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Citation: Dludla, P.V.; Cirilli, I.;
Marcheggiani, F.; Silvestri, S.;
Orlando, P.; Muvhulawa, N.;
Moetlediwa, M.T.; Nkambule, B.B.;
Mazibuko-Mbeje, S.E.; Hlengwa, N.;
et al. Bioactive Properties,
Bioavailability Profiles, and Clinical
Evidence of the Potential Benefits of
Black Pepper (Piper nigrum) and Red
Pepper (Capsicum annum) against
Diverse Metabolic Complications.
Molecules 2023,28, 6569. https://
doi.org/10.3390/molecules28186569
Academic Editor: George Grant
Received: 23 July 2023
Revised: 29 August 2023
Accepted: 7 September 2023
Published: 11 September 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
molecules
Review
Bioactive Properties, Bioavailability Profiles, and Clinical
Evidence of the Potential Benefits of Black Pepper
(Piper nigrum) and Red Pepper (Capsicum annum) against
Diverse Metabolic Complications
Phiwayinkosi V. Dludla 1,2 ,* , Ilenia Cirilli 3, Fabio Marcheggiani 3, Sonia Silvestri 3, Patrick Orlando 3,
Ndivhuwo Muvhulawa 1,4 , Marakiya T. Moetlediwa 4, Bongani B. Nkambule 5, Sithandiwe
E. Mazibuko-Mbeje 4, Nokulunga Hlengwa 2, Sidney Hanser 6, Duduzile Ndwandwe 1,
Jeanine L. Marnewick 7, Albertus K. Basson 2and Luca Tiano 3
1Cochrane South Africa, South African Medical Research Council, Tygerberg 7505, South Africa;
mn.muvhulawa@gmail.com (N.M.); duduzile.ndwandwe@mrc.ac.za (D.N.)
2Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa;
hlengwan@unizulu.ac.za (N.H.); bassona@unizulu.ac.za (A.K.B.)
3Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy;
ilenia.cirilli@unicam.it (I.C.); f.marcheggiani@univpm.it (F.M.); s.silvestri@univpm.it (S.S.);
p.orlando@univpm.it (P.O.); l.tiano@staff.univpm.it (L.T.)
4Department of Biochemistry, North-West University, Mafikeng Campus, Mmabatho 2735, South Africa;
mtdmoetlediwa@gmail.com (M.T.M.); sithandiwe.mazibukombeje@nwu.ac.za (S.E.M.-M.)
5School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal,
Durban 4000, South Africa; nkambuleb@ukzn.ac.za
6Department of Physiology and Environmental Health, University of Limpopo, Sovenga 0727, South Africa;
sidney.hanser@ul.ac.za
7Applied Microbial and Health Biotechnology Institute, Cape Peninsula University of Technology,
Bellville 7535, South Africa; marnewickj@cput.ac.za
*Correspondence: pdludla@mrc.ac.za; Tel.: +27-021-938-0333
Abstract:
The consumption of food-derived products, including the regular intake of pepper, is
increasingly evaluated for its potential benefits in protecting against diverse metabolic complications.
The current study made use of prominent electronic databases including PubMed, Google Scholar,
and Scopus to retrieve clinical evidence linking the intake of black and red pepper with the ame-
lioration of metabolic complications. The findings summarize evidence supporting the beneficial
effects of black pepper (Piper nigrum L.), including its active ingredient, piperine, in improving
blood lipid profiles, including reducing circulating levels of total cholesterol, low-density lipoprotein
cholesterol, and triglycerides in overweight and obese individuals. The intake of piperine was also
linked with enhanced antioxidant and anti-inflammatory properties by increasing serum levels of
superoxide dismutase while reducing those of malonaldehyde and C-reactive protein in individuals
with metabolic syndrome. Evidence summarized in the current review also indicates that red pepper
(Capsicum annum), together with its active ingredient, capsaicin, could promote energy expenditure,
including limiting energy intake, which is likely to contribute to reduced fat mass in overweight
and obese individuals. Emerging clinical evidence also indicates that pepper may be beneficial in
alleviating complications linked with other chronic conditions, including osteoarthritis, oropharyn-
geal dysphagia, digestion, hemodialysis, and neuromuscular fatigue. Notably, the beneficial effects
of pepper or its active ingredients appear to be more pronounced when used in combination with
other bioactive compounds. The current review also covers essential information on the metabolism
and bioavailability profiles of both pepper species and their main active ingredients, which are all
necessary to understand their potential beneficial effects against metabolic diseases.
Keywords:
metabolic disease; oxidative stress; inflammation; pepper; piperine; capsaicin; capsinoid
Molecules 2023,28, 6569. https://doi.org/10.3390/molecules28186569 https://www.mdpi.com/journal/molecules
Molecules 2023,28, 6569 2 of 24
1. Introduction
Metabolic syndrome describes a cluster of metabolic complications, including insulin
resistance, hypertension, and hyperlipidemia, that increase the risk for the development of
cardiovascular diseases [
1
,
2
]. Cardiovascular diseases remain the leading cause of death
worldwide [
3
], especially in people with metabolic disorders [
4
]. Recent numbers indicate
that a growing number of individuals present with a cluster of metabolic disorders such as
hyperglycemia and dyslipidemia that are also linked with the development and progression
of type 2 diabetes [
5
]. This emphasizes an urgent need for multisectoral interventions to
decrease the global burden of metabolic syndrome and associated complications, especially
those involving overweight and obesity (Figure 1). Indeed, the consumption of a high-
calorie diet, in combination with reduced physical activity or a sedentary lifestyle, is known
to be the major cause of obesity that accelerates the development of metabolic syndrome [
6
].
