolar concentrations in vitro, it
exhibited potent antitumor activity in vivo at non-toxic dosages [134].
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Biomedicine & Pharmacotherapy 167 (2023) 115467
Another investigation revealed that 1,8-cineole influenced cell cycle
distribution differently based on concentration [15]. 1,8-cineole trig­
gered a robust G0/G1 arrest along with a considerable decrease of
S-phase cells at both concentrations (4.0–8.0 mM). At 8.0 mM, 1,
8-cineole increased the percentage of cells in the G2/M phase and
slightly decreased the number of G0/G1 cells compared to a lower
concentration of 4.0 mM.
3.7. The effect of 1,8-cineole on platelet reactivity and blood parameters
An investigation has shed light on platelet activation, thrombosis,
and hemostasis, showcasing the potential for 1,8-cineole therapeutic
application [138]. 1,8-cineole demonstrated significant inhibitory ef­
fects on platelet activation incited by glycoprotein VI stimulants such as
collagen and cross-linked collagen-related peptides. However, it
exhibited minimal restraint on thrombin or ADP-induced platelet ag­
gregation. It obstructed both inside-out and outside-in signaling related
to integrin αIIbβ3, along with granule secretion and the intracellular
calcium mobilization in platelets. In mice, it affected thrombus forma­
tion on collagen-coated surfaces under arterial flow conditions but had a
minimal effect on hemostasis. Importantly, up to a concentration of
50 µM, 1,8-cineole did not show toxic effect on platelets. Studies eluci­
dating the molecular mechanisms underlying the inhibitory effects of 1,
8-cineole on platelet function have revealed its influence on signaling
pathways mediated by key molecules such as AKT, Syk, LAT, and cAMP
within platelets. This suggests that 1,8-cineole holds promise as a po­
tential therapeutic agent for modulating excessive platelet reactivity
observed in various pathophysiological conditions.
4. Clinical applications of 1,8-cineole across different diseases
4.1. Respiratory disorders
Similar to other aromatic oils, 1,8-cineole is commonly used to treat
respiratory tract infections due to its ability to increase the ciliary beat
frequency in the mucus membrane and its bronchodilating and anti-
inflammatory properties, as evidenced by preclinical studies. The effi­
cacy of 1,8-cineole (Soledum™ capsules; CNL-1976) has been explored
in clinical trials for a range of respiratory disorders, including acute
rhinosinusitis, COPD, asthma, acute bronchitis, and the common cold. A
detailed overview of the relevant findings from these trials is compiled
in Table 2.
4.1.1. Acute rhinosinusitis
Acute rhinosinusitis arises from viral and bacterial infections, as well
as the accumulation of thick, abnormal mucus and inflammatory sub­
stances that impair the mucociliary transport system [149].
In a prospective, randomized, double-blinded, placebo-controlled
study with 152 patients with acute nonpurulent rhinosinusitis, re­
searchers assessed 1,8-cineole efficacy and safety [139]. Participants
received either 1,8-cineole capsules (3 ×200 mg/day) or placebo cap­
sules for 7 days. The findings indicated that the 1,8-cineole group
experienced a significant reduction in their symptoms-sum-score (SSS)
and improvements in secondary endpoints, including headache, nasal
obstruction, and rhinological secretion.
Another prospective, randomized, double-blinded controlled study
compared the efficacy and safety of 1,8-cineole (3 ×200 mg/day) and a
combination of five components to treat acute viral rhinosinusitis [140].
The study involved 150 patients, 75 in each treatment group, and used a
7-day treatment period to assess the primary endpoint: improving a SSS
including various rhinosinusitis symptoms. The results demonstrated
that the 1,8-cineole group experienced a clinically relevant and statis­
tically significant improvement in the SSS after 4 and 7 days compared
to the control group. Thus, both medications are considered as safe for
treating acute viral rhinosinusitis. However, 1,8-cineole was found to be
more effective than the alternative herbal preparation containing five
C.C. Hoch et al. Biomedicine & Pharmacotherapy 167 (2023) 115467

Table 2
Overview of clinical trials demonstrating beneficial effects of 1,8-cineole (CNL-1976) for the treatment of respiratory disorders. COPD: chronic obstructive pulmonary
disease; VC: vital capacity; Raw: airway resistance; sGaw: specific airways conductance; ITGV: intrathoracic gas volume; t.i.d.: three times a day; FEV1: forced
expiratory volume in the first second; BSS: bronchitis severity scale; N/A: not available; CC: common cold.
