Cloves are the aromatic flower buds of a tree in the family Myrtaceae, Syzygium aromaticum. They are native to the Maluku Islands in Indonesia and are commonly used as a spice. Their flavor, medicinal properties and high value sparked off the Dutch-Portuguese war from 1602 to 1654. The main bioactive compound called eugenol has been found to have antioxidant, anti-inflammatory , immuno-modulatory, anticancer and organ protective properties .

1. SPICE AS MEDICINE:
CLOVE
A VERSATILE SPICE
By
Kevin KF Ng, MD, PhD.
Former Associate Professor of Medicine
Division of Clinical Pharmacology
University of Miami, Miami, FL., USA
Email: kevinng68@gmail.com
A Slide Presentation for HealthCare Providers May 2023

2. Outline of Lecture
▪ History
▪ Scientific classification
▪ Nutrient composition
▪ Bioactive compounds
▪ Pharmacology of eugenol
▪ Pharmacokinetics
▪ Bioavailability
▪ Side effects, toxicity
▪ Commercial products
▪ Summary

3. HISTORY

4. What is a Clove?
▪ Cloves are the aromatic flower buds of a tree in the
family Myrtaceae, Syzygium aromaticum.
▪ They are native to the Maluku Islands in Indonesia
and are commonly used as a spice.
▪ The name comes from the Latin word clavus, which
means nail since the shape of a dried clove
resembles that of a nail

5. Difference between whole cloves and garlic cloves?
These are cloves, they have a sweet, spicy taste.
These are garlic cloves. They have a buttery savory taste.
https://www.quora.com/What-is-the-difference-between-whole-cloves-and-garlic-cloves

6. Silk-Spice Trade Routes, 100-1500 CE
https://www.pinterest.com/pin/513340057498258660/?autologin=true

7. 1602 – 1654: The Dutch–Portuguese War
▪ 1602 – 1654: Dutch East India Company and the Dutch West
India Company against the Portuguese Empire.
▪ Pepper, cinnamon, cloves and nutmeg, drove nations to sail
across vast oceans searching for new routes to the spice-rich
Orient
▪ In the Middle Ages, Europeans lacked refrigeration leading to
food spoiling quickly. Spices helped mask the flavor of not-
so-fresh food.
▪ After Vasco de Gama discovered the sea route to
India Portuguese ships monopolized the spice
trade. Portugal grew rich on the trade between Asia and
Europe .
http://benedante.blogspot.com/2021/08/the-dutch-portuguese-war-1602-1661.html

8. The major clove producers of the world (2021)
https://scienceagri.com/9-biggest-clove-producing-countries-in-the-world/

9. • SCIENTIFIC CLASSIFICATION
• SCIENTIFIC PUBLICATIONS

10. Scientific classification of clove
https://en.wikipedia.org/wiki/Clove

11. Number of publications “clove” in PubMed
from 1854 to 2022
https://pubmed.ncbi.nlm.nih.gov/?term=clove

12. • ANATOMY
• NUTRIENT COMPOSITION
• BIOACTIVE COMPOUNDS
• CLOVE OIL

13. Anatomy and histology of a clove flower bud
https://www.youtube.com/watch?v=asXIwiXLGYA

14. Chemical Composition of Clove

15. Nutrient composition of ground cloves per 100 grams
https://ndb.nal.usda.gov/ndb/foods/show/02025?fgcd=&manu=&format=&count=&max=25&offset
=&sort=default&order=asc&qlookup=GROUND+NUTMEG%2C+UPC%3A+016291441323&ds=&qt=&
qp=&qa=&qn=&q=&ing=

16. Bioactive compounds in Clove (dried flower buds)
▪ Eugenol (up to 90%),
▪ Acetyl eugenol,
▪ Beta-caryophyllene and vanillin;
▪ Crategolic acid;
▪ Tannins,
▪ Gallotannic acid,
▪ Methyl salicylate,
▪ Flavonoids: eugenin, kaempferol, rhamnetin, and eugenitin;
▪ Triterpenoids: oleanolic acid, stigmasterol and campesterol;
▪ Several sesquiterpenes.
https://www.gaiaherbs.com/products/ingredient/485/Clove

17. chemical composition of clove leaf oil? (2012)
▪ Clove oil is a mixture of different compounds, with the
three main active ingredients being
▪ Eugenol
▪ eugenyl acetate
▪ caryophyllene.
▪ Jirovetz et al. (2006) found 23 main constituents:
▪ eugenol (76.8 %)
▪ β-caryophyllene (17.4 %)
▪ α-humulene (2.1 %)
▪ eugenyl acetate (1.2 %)
https://www.sciencedirect.com › topics › clove-oil

18. Major bioactive compounds in Clove Oil
International Journal of Research in Ayurveda & Pharmacy, 2(1), Jan-Feb 2011 47-54

19. Characteristics of clove oil derived from buds, stem and leaf
of Indonesian origin (2012)
https://www.sciencedirect.com/topics/agricultural-and-
biological-sciences/clove-oil

20. • FLAVOR
• PHARMACOLOGICAL EFFECTS
• PRECLINICAL STUDIES
• PHARMACOKINETICS

21. Flavor of clove
▪ The flavors of Cloves are strong,
pungent, sweet--almost hot.
▪ They are one of the most penetrating of
all spices and their bitter, astringent
flavor leaves a numbing sensation in the
mouth.