An obese state is accompanied by excessive adiposity and enhanced ectopic accumulation,
which is associated with increased levels of oxidative stress and inflammation [
7
]. Both
oxidative stress and inflammation are considered prominent pathological mechanisms that
alter biochemical processes and cause cellular damage within many metabolic diseases [
8
,
9
].
Molecules2023,28,xFORPEERREVIEW2of24
Keywords:metabolicdisease;oxidativestress;inflammation;pepper;piperine;capsaicin;
capsinoid
1.Introduction
Metabolicsyndromedescribesaclusterofmetaboliccomplications,includinginsulin
resistance,hypertension,andhyperlipidemia,thatincreasetheriskforthedevelopment
ofcardiovasculardiseases[1,2].Cardiovasculardiseasesremaintheleadingcauseofdeath
worldwide[3],especiallyinpeoplewithmetabolicdisorders[4].Recentnumbersindicate
thatagrowingnumberofindividualspresentwithaclusterofmetabolicdisorderssuch
ashyperglycemiaanddyslipidemiathatarealsolinkedwiththedevelopmentandpro-
gressionoftype2diabetes[5].Thisemphasizesanurgentneedformultisectoralinterven-
tionstodecreasetheglobalburdenofmetabolicsyndromeandassociatedcomplications,
especiallythoseinvolvingoverweightandobesity(Figure1).Indeed,theconsumptionof
ahigh-caloriediet,incombinationwithreducedphysicalactivityorasedentarylifestyle,
isknowntobethemajorcauseofobesitythatacceleratesthedevelopmentofmetabolic
syndrome[6].Anobesestateisaccompaniedbyexcessiveadiposityandenhancedectopic
accumulation,whichisassociatedwithincreasedlevelsofoxidativestressandinflamma-
tion[7].Bothoxidativestressandinflammationareconsideredprominentpathological
mechanismsthatalterbiochemicalprocessesandcausecellulardamagewithinmanymet-
abolicdiseases[8,9].
Figure1.Ageneraloverviewofmetabolicsyndrome,representingsomeofthediversepathological
conditionsassociatedwiththisabnormalmetabolicstate,includingdiabeticneuropathy,type2di-
abetes,non-alcoholicfayliverdisease,skeletalmuscledysfunction,andincreasedriskofheart
failure.
Therehasbeenanincreasinginterestinevaluatingthetherapeuticpotentialofdie-
tarysources,includingfoodsrichinantioxidants,fortheirameliorativeeffectsagainst
oxidativestressandinflammationindiversemetabolicconditions.Infact,ourgroupand
othershaveprogressivelyreportedonthepotentialbenefitsofplant-and/orfood-derived
bioactivecompoundsfortheircapacitytoimprovemetabolicstatusbyblockingthetoxic
effectsofoxidativestressandinflammation[10–14].Agrowingbodyofliteraturehasalso
progressivelyreportedonthepotentialbenefitsofpepperagainstdiversemetabolic
Figure 1.
A general overview of metabolic syndrome, representing some of the diverse pathological
conditions associated with this abnormal metabolic state, including diabetic neuropathy, type 2
diabetes, non-alcoholic fatty liver disease, skeletal muscle dysfunction, and increased risk of heart
failure.
There has been an increasing interest in evaluating the therapeutic potential of dietary
sources, including foods rich in antioxidants, for their ameliorative effects against oxidative
stress and inflammation in diverse metabolic conditions. In fact, our group and others have
progressively reported on the potential benefits of plant- and/or food-derived bioactive
compounds for their capacity to improve metabolic status by blocking the toxic effects of ox-
idative stress and inflammation [
10
–
14
]. A growing body of literature has also progressively
reported on the potential benefits of pepper against diverse metabolic complications [
15
–
18
].
Piper, the genus of pepper plants or pepper vines, is contemplated to be part of the most
ancient pan-tropical flowering plant groups [
19
]. With an estimated 1000 species of herbs,
encompassing small trees, shrubs, and hanging vines, the genus Piper is considered to
have a rich ethnobotanical and ethnopharmaceutical history [
20
]. The reviewed literature
already indicates the potential therapeutic effects of pepper; however, it predominantly
focuses on preclinical findings [
15
–
18
]. In particular, reviewed information shows that
Molecules 2023,28, 6569 3 of 24
black and red pepper, including their respective main bioactive compounds piperine and
capsaicin, display a variety of biological effects, including antimicrobial, anti-inflammatory,
gastro-protective, antidepressant, and antioxidant properties, in preclinical models [
16
,
17
].
Azlan and colleagues also recently reviewed evidence of the antioxidant and anti-obesity
effects of different chili peppers [
18
]. However, a gap remains in the evidence on the
clinical benefits of pepper against metabolic diseases. Importantly, there are no reviews that
have compared the therapeutic effects of both black pepper (Piper nigrum) and red pepper
(Capsicum annum) against metabolic diseases. This highlights the importance of the current
review, which critically discusses clinical evidence of the potential benefits of both black
and red peppers against diverse metabolic complications. The current review also covers
essential information on the biological properties, metabolism, and bioavailability profiles,
as well as the toxic effects, of pepper types and their main active ingredients, which are all
necessary to underscore its potential pharmacological relevance.