Study Study Design Population Intervention Control Main Findings (1,8-Cineole)

Acute nonpurulent Prospective, 152 patients with acute 3 × 200 mg 1,8-cineole Placebo t.i.d. Significant reduction in symptoms-
rhinosinusitis treatment randomized, double- rhinosinusitis per day for 7 days sum-scores and improvements in
with 1,8-cineole[139] blinded, placebo- secondary endpoints (headache,
controlled study nasal obstruction, and rhino-
secretion)
Comparison of 1,8-cineole Prospective, 150 patients with acute viral 3 × 200 mg 1,8-cineole Alternative herbal Significant reduction in symptoms-
and a combination of five randomized, double- rhinosinusitis per day for 7 days preparation with sum-scores and improvements in
different components for blinded controlled five different secondary endpoints (headache,
acute viral rhinosinusitis study components sensitivity of pressure points of
[140] trigeminal nerve, impairment of
general condition, nasal
obstruction, and rhino-secretion)
Comparison of oral therapy Randomized, double- 29 patients with COPD (4 3 × 200 mg 1,8-cineole 3 × 30 mg Significant improvements in lung
with 1,8-cineole and blind, double- excluded due to acute upper per day for 7 days Ambroxol per day function parameters (VC, Raw, and
Ambroxol in patients with dummy, cross-over airway infections, 1 due to for 7 days sGaw) and significant reduction in
COPD[141] trial allergic exanthem under ITGV.
Ambroxol therapy)
1,8-cineole in patients with Double-blind, 242 patients with stable COPD 3 × 200 mg 1,8-cineole Placebo t.i.d. Significant decrease in the
stable COPD as placebo-controlled, per day for six months frequency, duration, and severity
concomitant therapy multi-center study of COPD exacerbations; significant
[142] improvement of lung function,
dyspnea, and quality of life
Anti-inflammatory efficacy Double-blind, 32 patients with steroid- 3 × 200 mg 1,8-cineole Placebo t.i.d. Significant decrease of 36% in daily
of 1,8-cineole in patients placebo-controlled dependent bronchial asthma per day for 12 weeks prednisolone dosage; steroid-like
with severe asthma[7] trial anti-inflammatory properties
1,8-cineole as a concomitant Double-blind, 247 patients with confirmed 3 × 200 mg 1,8-cineole Placebo t.i.d. Significant improvement in lung
therapy for asthma placebo-controlled, asthma per day for six months function and significant reduction
patients[143] multi-center study in dyspnea as evidenced by primary
endpoints (FEV1, asthma
symptoms, and quality of life)
1,8-cineole as add-on to Open-label, 132 patients diagnosed with 3 × 200 mg 1,8-cineole Antiviral Significant reduction in BSS and
antiviral treatment for randomized, acute bronchitis or acute on top of antiviral treatment alone cough frequency after 4 days
acute bronchitis or acute parallel-group phase tracheobronchitis treatment (Ingavirin® (Ingavirin 90 mg
tracheobronchitis[144] III trial 90 mg once daily) for 4–9 once daily) for 4–9
days days
Effects of 1,8-cineole Double-blind, 242 acute bronchitis patients 3 × 200 mg 1,8-cineole Placebo t.i.d. Significant reduction in BSS and
treatment on acute placebo-controlled, per day for 10 days frequency of cough fits after 4 days
bronchitis patients[145] multi-center study
Effects of 1,8-cineole Multi-center, non- 336 children (Group A: 3 × 100 mg 1,8-cineole N/A Significant reduction in BSS;
treatment in children and interventional study n = 178; 2–7 years; Group B: per day for 7–9 days compliance rated as very good and
toddlers with acute n = 158; 8–11 years) with good in both groups; tolerability
bronchitis[146] acute bronchitis rated as very good and good
Effects of 1,8-cineole Non-interventional 893 patients aged 4–90 years 3 × 100 mg 1,8-cineole N/A Reduction in BSS and improvement
treatment in patients with study old, diagnosed with acute per day for children under in primary symptom cough within
acute bronchitis[147] bronchitis 10 years; 3 × 200 mg 1,8- 3–4 days; well-tolerated
cineole for individuals
aged 10 and above
Impact of 1,8-cineole Phase IV, 522 adults (18–70 years) with 3 × 200 mg 1,8-cineole N/A Earliest treatment initiation
treatment timing on CC exploratory, open- at least 1 CC during previous per day for up to 15 days resulted in lower burden of disease,
progress[148] label, non- winter, 329 subsequently faster decline in symptoms and
randomized, multi- developed a CC significantly higher and faster
center trial recovering quality of life

different components. observed. Whether preoperatively administered 1,8-cineole can reduce

4.1.2. Chronic rhinosinusitis
Chronic rhinosinusitis (CRS) refers to a prolonged inflammatory
condition of the sinus and nasal mucosa, characterized by symptoms
persisting for more than 12 weeks [150]. It is estimated that approxi­
mately a quarter to a third of CRS patients develop nasal polyps [151].