22. What are the aromatic compounds in clove ?
▪ The primary aromatic compound found in cloves is
eugenol, which is responsible for the characteristic
spicy and sweet aroma.
▪ In addition to eugenol, cloves contain other aromatic
compounds, including:
▪ Acetyl eugenol: It is a derivative of eugenol, contributing to the
overall aroma and flavor of cloves.
▪ Caryophyllene: This compound has a woody and spicy aroma
and is responsible for the unique flavor of cloves.
▪ Beta-caryophyllene: Another member of the caryophyllene
family, this compound adds a peppery note to the aroma of
cloves.
▪ Methyl eugenol: It is a methylated form of eugenol and
contributes to the overall fragrance of cloves.
.

23. Physicochemical properties of cloves
https://www.mccormickscienceinstitute.com/resources/culinary-spices/herbs-
spices/cloves_old#:~:text=The%20flavor%20of%20Cloves%20are,numbing%20sen
sation%20in%20the%20mouth.

24. Reported pharmacological properties of eugenol
▪ Antifungal
▪ Antimicrobial.
▪ Antiviral
▪ Antioxidant.
▪ Antinociceptive
▪ TRPV1, TRPA1
▪ Anti-inflammatory
▪ COX-2, 5-LOX, TNF-α, TNF-β, NF-kB, IFN-‫ץ‬
▪ Immuno-modulatory
▪ Anti-cancer
▪ Antispasmodic
▪ Antiplatelet aggregation
▪ Local anesthetic
No clinical studies on the above pharmacological properties have been reported
Preclinical studies:

25. Cumulative minimum inhibitory concentration (MIC), minimum bactericidal concentration
(MBC) and minimum biofilm eradication concentration (MBEC) of eugenol against
Staphylococcus aureus expressed as a percentage of tested strains (2015)
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119564#pone-0119564-g001
antimicrobial

26. Effects of i.p. administration of clove oil and indomethacin (10 mg/kg)
on mouse paw edema 3 h after injection of carrageenan (2015)
http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.841.3085&rep=rep1&type=pdf
Anti-inflammation

27. Effect of clove oil on the number of writhing induced by
acetic acid injection in mice (2015)
http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.841.3085&rep=rep1&type=pdf
analgesic

28. Eugenol as the inhibitors of human platelet aggregation and
thromboxane biosynthesis. (2009)
https://www.ncbi.nlm.nih.gov/pubmed/19501497
platelet

29. Eugenol dilates mesenteric arteries and reduces systemic BP
by activating endothelial cell TRPV4 channels (2015)
https://pubmed.ncbi.nlm.nih.gov/25832173/#:~:text=Eugenol%20dilates%20mesent
eric%20arteries%20and,activating%20endothelial%20cell%20TRPV4%20channels
BP

30. Eugenol ameliorates insulin resistance, oxidative stress and inflammation
in high fat-diet/streptozotocin-induced diabetic rat (2019)
https://www.sciencedirect.com/science/article/abs/pii/S0024320518307483
Diabetes

31. Effect of eugenol on serum lipid profle expressed in mg/dL(A–D),
atherogenic index (E) and body weight (F) of rats (2019)
https://link.springer.com/content/pdf/10.1038/s41598-019-50352-4.pdf
Lipids

32. Mechanism of analgesia by eugenol
1.Activation of TRPV1 Receptors
2.Inhibition of Prostaglandin Synthesis.
3.Blockade of Voltage-Gated Sodium Channels
4.Modulation of Neurotransmitter Receptors
5.NMDA Receptor Antagonism
6.Local Anesthetic Effects

33. Effects of eugenol and beta-caryophyllene on
neuropeptides (SP, CGRP) and ion channels (TRVPV1, TRPA1)
1. Substance P (SP):
1. Eugenol: Eugenol has been shown to inhibit the release of SP in various experimental models. It can reduce SP levels by
modulating the activity of enzymes involved in its synthesis or by inhibiting the release of SP from nerve terminals.
2. Beta-caryophyllene: There is limited research specifically examining the effects of beta-caryophyllene on SP. Further studies are
needed to fully understand its impact on SP levels.
2. Calcitonin Gene-Related Peptide (CGRP):
1. Eugenol: Eugenol has demonstrated the ability to inhibit the release of CGRP. It exerts its effects by reducing the activity of
enzymes involved in CGRP synthesis or by modulating the release of CGRP from neurons.
2. Beta-caryophyllene: Similar to SP, there is limited research specifically focused on beta-caryophyllene's effects on CGRP. Further
investigation is required to determine its influence on CGRP levels.
3. Transient Receptor Potential Vanilloid 1 (TRPV1):
1. Eugenol: Eugenol can activate and desensitize TRPV1 channels. It acts as a partial agonist, meaning it can both activate and
inhibit the channels depending on the concentration and context.
2. Beta-caryophyllene: Beta-caryophyllene has been shown to possess TRPV1 antagonist properties. It can inhibit the activation of
TRPV1 channels by other agonists.
4. Transient Receptor Potential Ankyrin 1 (TRPA1):
1. Eugenol: Eugenol can activate TRPA1 channels. It acts as an agonist, leading to the opening of the channels and subsequent
neuronal excitation.
2. Beta-caryophyllene: Beta-caryophyllene has been found to have both agonistic and antagonistic effects on TRPA1 channels,
depending on the concentration and context.