2. General Overview of Black Pepper (Piper nigrum), including Its Metabolism and
Bioavailability Profile
The genus Piperaceae, of the pepper family, contains flowering plants including small
trees, shrubs, or herbs. This class consists of about 3600 species and five genera, including
Piper,Peperomia,Zippelia,Manekia, and Verhuellia. Most of the species are found in the
Piper genera, with about 2171 species, and Peperomia, with over 1000 species [
21
]. The
most popular species of the Piperaceae family is Piper nigrum, which produces peppercorns
that are generally used as spices, including black pepper, which is considered the king
of spices [
22
]. Another well-known species of the Piperaceae is Piper longum, which yields
black, white, and green peppercorns [
23
]. It is believed that the Piper genus is endogenous
to India [
24
], being broadly cultivated within the Karala region [
25
]. Black pepper contains
a major bioactive pungent alkaloid commonly known as piperine, which is found in the
fruits of Piper longum and Piper nigrum [
23
]. Piperine content within black pepper is
estimated to range from 2–10% [
26
–
31
]. Piperine was first extracted around the 1800s, while
its chemical composition was elucidated much later, around 1882–1894 [
32
]. Since then,
research has extensively studied black and its constituent piperine, with the description
of different isomers of the bioactive compound currently acknowledged, including the
trans–trans isomer (piperine), cis–trans isomer (isopiperine), cis–cis isomer (chavicine),
and trans–cis isomer (isochevicine) (Figure 2). Other alkaloids that have been identified
in black pepper include piperanine, piperettine, piperolein, piperylin, and pipericine [
22
].
Reviewed information already indicates that other bioactive compounds can be found in
the African Piper species [
33
]. Like other natural compounds that are widely ingested orally,
piperine gets broken down within the body into small components or metabolites.
Molecules2023,28,xFORPEERREVIEW4of24
Figure2.Thechemicalstructureofpiperine,includingitsisomersisopiperine,chavivine,and
isochavicine;adaptedfrompublishedliterature[34].
Evidencefromanimalstudiesshowsthatoraladministrationof170mgofpiperine
yieldsapproximately3–4%oftheoriginalingestedbioactivecompounds,whichisde-
tectedmainlyinfecesafter4or5daysinrats,whileabout96–97%isprojectedtobeab-
sorbed[35,36].Ingestedpiperineisnormallyabsorbedwithinthesmallintestinesofrats
[35].When170mgofthebioactivecompoundisgiventorats,about38.8µmolofpiperine
isdetectedintheserum,whilesomeofthetraceelementsofthecompoundarefoundin
theliverandkidneys[36].Althoughsomestudiescouldnotdetectthepresenceofpiper-
ineinurineorserum[35–38],othershavereportedpiperinemetabolitesincludingpiper-
onylicacid,piperonylalcohol,piperonal,andtheirconjugatesintheurineofrats[39].
Piperine,whenconjugatedwithiron,caninhibittheactivityofCYP4503A4[40],anes-
sentialenzymeinvolvedindrugmetabolismanddetoxicationprocesseswithintheliver
[41].Additionalevidenceindicatesthattwelvemetabolitesofpiperinecanbedetectedin
ratplasma,bile,feces,andurine[42].Apparently,piperinecanundergoaseriesofchem-
icalmodificationsthroughtheenzymesresponsiblefortheliverfirst-passmetaboliceffect
[43].Studiessupporteffectiveabsorptionofpiperineinrats,especiallyafteraninitialoral
doseof20mgisgiven[44].Othershavealsoaffirmedeffectiveabsorptionofpiperine
throughenhancedlevelsinthebrainandplasmaofratsaftertheingestionofadoseof35
mg[45].Themetabolismof50mgofpiperineinhumanstranslatestoabout0.71–0.83mg
ofthebioactivecompoundbeingdetectedwithintheplasma[46].Importantly,piperine
metabolites,including5-(3-4-dihydroxphenyl)valericacidpiperidideanditsderivative5-
(3-4-dihydroxphenyl)valericacid-4-hydroxypiperidide,havebeendetectedintheurineof
humans[47].
Likewithothernaturalcompounds,thedeliveryofpiperineissupposedlycompro-
misedbyitslowwatersolubility,whichcouldleadtopoorclinicalapplications[48].How-
ever,researchhasevaluatedthepotentialuseofdeliverysystemslikenanoparticles,
nanoliposomes,andmicellesamongadvancestoimprovethebioavailabilityofnatural
bioactiveandfoodcompounds[49].Forexample,theencapsulationofpiperineinana-
noparticleofsodiumchitosantriphosphatecouldimproveitsabsorption,leadingtoen-
hancedbiologicalactivity[50].Acombinationofpiperineandcurcuminshowsimproved
efficacycomparedtothatofeachbioactivecompoundalone[51].Othershaveindicated
thattheuseofmixedmicellesofD-alphatocopherolpolyethyleneglycolsuccinateand
solupluscouldimprovetheefficacyofencapsulatedpiperineoverthatoffreepiperine
[52].Cubic-nanoparticle-encapsulatedpiperineandprotopanaxadiolalsoshowimproved
bioavailability[53].Suchstudiesindicatethatpiperineisreleasedatamuchfasterrate
withininvivosystems,whilealsopromotingincreasedabsorption.Anotherinteresting
formulationisananoliposomewithpiperineandgentamicin,asinvestigatedinbacterial
growth[54].Ithasbeenfoundthatthisliposomalcombinationwaseffectiveininducing
deathandbacterialinhibition.Lastly,otherresearchershaveusedsolidlipidnanoparti-
clesencapsulatingpiperinetotesttheameliorativeeffectofpiperineagainstthecompli-
cationsofAlzheimer’sdisease[55].Interestingly,itwasfoundthatthisnano-formulation
Figure 2.
The chemical structure of piperine, including its isomers isopiperine, chavivine, and
isochavicine; adapted from published literature [34].