Generally, medical practitioners manage these symptoms using a treat­
ment plan that combines steroids, nasal washes, and antibiotics when
the presence of purulence is confirmed [152,153].
In CRS, 1,8-cineole has not been established as a routine treatment,
yet recent data revealed a highly sensitive detection of 1,8-cineole in
nasal polyps from CRSwNP patients after 14 days of oral 1,8-cineole
administration prior to surgical treatment [10]. No significant correla­
tion between the measured 1,8-cineole concentrations and the body­
weight or body mass index values of the examined patients was
inflammation and thus ease sinus surgery must be evaluated in future
studies.
Experimental observations demonstrated that 1,8-cineole effectively
impedes biofilm formation in CRS patients, establishing a correlation
between the inhibition of growth in both planktonic and sessile forms of
E. coli and M. catarrhalis [94]. Interestingly, the bacterium S. aureus
exhibited elevated sensitivity to 1,8-cineole, with a level of suscepti­
bility that cannot be attributed solely to straightforward inhibition of
bacterial growth. Further exploration into the effects of 1,8-cineole on
major components of the S. aureus biofilm formation pathways revealed
a substantial inhibitory impact on the transcription of AgrA, SarA, and
σB genes. This novel approach to treating bacterial biofilm infections
may have utility beyond CRS, extending to a variety of biofilm-related
infectious diseases [154].

8
C.C. Hoch et al.
4.1.3. COPD
COPD patients frequently experience exertional breathlessness due
to bronchoconstriction, excessive mucus production, airway wall
edema, and loss of terminal airway attachments. Established pharma­
cotherapy options include bronchodilators and glucocorticosteroids
[155].
In a randomized, double-blind, double-dummy, cross-over trial
involving 29 COPD patients, researchers compared the effects of one-
week oral therapy with 1,8-cineole (3 ×200 mg/day) and Ambroxol
(3 ×30 mg/day) on lung function [141]. Both 1,8-cineole and Ambroxol
demonstrated significant improvements in lung function parameters
such as vital capacity, airway resistance, and specific airway conduc­
tance from day 1 to day 7. Forced expiratory volume in the first second
(FEV1) also improved, but without significance. Only 1,8-cineole
significantly reduced intrathoracic gas volume compared to Ambroxol.
Peak flow and the symptom score for dyspnea at rest improved under 1,
8-cineole therapy. However, the difference failed to reach statistical
significance compared to Ambroxol due to the small number of patients.
Thus, these findings suggest that 1,8-cineole may have an additional
bronchodilator effect. Additionally, the data are in accordance with a
previous controlled investigation, in which Ambroxol and 1,8-cineole
were shown to improve FEV1 and forced vital capacity in COPD pa­
tients versus placebo [156].
Worth et al. conducted a placebo-controlled, double-blind trial with
242 moderate/severe COPD patients who were either smokers or former
smokers already receiving standard therapy [142]. The study investi­
gated the effects of 1,8-cineole treatment (3 ×200 mg/day) for 6 months
on this population and found a significant decrease in the frequency,
duration, and severity of COPD exacerbations in the 1,8-cineole group
compared to the control. Although improvements in secondary outcome
measures, including lung function, breathlessness, and quality of life
were noted, these changes did not reach statistical significance.