34. Pharmacokinetics of eugenol
▪ Absorption: Eugenol can be absorbed through different routes, including oral ingestion, inhalation,
and topical application. When taken orally, it is readily absorbed from the gastrointestinal tract.
Inhalation allows for direct absorption into the bloodstream through the lungs, while topical
application allows for absorption through the skin.
▪ Distribution: Once absorbed, eugenol is distributed throughout the body via the bloodstream. It
can cross the blood-brain barrier and placenta, reaching various tissues and organs. Eugenol has a
moderate volume of distribution, indicating that it can distribute widely in the body.
▪ Metabolism: The primary site of metabolism for eugenol is the liver. It undergoes phase I and phase
II metabolism. In phase I metabolism, eugenol is primarily metabolized by cytochrome P450
enzymes, particularly CYP2A6, CYP2B6, and CYP2E1, to form various metabolites, including 4-
hydroxy-3-methoxybenzaldehyde (vanillin), 4-hydroxy-3-methoxyphenylacetic acid, and 4-hydroxy-
3-methoxymandelic acid. In phase II metabolism, these metabolites are further conjugated with
glucuronic acid, sulfate, or glycine, facilitating their elimination from the body.
▪ Elimination: The elimination of eugenol and its metabolites primarily occurs through urine and
feces. The glucuronide and sulfate conjugates of eugenol metabolites are excreted via urine, while
the unchanged eugenol and some metabolites are eliminated through feces.
▪ In a pharmacokinetic study, average half-life values of eugenol in plasma and blood were long (14.0
and 18.3 h, respectively), suggesting a potential accumulation of the drug following repeated
administrations

35. • SIDE EFFECTS
• TOXICITY

36. Side effects of clove oil (2010)
▪ Clove oil is considered safe in small quantities
(< 1,500 ppm) as a food additive.
▪ However, clove oil is toxic to human cells.
▪ If ingested in sufficient quantity or injected, it
has been shown to cause life-threatening
complications, including
▪ Acute Respiratory Distress Syndrome,
▪ Fulminant Hepatic (Liver) Failure, and
▪ Central Nervous System Depression;
▪ the lethal oral dose is 3.75 g per kg body weight
https://www.marinwater.org/DocumentCenter/View/253/Herbicide-Risk-
Assessment-Chapter-6-Clove-Oil-January-1-2010?bidId=

37. The median (i.p.) LD50 of clove oil was
161.9 mg/kg with a 95% Cl of 106.9-244.9 mg/kg
http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.841.3085&rep=rep1&type=pdf

38. Near fatal ingestion of oil of cloves in a 2 yr old boy (1993)
▪ A case of ingestion of oil of cloves is presented, which resulted in coma, fits, a
coagulopathy, and acute liver damage.
▪ This is not unlike the syndrome produced in the late stages of a substantial
paracetamol overdose, and a similar treatment regimen is proposed. (Arch Dis
Child 1993; 69: 392-393)
https://adc.bmj.com/content/archdischild/69/3/392.full.pdf

39. • COMMON USES
• COMMERCIAL PRODUCTS
• DELICIOUS CUISINE

40. Common uses for cloves:
▪ Flavoring agents
▪ Traditional medicine
▪ Aromatherapy
▪ Cosmetic and personal care products
▪ Oral health
▪ Digestive aid
▪ Insect repellant

41. Commercially available clove products

42. Examples of some delicious clover cuisines

43. Summary
▪ Cloves are the aromatic flower buds of a tree in the family
Myrtaceae, Syzygium aromaticum.
▪ Its demand for flavor and medicinal usage led to the Dutch-
Portuguese war from 1602-1654.
▪ The flower buds and leaves yield 80% of essential oil wch contain
three main active ingredients: eugenol, eugenyl acetate and
caryophyllene.
▪ Clinica studies are rare, and most of the scientific studies were
done with eugenol.
▪ Eugenol has been shown to have diverse pharmacological effects
ranging from local anesthesia to antioxidant, anti-inflammatory,
immuno-modulatory, anticancer, antihypertensive,
antihyperglycemia, antihyperlipidemic and anti-platlet aggregation
effects.
▪ Cloves and clove oil are now widely used as flavor enhancer,
traditional medicine, aromatherapy, cosmetic and personal care,
larvicide and insect repellants.