Molecules 2023,28, 6569 4 of 24
Evidence from animal studies shows that oral administration of 170 mg of piper-
ine yields approximately 3–4% of the original ingested bioactive compounds, which is
detected mainly in feces after 4 or 5 days in rats, while about 96–97% is projected to be
absorbed [
35
,
36
]. Ingested piperine is normally absorbed within the small intestines of
rats [
35
]. When 170 mg of the bioactive compound is given to rats, about 38.8
µ
mol of
piperine is detected in the serum, while some of the trace elements of the compound are
found in the liver and kidneys [
36
]. Although some studies could not detect the presence
of piperine in urine or serum [
35
–
38
], others have reported piperine metabolites includ-
ing piperonylic acid, piperonyl alcohol, piperonal, and their conjugates in the urine of
rats [
39
]. Piperine, when conjugated with iron, can inhibit the activity of CYP450 3A4 [
40
],
an essential enzyme involved in drug metabolism and detoxication processes within the
liver [
41
]. Additional evidence indicates that twelve metabolites of piperine can be detected
in rat plasma, bile, feces, and urine [
42
]. Apparently, piperine can undergo a series of
chemical modifications through the enzymes responsible for the liver first-pass metabolic
effect [
43
]. Studies support effective absorption of piperine in rats, especially after an
initial oral dose of 20 mg is given [
44
]. Others have also affirmed effective absorption of
piperine through enhanced levels in the brain and plasma of rats after the ingestion of a
dose of
35 mg [45]
. The metabolism of 50 mg of piperine in humans translates to about
0.71–0.83 mg
of the bioactive compound being detected within the plasma [
46
]. Impor-
tantly, piperine metabolites, including 5-(3-4-dihydroxphenyl) valeric acid piperidide and
its derivative 5-(3-4-dihydroxphenyl)valeric acid-4-hydroxypiperidide, have been detected
in the urine of humans [47].
Like with other natural compounds, the delivery of piperine is supposedly com-
promised by its low water solubility, which could lead to poor clinical applications [
48
].
However, research has evaluated the potential use of delivery systems like nanoparticles,
nanoliposomes, and micelles among advances to improve the bioavailability of natural
bioactive and food compounds [
49
]. For example, the encapsulation of piperine in a
nanoparticle of sodium chitosan triphosphate could improve its absorption, leading to
enhanced biological activity [
50
]. A combination of piperine and curcumin shows im-
proved efficacy compared to that of each bioactive compound alone [
51
]. Others have
indicated that the use of mixed micelles of D-alpha tocopherol polyethylene glycol succi-
nate and soluplus could improve the efficacy of encapsulated piperine over that of free
piperine [
52
]. Cubic-nanoparticle-encapsulated piperine and protopanaxadiol also show im-
proved bioavailability [
53
]. Such studies indicate that piperine is released at a much faster
rate within
in vivo
systems, while also promoting increased absorption. Another interesting
formulation is a nanoliposome with piperine and gentamicin, as investigated in bacterial
growth [
54
]. It has been found that this liposomal combination was effective in inducing
death and bacterial inhibition. Lastly, other researchers have used solid lipid nanoparticles
encapsulating piperine to test the ameliorative effect of piperine against the complications
of Alzheimer’s disease [
55
]. Interestingly, it was found that this nano-formulation could
reduce the levels of superoxide dismutase (SOD) as well as oxidative stress at a dose of
2 mg/kg
[
55
]. This further indicates that the bioavailability profile or bioactivity of piperine
can be enhanced through recent developments in drug discovery, especially when used in
combination with other bioactive compounds or food products [56,57].
3. Red Pepper (Capsicum annum), including Its Metabolism and Bioavailability Profile
Red pepper belongs to the Solanaceae family of the genus Capsicum, consisting of five
domesticated species such as C. annuum L., C. chinense Jacq., C. frutescens L., C. baccatum
L., and C. pubescens Ruiz et Pav [
58
,
59
]. It appears the capsicum species were first discov-
ered in Bolivia, with their cultivation expanding to Mexico prior to the Columbian times
(
7000 B.C.
) [
60
]. The capsicum genus is known by different names including hot pepper,
chili pepper, bell pepper, sweet pepper, and sometimes just pepper across the world. Red
pepper consists of different secondary metabolites collectively called capsaicinoids [
61
].
Capsaicinoids include capsaicin (8-methyl-N-vanillyl-6-nonenamide) and homologs of
Molecules 2023,28, 6569 5 of 24
capsaicin with acid amides of vanillyl amine, as well as 8–to–18 carbon fatty acids. Other
capsaicinoids that exist in pungent red pepper apart from capsaicin include the 6,7-dihydro
analog of capsaicin, called dihydrocapsaicin, and nordihydrocapsaicin, which contains the
mono-nor homolog of the acyl residue of dihydrocapsaicin [62].
Figure 3shows some homo-capsaicinoids, including homocapsaicin, homodihydro-
capsaicin and N-vanillyl nanoamide [
63
]. However, capsaicin, a major bioactive capsai-
cinoid that occurs as a colorless and odorless hydrophobic compound and is crystalline
to waxy [
64
], is mainly responsible for the burning sensation of the fruit when orally in-
gested [
65
]. It has been reported that capsaicin and dihydrocapsaicin make up about 70–90%
of the capsaicinoids within the Capsicum genus [
66
,
67
]. Studies have also discovered other
capsaicinoid-like residues that are structurally related to capsaicin but of the non-pungent
cultivar of Capsicum annuum L. [
68
]. The other structures of these capsaicinoid-like residues
have been identified and denoted as capsiate, dihydrocapsiate, and nordihydrocapsiate,
with the chemical nomenclature 4-hydroxy-3-methoxybenzyl [E]-8-methyl-6-nonenoate,
4-hydroxy-3-methoxybenzyl 8-methyloctanoate, and 4-hydroxy-3-methoxybenzyl, respec-
tively [
68
,
69
]. Structurally, these capsinoids differ from capsaicin by their two moieties
that are linked by an ester bond rather than an amine bond [
70
], and they are called capsi-
noids [
69
]. Studies on the pungent components of capsicum with different names such as
capsicol, capsaicin, and capsaicin began as early as the 1800s [71]. This is almost the same
time when capsaicin was extracted from Capsicum [
72
], and its chemical composition was
then characterized by the 1900s [73].