4.1.4. Asthma
Asthma is characterized by an inflammation that leads to bronchial
hyperresponsiveness and reversible airway obstruction. Current treat­
ment guidelines for managing asthma and reducing airway inflamma­
tion recommend inhaled corticosteroids regularly [157].
A double-blind, placebo-controlled study evaluated the effects of
prednisolone reduction on 32 asthmatic patients who received either
3 × 200 mg/day of 1,8-cineole or a placebo for 12 weeks [7]. The results
demonstrated a significant decrease of 36% in prednisolone medication
usage within the treatment group. Noteworthy, the dyspnea score was
significantly higher in the placebo group. This trial provides compelling
evidence that 1,8-cineole exhibits anti-inflammatory properties com­
parable to those of steroids.
The same dosage of 1,8-cineole for 6 months was analyzed as
adjunctive therapy in a more recent multicenter, placebo-controlled,
double-blind study involving 247 asthmatic patients already on medi­
cation [143]. As indicated by primary endpoints such as FEV1, asthma
symptoms, and quality of life, the treatment group showed a significant
improvement in lung function compared to the placebo group.
4.1.5. Acute bronchitis
Acute bronchitis is commonly associated with common cold, with its
primary symptom being a dry or productive cough, which is frequently
caused by viral infections [158]. Interestingly, an open-label, random­
ized, parallel-group phase III clinical trial showed that supplementing 1,
8-cineole to antiviral treatment significantly decreased the frequency of
cough and other acute bronchitis symptoms compared to antiviral
medication alone [144].
In a placebo-controlled clinical trial with 242 acute bronchitis pa­
tients, researchers assessed the impact of administering 3 × 200 mg/day
of 1,8-cineole for ten days on the bronchitis severity scale (BSS) [145].
The 1,8-cineole-treated group substantially decreased BSS compared to
the placebo group on day 4. 1,8-cineole was particularly effective at
9
Biomedicine & Pharmacotherapy 167 (2023) 115467
reducing cough frequency.
A multi-center, non-interventional study evaluated the compliance,
tolerability, and clinical progress of 336 children with acute bronchitis
during 7–9 days of therapy with 3 × 100 mg/day of 1,8-cineole [146].
In the course of the treatment period, the BSS decreased significantly
from an initial value of 8.61–5.09 at 4 days and to 1.38 at 7–9 days.
Remarkably, 79% of patients reported being symptom-free at the end of
therapy, and 1,8-cineole therapy was rated as well-tolerated and
acceptable.
In another non-interventional study, a cohort of 893 patients aged
4–90 years old, all diagnosed with acute bronchitis, underwent an 8-day
treatment course with 1,8-cineole [147]. Children under 10 years
received a dosage of 3 × 100 mg/day of 1,8-cineole, while individuals
aged 10 and above, including adults, were prescribed 3 × 200 mg/day
of 1,8-cineole. Significant improvements were observed, with the initial
BSS decreasing from 7.7 to 1.4 after treatment completion. The primary
cough symptom showed a 95.6% improvement rate, and treatment was
well tolerated. Notably, 81.4% of participants experienced distinct relief
from their symptoms within 3–4 days.
Acute bronchitis is a transient respiratory disorder that typically
resolves within 14 days [158]. Achieving accelerated symptom
improvement by day 3 is crucial for any intervention during a common
cold. 1,8-cineole exhibited faster symptom relief, although the natural
course of the condition suggests no significant divergence beyond the
14-day timeframe [145].
4.2. Neurological disorders
Considering its lipophilic nature, 1,8-cineole has the ability to tra­
verse the blood-brain barrier [159]. This unique characteristic has
caused growing enthusiasm to investigate the impact of 1,8-cineole on
different neurological disorders (Fig. 3).
4.2.1. Alzheimer’s disease
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder
characterized by cognitive decline and memory loss. Currently, the U.S.
Food and Drug Administration has approved five medications for man­
aging AD symptoms, including cholinesterase inhibitors, an NMDA re­
ceptor antagonist, and an anti-amyloid monoclonal antibody [160]. AD
research primarily focuses on studying the formation, aggregation, and
functional aspects of amyloid-beta (Aβ).
The administration of 1,8-cineole in rat PC12 cells (pheochromocy­
toma cells) demonstrated effective mitigation of the Aβ induced cyto­
toxicity and oxidative stress [161]. Additionally, 1,8-cineole exhibited
the ability to inhibit Aβ42 oligomerization in vitro and protect against
iron-induced cell death in human neuroblastoma cells [162].
In recent years, a mounting body of evidence points toward the
impact of advanced glycation end products (AGEs) on natural aging and
neurodegenerative disorders such as AD [163]. Research suggests that
AGEs can contribute to oxidative stress, tau hyperphosphorylation, and
Aβ production [13]. Importantly, 1,8-cineole has shown the ability to
modulate tau phosphorylation by suppressing GSK-3β activity and to
reduce Aβ production by inhibiting beta-site amyloid precursor protein
cleaving enzyme-1 (BACE-1), both in vitro and in vivo [13].
Considering that oxidative damage, Aβ aggregation, and a decline in
cell viability (iron-induced) are indicative of the onset of AD pathology,
these findings strongly support the hypothesis of a potential therapeutic
role of 1,8-cineole in AD, particularly in cases associated with diabetes
mellitus (DM).
4.2.2. Anxiety and depression
Anxiety and depression are widespread mental disorders that affect a
substantial number of adults globally. These conditions present
numerous challenges, as the existing therapeutics used to treat these
conditions are associated with various limitations and drawbacks,
leading to low response rates [164].
C.C. Hoch et al.
Fig. 3. Neurological disorders mediated by 1,8-cineole (Figure created using BioRender, Toronto, ON, Canada).
A recent study aimed to explore the anxiolytic properties of 1,8-
cineole through two established behavioral models used to screen
anxiolytic drugs in mice: the light-dark box test and the marble-burying
test [165]. The study also investigated the potential involvement of the
GABAergic transmission system in 1,8-cineole’s anxiolytic effects by
administering flumazenil (FLU), an antagonist to the GABAergic trans­
mission system. As compared to the tests conducted with 1,8-cineole
alone, the combined treatment with FLU resulted in a significant
decrease in the total number of square lines crossed and the number of
entries in the lit box. The results imply that FLU exhibits an antagonistic
impact on the anxiolytic effects of 1,8-cineole and are consistent with
prior studies that suggest the involvement of the GABAergic trans­
mission system in the mechanisms underlying the anxiolytic properties
of 1,8-cineole [166]. Correspondingly, a study by Kim et al. identified
the effectiveness of inhaled 1,8-cineole in reducing preoperative anxiety
in humans [167].
Substances that decrease immobility time are commonly associated
with antidepressant properties in humans. In the forced swimming test
(FST), 1,8-cineole administration led to a significant reduction in the
immobility time of mice compared to the control group [165]. Addi­
tionally, 1,8-cineole exhibited greater antidepressant effects than
fluoxetine. However, when 1,8-cineole was administered intraperito­
neally, no significant antidepressant activity was observed [166].
Consistent with the FST results, 1,8-cineole significantly reduced
immobility times in mice compared to the control group in the tail
suspension test.
4.2.3. Epilepsy and acute seizure
An estimated portion of 20–30% of epilepsy patients suffer from
seizures unresponsive to available antiepileptic drugs [168].
A study investigating 1,8-cineole’s effects on acute seizures was
conducted using rats [169]. Brain activity was analyzed using wavelet
and fractal analysis before and after 1,8-cineole administration. The
analysis revealed that the delta frequency band dominated brain activ­
ity. Other frequency bands decreased during the ictal stage and
10
Biomedicine & Pharmacotherapy 167 (2023) 115467
increased during the inter-ictal stage. 1,8-cineole’s effects were
dose-dependent, with higher concentrations increasing relative wavelet
energy in the delta frequency band. However, the mean fractal dimen­
sion, which indicates system complexity, exhibited only marginal
changes.