Molecules2023,28,xFORPEERREVIEW5of24
couldreducethelevelsofsuperoxidedismutase(SOD)aswellasoxidativestressatadose
of2mg/kg[55].Thisfurtherindicatesthatthebioavailabilityprofileorbioactivityofpip-
erinecanbeenhancedthroughrecentdevelopmentsindrugdiscovery,especiallywhen
usedincombinationwithotherbioactivecompoundsorfoodproducts[56,57].
3.RedPepper(Capsicum annum),includingItsMetabolismandBioavailabilityProfile
RedpepperbelongstotheSolanaceaefamilyofthegenusCapsicum,consistingoffive
domesticatedspeciessuchasC.annuumL.,C.chinenseJacq.,C.frutescensL.,C.baccatum
L.,andC.pubescensRuizetPav[58,59].Itappearsthecapsicumspecieswerefirstdiscov-
eredinBolivia,withtheircultivationexpandingtoMexicopriortotheColumbiantimes
(7000B.C.)[60].Thecapsicumgenusisknownbydifferentnamesincludinghotpepper,
chilipepper,bellpepper,sweetpepper,andsometimesjustpepperacrosstheworld.Red
pepperconsistsofdifferentsecondarymetabolitescollectivelycalledcapsaicinoids[61].
Capsaicinoidsincludecapsaicin(8-methyl-N-vanillyl-6-nonenamide)andhomologsof
capsaicinwithacidamidesofvanillylamine,aswellas8–to–18carbonfayacids.Other
capsaicinoidsthatexistinpungentredpepperapartfromcapsaicinincludethe6,7-dihy-
droanalogofcapsaicin,calleddihydrocapsaicin,andnordihydrocapsaicin,whichcon-
tainsthemono-norhomologoftheacylresidueofdihydrocapsaicin[62].
Figure3showssomehomo-capsaicinoids,includinghomocapsaicin,homodihydro-
capsaicinandN-vanillylnanoamide[63].However,capsaicin,amajorbioactivecapsai-
cinoidthatoccursasacolorlessandodorlesshydrophobiccompoundandiscrystallineto
waxy[64],ismainlyresponsiblefortheburningsensationofthefruitwhenorallyingested
[65].Ithasbeenreportedthatcapsaicinanddihydrocapsaicinmakeupabout70–90%of
thecapsaicinoidswithintheCapsicumgenus[66,67].Studieshavealsodiscoveredother
capsaicinoid-likeresiduesthatarestructurallyrelatedtocapsaicinbutofthenon-pungent
cultivarofCapsicumannuumL.[68].Theotherstructuresofthesecapsaicinoid-likeresi-
dueshavebeenidentifiedanddenotedascapsiate,dihydrocapsiate,andnordihydrocap-
siate,withthechemicalnomenclature4-hydroxy-3-methoxybenzyl[E]-8-methyl-6-non-
enoate,4-hydroxy-3-methoxybenzyl8-methyloctanoate,and4-hydroxy-3-methoxyben-
zyl,respectively[68,69].Structurally,thesecapsinoidsdifferfromcapsaicinbytheirtwo
moietiesthatarelinkedbyanesterbondratherthananaminebond[70],andtheyare
calledcapsinoids[69].Studiesonthepungentcomponentsofcapsicumwithdifferent
namessuchascapsicol,capsaicin,andcapsaicinbeganasearlyasthe1800s[71].Thisis
almostthesametimewhencapsaicinwasextractedfromCapsicum[72],anditschemical
compositionwasthencharacterizedbythe1900s[73].
Figure3.Thechemicalstructureofcapsaicinoids,includingcapsaicin,homocapsaicin,homodihy-
drocapsaicinandN-vanillylnanoamide.Informationadaptedfrompreviousliterature[63,74].
Figure 3.
The chemical structure of capsaicinoids, including capsaicin, homocapsaicin, homodihydro-
capsaicin and N-vanillyl nanoamide. Information adapted from previous literature [63,74].
Just like piperine, capsaicin also undergoes liver first-pass metabolism upon oral
administration [
75
]. Evidence indicates that capsaicin can undergo hepatic metabolism,
leading to the generation of metabolites like hydroxycapsaicin and dihydrocapsaicin [
76
].
Apparently, five metabolites of capsaicin have been detected in the human liver, with
hydroxycapsaicin, hydroxycapsaicin, and dehydrocapsaicin being the most abundant [
77
].
Accordingly, the most abundant metabolites in the liver fractions of rats included vanilly-
lamine, hydroxycapsaicin, and dehydrocapsaicin [
77
]. This finding indicates that capsaicin
is metabolized at a higher rate within the liver of rodents. Others have indicated the dis-
tribution of capsaicin in different organs of rats, showing that this bioactive compound is
abundantly found in the spinal cord and the brain when compared to levels in the liver after
intravenous administration [
75
]. It has also been indicated that reduced levels of capsaicin
within the liver may be due to the detoxification process, which produces tolerable con-
jugates with glucuronic acid or sulfuric acid [
75
]. This hypothesis has been confirmed by
others showing that hydrocapsaicin and other metabolites are found in the urine and feces
Molecules 2023,28, 6569 6 of 24
of rats [71]. It appears that hydrocapsaicin is mainly hydrolyzed by the liver to yield fatty
acids and vanillylamine, which are later reduced to vanillin and lastly vanillic acid and/or
vanillyl alcohol. Dicapsaicin is another identified metabolite of capsaicin within the liver of
rats [
78
]. Apparently, the P450 enzymes can metabolize capsaicin to produce free-radical in-
termediates. Other studies have also reported the involvement of a monooxidase system in
livers treated with capsaicinoids. For instance, it was previously reported that capsaicinoids
were converted to N-(4,5,dihydroxy-3-methoxybenzy1) acylamides in rat livers through a
mixed-function monooxidase system promoted by hexobarbital injection [
71
].
In vitro
, it
was shown that N-(4,5,dihydroxy-3-methoxybenzy1) acylamide was the only metabolite
detected in the incubation medium containing rat liver homogenate and capsaicin [71].
In terms of bioavailability, intestinal absorption of capsaicin in rats and hamsters
in vitro
has been reported [
79
]. From these results, it was evident that hamsters had better
capsaicin intestinal absorption than rats [
71
]. Capsaicinoids are absorbed better in the
stomach than in the small intestine
in vivo
, while
in vitro
evidence through intestinal sacs
also supports enhanced intestinal absorption of capsaicin [
79
]. Capsaicin can also be better
absorbed by the jejunum and ileum than by the stomach in rats [
80
]. The absorption of
capsaicin in the lungs appears to be 20–40-fold slower than that in the liver microsomes of
both rats and humans [
76
]. However, the capsaicin metabolites observed in human lung
microsomes were similar to those in liver microsomes. Notably, the metabolic profile of red
pepper and capsaicin has been poorly investigated in clinical subjects.
With a rapid advancement in science, nanotechnology has been employed as a poten-
tial delivery system to enhance the bioavailability of capsaicin. In this context, polymeric
nanocapsules have been used to improve the efficacy of capsaicin [
81
]. Such data has
verified that capsaicin is insoluble in water; thus, the introduction of a high-water emulsion
reduces its loading efficacy. Solid-lipidic nanoparticles and nanostructured lipid carriers
have also been investigated as transdermal transporters of capsaicin. It has been reported
that this delivery emulsion exhibits enhanced transdermal permeability and retention in
mice skin [
82
]. Like most of the formulations, the nano-vascular ethosomal formulation
was found to improve permeability in ex vivo human skin and improved the anti-arthritic
form of capsaicin [
83
,
84
]. Also, there has been interest in exploring the use of nanofibers as
a capsaicinoid transdermal delivery strategy. A nanofiber was loaded 0.5–2% of capsaicin
extract, and it was demonstrated that the release of this bioactive compound and its perme-
ability in snakeskin were high [
85
]. Lastly, researchers attempted to encapsulate capsaicin
in nanoparticles and incorporate chitosan hydrogel to improve its permeability through the
skin [
86
]. This study compiled as many of the formulation strategies for capsaicin delivery
systems as possible. Ongoing research continues to cover the different formulations that
can be used to enhance the absorption of capsaicin [63].
4. Traditional Uses and Proposed Pharmacological Properties of Pepper and Its
Bioactive Compounds
Black pepper and piperine have been acknowledged to have beneficial effects on
human health. Starting with preclinical evidence, it has been shown that the administration
of piperine at a dose of 50 mg/kg could improve the digestive system while reducing
oxidative stress and inflammation in mice [
87
]. In diverse experimental models of chronic
diseases, it was shown that piperine can reduce complications of arthritis [
88
], hepatic
steatosis [
89
,
90
], and type 2 diabetes or obesity [
91
]. It was disclosed that piperine can also
reduce depression in mice when given at doses of 2.5, 5, or 10 mg/kg for 14 days [
92
,
93
].
Reviewed information has also covered the beneficial effects of black pepper and piperine in
various experimental models of disease [
94
,
95
]. The molecular mechanisms and signaling
pathways that are associated with the ameliorative effects of piperine against the toxic
effects of oxidative stress have been discussed, and these include the activation of nuclear
factor erythroid 2-related factor 2, peroxisome proliferator-activated receptor-gamma,
cyclooxygenase-2, and nitric oxide synthases-2, which is essential to promote intracellular
antioxidant responses [
96
,
97
]. This bioactive compound can also block inflammation
Molecules 2023,28, 6569 7 of 24
and improve cellular function by effectively modulating or inhibiting multiple signaling
pathways, such as those of protein-kinase-activated NLR family pyrin domain containing-3
inflammasome, nuclear factor-
κ
B, Jun N-terminal kinase/p38 mitogen-activated protein
kinase, and pro-inflammatory molecules [96,98].
On the other hand, red pepper has been used traditionally to relieve toothache. Other
traditional uses of red pepper include its application as a home remedy to heal lung
conditions like bronchitis, lower glucose levels in diabetes, stabilize blood pressure, and
relieve burning feet [
99
,
100
]. Scientific evidence indicates that red pepper can improve
blood circulation and gastric abnormalities [
101
] while ameliorating neuralgia and rheuma-
tism [
102
,
103
]. Capsaicin and its derivatives are effective against abdominal pain, bloat-
ing [
104
], and pain [
105
–
107
], as well as alleviating other complications that underlie
diabetes and overweight [
108
]. In addition, it has been shown that capsaicin alone has
anti-inflammatory [
109
] and antioxidant [
110
–
112
] properties. Other reviews have also
given a general perspective into the diverse biological activities of capsaicin, especially
in relation to the alleviation of metabolic-disease-related complications [
16
,
63
]. It appears
that the secondary metabolites of red pepper are equally important in improving human
health [
113
]. In terms of molecular insights, Caterina and colleagues [
114
] were fundamen-
tal in discovering the role of capsaicin as an analgesic agent. Their findings affirmed that
capsaicin receptor is a non-selective cation channel that is structurally linked to members of
the TRP family of ion channels. The latter encodes integral membrane proteins that function
as ion channels and are broadly expressed in diverse tissues and cell types, where they are
involved in different physiological processes, including sensation of different stimuli or
ion homeostasis [
115
]. As a result, accumulative research has explored the potential role of
capsaicin in stimulating painful sensations, particularly its chemical modulation of sensory
neurons through the vanilloid receptor subtype 1 [
116
–
118
]. Other studies show that mice
lacking TRPV1 exhibit no vanilloid-induced pain behavior, which is related to a reduced
capacity to feel pain [117].