Similarly, another study exploring the effects of 1,8-cineole on the
activity of central neurons in land snails reported excitatory and
epileptogenic properties [170]. The findings indicated that 1,8-cineole
depolarized the membrane potential, increased spontaneous neuronal
activity, and suppressed after-hyperpolarization. It also reduced the
action potential amplitude and slope. The study revealed that 1,
8-cineole inhibited potassium channels involved in repolarization and
after-hyperpolarization. Additionally, 1,8-cineole increased the fre­
quency of driven action potentials while inhibiting calcium-activated
potassium channels. At higher concentrations, 1,8-cineole induced
burst firing and paroxysmal depolarization shifts in neuronal activity.
These effects were independent of sodium currents or protein kinase A
and C phosphorylation, in contrast to calcium currents, which played a
crucial role.
4.3. Gastrointestinal disorders
4.3.1. Peptic ulcer disease
Peptic ulcer refers to damage caused by acid to the lining of the
digestive tract, extending into the submucosa. These ulcers are typically
found in the stomach or the upper part of the small intestine, known as
the proximal duodenum [171].
Experiments conducted with Wistar rats revealed that 1,8-cineole
effectively prevented gastric lesions induced by ethanol, ethanol/HCl,
and indomethacin. This suggests that the antiulcer activity of 1,8-cineole
may involve the production of prostaglandins and/or mucus [172].
Similar results have been reported in previous studies by Santos et al.
that 1,8-cineole significantly attenuates ethanol-induced gastric injury
in a manner similar to a known lipoxygenase inhibitor known as nor­
dihydroguaiaretic acid [173]. 1,8-cineole reduced basal acid secretion
C.C. Hoch et al.
volume without affecting stimulated acid secretion, implying a potential
lack of antisecretory activity [172]. Additionally, 1,8-cineole increased
mucus levels, protected against –SH groups depletion, reduced LP, and
inhibited MPO activity, thus preventing neutrophil infiltration in the
gastric mucosa [172]. In a chronic ulcer model, 1,8-cineole decreased
gastric area lesions, promoted regeneration and restoration of mucus
levels in glandular cells, and stimulated cell proliferation, as indicated
by reactivity to PCNA, Ki-67, and BrdU [172].
4.3.2. Diarrhea
Even though mortality rates have improved, diarrhea remains a
major cause of death in children under 5, accounting for approximately
15% of all death cases [174]. This translates into nearly 1.4 million
deaths in children annually in developing countries. Prolonged diarrhea
episodes can also lead to malnutrition, rendering it a crucial factor in
developing nutritional deficiencies.
In a study conducted by Jalilzadeh-Amin et al., 1,8-cineole was
shown to inhibit various parameters associated with diarrhea, including
the condition, such as the frequency and severity of diarrhea, the total
number of stools, and the weight of wet stools, although these effects did
not reach statistical significance [175]. Interestingly, the inhibitory ef­
fects of 1,8-cineole were lower than those of loperamide and atropine,
commonly used as standard antidiarrheal drugs. Studies on enter­
opooling, which measures intestinal contents volume, showed that 1,
8-cineole pretreatment reduced intraluminal contents [175]. These ef­
fects, resulting from reduced secretion into the intestine, suggest that 1,
8-cineole may enhance electrolyte reabsorption, demonstrating the in­
hibition of excessive secretion or increased absorption of other intestinal
contents. Additionally, 1,8-cineole decreased normal intestinal propul­
sive movement and transit in rats. These findings are consistent with
observations by Magalhães et al., who noted delayed gastric emptying
and affected liquid transit after intravenous administration of 1,
8-cineole in rats [176]. The delay in intestinal motility caused by 1,
8-cineole may contribute to increased water absorption from feces,
reducing watery feces consistency.
Experimental data suggest that 1,8-cineole exerts its inhibitory effect
on gastrointestinal hypermotility primarily through its anticholinergic
properties [175]. This implies that 1,8-cineole acts by blocking or
reducing the activity of cholinergic receptors in the gastrointestinal
tract, resulting in a reduction in smooth muscle contractions and
motility.
4.4. Cardiac hypertrophy-related heart disorders
Pulmonary Arterial Hypertension (PAH) is a rare and life-threatening
pulmonary vascular disorder, affecting approximately 15–50 cases per
million people [177]. Cardiac hypertrophy is characterized by car­
diomyocyte enlargement, increased protein synthesis, and sarcomere
reorganization [178]. This process can become maladaptive due to
metabolic dysfunction, increased stiffness, dilatation, and fibrosis, ulti­
mately leading to heart failure [179].