5. Potential Toxic Effects of Pepper
An increasing body of evidence shows that pepper has toxicological effects when
used at very high doses. In fact, although considered beneficial to human health, even
black pepper is a culprit for such toxic effects. For instance, the administration of its active
ingredient, piperine, at doses as high as 60 mg/kg could be lethal in female rats, while
a dose of 35.5 mg/kg could be toxic in weaning male rats, although this could also be
dependent on prolonged exposure to the compound [
119
]. It appears that doses of piperine
ranging from 35.7 mg/kg–140 mg/kg administered orally could cause liver damage, with
140 mg/kg also affecting kidneys and lungs in mice [
120
]. Also, high doses of piperine
could affect sperm quality in rats [
121
]. Several authors have also reported that piperine
can negatively influence maternal reproduction in association with embryonic toxicity
in various preclinical models [
122
–
124
]. However, more work is required to determine
the role of dose dependence, as well as intervention period, in driving the toxic effects
of piperine or black pepper. Although piperine has also been studied in humans, it is
noteworthy that there is lack of information on its toxicity profile. On the other hand, it
has been shown that red pepper constituents (capsaicinoids) could induce skin irritation
and inflammation in the mucus and eyes [
125
]. It has been previously reported that high
quantity of capsaicinoids have severe effects on the gastrointestinal tract [
126
,
127
]. Since the
identification of capsaicinoid toxicity, studies have elucidated the lethal dose of capsaicin
in mice, which could be about 122–294 mg/kg, whereas a lethal intravenously injected
dose was predicted to be 0.36–0.87 mg/kg [
128
]. In rats, capsaicin was found to damage
the liver mitochondria [
129
,
130
]. Apart from being fatal, capsaicin was also reported
to suppress stimulus response and induce neurotoxicity, mainly when administered in
neonates
[130–132]
. In humans, capsaicin at 0.006% is routinely used to induce a burning
stimulus [
133
]. The intolerable effects of capsaicin could include coughing, diarrhea, and
vomiting [
134
]. Also, capsaicin plasters containing 345.8 mg and 34.58 mg tinctures were
Molecules 2023,28, 6569 8 of 24
shown to induce pain and nausea [
135
]. There is a large body of knowledge on capsaicin
toxicity that has been reported elsewhere [71,74,136].
6. Available Clinical Evidence of the Potential Benefits of Pepper
6.1. Characteristic Features of Clinical Studies
To identify relevant clinical studies, a systematic search was conducted using major
electronic databases including PubMed, Scopus, and Google Scholar. The search strategy
was compiled using the following keywords or Medical Subject Headings (MeSH): “pepper”
and “metabolic diseases”, including most relevant synonyms as well as keywords related to
the search topic. The literature search was performed from inception until June 2023, while
a manual search was performed to identify additional relevant studies. The final search
results yielded 14 relevant studies reporting on black pepper or its main active ingredient,
piperine, and its potential therapeutic effects against diverse metabolic complications
(Table 1), whereas 16 records were identified for clinical studies on red pepper, including its
active ingredients, capsinoids, against diverse metabolic complications. Besides those from
Argentina, Australia, Brazil, China, India, and Japan, which were outliers, most included
studies were from Iran, Europe, and the United States, predominantly focusing on adults
over the age of 18 years (Table 1). Summarized literature mainly included overweight and
obese subjects and those with metabolic syndrome (Tables 1and 2). However, evidence
involving healthy subjects was also included, provided it was reporting on the therapeutic
effects of pepper or its active ingredients on metabolic parameters in individuals with
chronic or metabolic conditions.
Molecules 2023,28, 6569 9 of 24
Table 1. An overview of human studies on the effects of black pepper (Piper nigrum) and its active ingredient, piperine, against diverse metabolic complications.
Author, Year Country Study Population Intervention Comparator (If Any) Main Findings
Gregerse et al.,
2013 [137]Denmark
Individuals subjected to
diet-induced thermogenesis
(n = 22), with an average age of
25 years
Brunch meal with black pepper at 1.3 g,
ginger (20 g), horseradish (8.3 g), and
mustard (21 g) for 4 h
Placebo
Did not affect diet-induced thermogenesis;
measurements of appetite and energy
balance were also not affected
O’Connor
et al., 2013
[138]
United States
Overweight women (n = 17), with
an average age between
52–69 years
Black pepper at 1.5 g for 24 h Placebo
Did not affect energy expenditure or
respiratory quotient, including levels of
glucose, insulin, catecholamines, and gut
peptides
Rondanelli
et al., 2013 [91]Italy
Overweight individuals (n = 41),
with an average age between 25
and 45 years
Two capsules per day, mainly containing
Camellia sinensis decaffeinated dried
extract (150 mg/cpr), microencapsulated
oleoresin of Capsicum annum
(7.5 mg/cpr), and piper nigrum dry
extract, (3 mg/cpr) for 8 weeks
Placebo
Reduced obesity-related inflammatory
metabolic dysfunction by ameliorating
insulin resistance, improving the
leptin/adiponectin ratio, respiratory
quotient, and low-density lipoprotein
(LDL) cholesterol levels
Hobbs et al.,
2014 [139]United States
Individuals with
hypercholesterolemia (n = 19), with
an average age between 18 and
80 years
Softgel that contained different active
ingredients (such as bioflavonoids,
vitamins, omega-3 fatty acids, and black
pepper) for 30 days
Placebo Reduced total cholesterol, low-density
lipopolysaccharide, and triglyceride levels
Rofes et al.,
2014 [140]Spain
Individuals with oropharyngeal
dysphagia (n = 40), with an
average age between 74 and
78 years
Piperine at 1 mM or 150 µM during
oropharyngeal swallow response None
Alleviated oropharyngeal dysphagia by
improving swallowing, with the time of
laryngeal vestibule closure shortened at
both concentrations
McCrea et al.,
2015 [141]United States
Overweight individuals given a
high-fat meal (1000 kcal, 45 g fat)
(n = 20), with an average age
between 30 and 36 years
Capsule with a combination of spices
(black pepper, cinnamon, cloves, garlic,
ginger, oregano, paprika, rosemary, and
turmeric) at 14.5 g for up to 210 min
Placebo Reduced triglyceride levels, but did not
have effects on glucose or insulin levels
Panahi et al.,
2015 [142]Iran
Individuals with metabolic
syndrome (n = 50), with an average
age between 36 and 53 years
Curcuminoids at 1 g, co-administered
with piperine at 10 mg daily for 8 weeks Placebo
Improved oxidative and inflammatory
status by enhancing serum levels of
superoxide dismutase (SOD) while
reducing that of malonaldehyde (MDA),
together with C-reactive protein
Molecules 2023,28, 6569 10 of 24
Table 1. Cont.