Recent studies have demonstrated the hypotensive effects of 1,8-
cineole in normotensive rats and its ability to cause vasodilation in
isolated aortic rings constricted with phenylephrine [180,181].
Alves-Silva et al. developed an in vitro model to mimic the afterload
experienced by the right ventricle (RV) during PAH progression [182].
They investigated the potential of 1,8-cineole to counteract cell hyper­
trophy in H9c2 cells and neonatal rat ventricular cardiomyocytes
exposed to high pressure. The results showed that 1,8-cineole effectively
reversed cell hypertrophy by reducing cell surface area, sarcomere
thickness, and hypertrophic gene expression. Moreover, 1,8-cineole
reversed RV hypertrophy and fibrosis, improving cardiac function as
observed through microscopy and echocardiography analysis. These
findings are consistent with a study by Wang et al., in which 1,8-cineole
enhanced cell viability, inhibited cardiac hypertrophy, attenuated car­
diac remodeling, improved cardiac function, and decreased the
11
Biomedicine & Pharmacotherapy 167 (2023) 115467
concentrations of atrial natriuretic peptide and brain natriuretic peptide
in rat hearts [131].
Of note, 1,8-cineole treatment restored gap junction protein Cx43
levels and distribution back to the intercalated disks [182]. This resto­
ration may improve anisotropic conduction, potentially enhancing RV
function. Additionally, 1,8-cineole restored SERCA2a and ryanodine
receptor 2, proteins involved in calcium regulation, which have been
linked to RV hypertrophy in PAH [183]. 1,8-cineole was also found to
inhibit the activation of dynamin-related protein 1 and promote mito­
chondrial fusion by increasing MFN2. Furthermore, 1,8-cineole partially
restored mitochondrial transcription factor A levels, suggesting a po­
tential role in mitochondrial biogenesis. Although 1,8-cineole decreased
oxygen consumption rates, it increased the expression of most assessed
electron transport chain subunits, except for NADH dehydrogenase
(ubiquinone) 1 beta subcomplex subunit 8.
4.5. Diabetes mellitus
DM encompasses a range of metabolic disorders characterized by
elevated blood glucose levels resulting from insulin resistance, inade­
quate insulin production, or excessive glucagon secretion [184].
Emerging research has elucidated potential advantages of 1,8-cineole in
the management of renal dysfunction, glycemic control, and dyslipide­
mia in diabetic animal models.
1,8-cineole has demonstrated its capacity to attenuate markers of
renal dysfunction in diabetic rats and ameliorate renal impairment in
both rat models of diabetic nephropathy and db/db mice by modulating
transforming growth factor beta-1 (TGF-β1) [185,186]. Additionally, 1,
8-cineole showed encouraging potential in hindering podocyte barrier
dysfunction and consequent proteinuria in db/db mice [187]. In studies
conducted on diabetic rats, 1,8-cineole has shown promising potential in
ameliorating hyperglycemia and improving insulin sensitivity [185].
These effects are likely due to the compound’s ability to enhance the
functionality of pancreatic β-cells. Recent reports have underscored the
capability of 1,8-cineole to diminish blood glucose levels in db/db mice
by activating glyoxalase 1 and mitigating various glycated products
[185,186]. Moreover, 1,8-cineole has exhibited lipid-lowering effects,
substantiated by investigations employing zebrafish atherosclerosis
models [188]. Collectively, these findings point to the promise to apply
1,8-cineole as a therapeutic intervention for addressing the multifarious
facets of diabetic complications.
5. Future directions and concluding remarks
1,8-cineole has been recognized for its health benefits, which have
been appreciated since ancient times and continue to be relevant today.
1,8-cineole exhibits a wide range of biological effects, including anti-
inflammatory, antioxidant, antibacterial, antiviral, mucolytic/secreto­
lytic, bronchodilatory, analgesic, pro-apoptotic, and numerous other
activities crucial for health-promoting properties. Clinical trials on pa­
tients with COPD, asthma, bronchitis, and rhinosinusitis support these
positive effects. By modulating key signaling pathways such as NF-κB,
MAPK, PPAR-γ, and Nrf2/Keap1, 1,8-cineole demonstrates potent anti-
inflammatory and antioxidative properties. Additionally, it targets
important effector molecules entities like the MUC gene family, caspases
(specifically caspase-3, − 8 and − 9), p53, ROS, p38, P2X receptors, and
TRP channels, further enhancing its therapeutic potential.
The potential of 1,8-cineole as an effective anticancer agent has been
substantiated by its effects on tumor angiogenesis, invasion, and
metastasis [189]. These effects can be attributed to the significant
downregulation of crucial factors including TGF-β1, Fascin-1, vascular
endothelial growth factors, matrix metalloproteinase-9, and the
epithelial-mesenchymal transition (EMT) marker vimentin. Notably,
EMT regulation relies on the Wnt/β-catenin pathway, which 1,8-cineole
has been shown to inhibit, underscoring its potential to impede the
acquisition of invasive and metastatic properties by tumors [65,190].
C.C. Hoch et al.
While limited research has explored the antiparasitic effects of 1,
8-cineole, a recent study has demonstrated promising results, high­
lighting its potential as an antimalarial agent capable of impacting the
parasite erythrocytic cycle and mitigating severe disease [191]. How­
ever, it is important to note that these findings exceed the scope of this
review article and warrant further investigation in future research.
Straddling the rich history of traditional medicine and the ad­
vancements of contemporary science, 1,8-cineole stands poised to
address modern challenges. Its versatility is evident in its ability to
combat conditions like multi-drug resistance, COVID-19, cancer, dia­
betes, Alzheimer’s disease, hypertension, and heart failure. In a world
grappling with complex diseases, 1,8-cineole does not simply present as
an alternative, but as an innovative solution, hinting at the dawn of more
tailored and effective treatments.
Despite the promising applications of 1,8-cineole, the clinical
translation is still in its early stages and faces several complications and
limitations. While considered as safe and well-tolerated at normal
therapeutic doses, excessive use and overdosage of 1,8-cineole through
oral ingestion, inhalation, or skin application can be hazardous, lead to
potential acute toxicity, including inflammatory gastrointestinal condi­
tions and rare symptoms like nausea, vomiting, and diarrhea [18,107].
To fully harness the previous research knowledge, an integrated
approach is necessary. This approach should aim to understand the exact
mechanisms underlying the pharmacological activities and safety as­
pects of 1,8-cineole, develop safe and effective formulations, enhance
clinical understanding, and consider economic and production aspects.
Additionally, exploring combination therapies to enhance the 1,
8-cineole activity in conjunction with other available agents holds
promise for improved clinical outcomes.
In summary, this review article has not only provided a compre­
hensive understanding of the properties and therapeutic potential of 1,8-
cineole in the realm of health sciences but has also shed light on the
potential benefits it might offer to patients dealing with a variety of
diseases. This valuable contribution paves the way for further explora­
tion and utilization of 1,8-cineole as an approach to diverse medical
conditions.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Cosima C. Hoch: Conceptualization, Investigation, Writing – orig­
inal draft preparation, Visualization. Julie Petry: Writing – review &
editing, Visualization. Lena Griesbaum: Writing – review & editing,
Visualization. Tobias Weiser: Writing – review & editing, Investigation.
Kathrin Werner: Writing – review & editing. Michael Ploch: Writing –
review & editing. Admar Verschoor: Writing – review & editing.
Gabriele Multhoff: Investigation, Writing – review & editing. Ali
Bashiri Dezfouli: Investigation, Writing – review & editing. Barbara
Wollenberg: Conceptualization, Writing – review & editing,
Supervision.
Declaration of Competing Interest
Michael Ploch is employed by Cassella-med GmbH & Co. KG, located
at Gereonsmühlengasse 1, 50670 Cologne, Germany. He provided
guidance during the writing process, but was not involved in the design,
exploration, or graphical representation of this review article. As such,
any potential conflict of interest does not affect the objectivity of this
review article. The other authors—Cosima C. Hoch, Julie Petry, Lena
Griesbaum, Tobias Weiser, Kathrin Werner, Admar Verschoor, Gabriele
Multhoff, Ali Bashiri Dezfouli, and Barbara Wollenberg—assert that this
research was carried out without any conflicts of interest influencing
12
Biomedicine & Pharmacotherapy 167 (2023) 115467
their work.
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