Author, Year Country Study Population Intervention Comparator (If Any) Main Findings
Gilardini et al.,
2016 [143]Italy
Obese females (n = 20), with an
average age between 40 and
60 years
Formulation containing Camellia sinensis,
titrated as > 60% polyphenols and > 40%
in epigallocatechin-O-gallate, complexed
with soy distearoylphosphatidylcholine
and pure piperine (15 mg/dose) for
3 months
Placebo Reduced body weight and fat mass
Zanzer et al.,
2018 [144]Sweden
Individuals receiving a meal rich in
carbohydrates (n = 16), with an
average age between 25 and
27 years
Black pepper-based beverage at 220 mL
(20 mg gallic acid equivalent) up to
180 min
Placebo
Did not affect metabolic status. Also, the
was no observed effects in the
gastrointestinal well-being. However,
there was suppression of hunger and
improved satiety.
Mahmoudpour
et al., 2019
[145]
Iran
Individuals with functional
bloating (n = 36), with an average
age between 20 and 50 years
Formulation containing Trachyspermum
ammi (L.) Sprague seed, Zingiber
officinale Roscoe. Rhizome, and Piper
nigrum L. berry at 500 mg three times a
day for 2 weeks
Placebo
Improved bloating status, including
eructation, defecation, and borborygmus,
better than dimethicone
Heidari-Beni
et al., 2020
[146]
Iran
Individuals with chronic knee
osteoarthritis (n = 30), with an
average age between 35 and
75 years
Herbal formulation containing curcumin
(300 mg), gingerols (7.5 mg), and
piperine (3.75 mg), taken twice a day for
4 weeks
Naproxen at 250 mg
Potentially protected against chronic knee
osteoporosis by reducing levels of
prostaglandin E2
Oh et al., 2020
[147]United States
Overweight or obese subjects
(n = 12) given a high-fat meal
(1000 kcal) (n = 20), with an
average age between 40 and
65 years
Combination of spices (basil, bay leaf,
black pepper, cinnamon, coriander,
cumin, ginger, oregano, parsley, red
pepper, rosemary, thyme, and turmeric)
at2gforupto4h
Placebo Alleviated high-fat-meal-induced
postprandial interleukin (IL)-1βsecretion
Pastor et al.,
2020 [148]Argentina
Individuals with metabolic
syndrome (n = 22), with an average
age between 63 and 73 years
Formulation containing resveratrol at
50 mg, piperine at 5 mg, and alpha
tocopherol a 25 mg, with habitual
treatment for 3 months
Placebo
Ameliorated inflammation by reducing
levels of ferritin, ultrasensitive C-reactive
protein, and oxygen consumption
Lindheimer
et al., 2023
[149]
United States
Young adults with low energy
(n = 40), with an average age
between 18 and 34 years
Black pepper capsules twice a day at
0.504 g for 2 days Rosemary at 0.425 g
Did not affect energy levels or fatigue
feelings; however, rosemary induced a
reduction in false alarm errors and mental
fatigue at different time periods
Molecules 2023,28, 6569 11 of 24
Table 2. Clinical evidence of the effects of red pepper (Capsicum annum) and its active ingredient, capsaicin, against diverse metabolic complications.
Author, Year Country Study Population Intervention Comparator Main Findings
Yoshioka et al.,
1999 [150]Canada
Healthy individuals given high-fat
and high-carbohydrate meals
(n = 23), with an average age
between 23 and 41 years
Breakfast with red pepper at 10 g None Reduced appetite and subsequent protein and fat
intake while also limiting energy intake
Lutgendorf
et al., 2000
[151]
Denmark
Healthy individuals subjected to
stressful conditions, with an
average age between 21 and
33 years
Capsaicin at 510 mg for 10 days Placebo
Ameliorated stressful related inflammation by
enhancing relaxation; this was related to
amendments in norepinephrine, heart rate, and
systolic blood pressure during the experimental
task
Belza and
Jessen, 2005
[152]
Denmark
Overweight and obese individuals
(n = 19), with an average age
between 28 and 54 years
A tablet containing green tea extract at
250 mg, tyrosine at 203 mg, anhydrous
caffeine at 25.4 mg, and capsaicin at
0.2 mg for 7 days
Placebo
Promoted a thermogenic effect through enhanced
energy expenditure without raising the heart rate
Ahuja et al.,
2006 [153]Australia
Overweight individuals (n = 36),
with an average age between 22
and 70 years
Chili blend (30 g/d; 55% cayenne chili)
diet supplement for 4 weeks None Attenuated postprandial hyperinsulinemia
Inoue et al.,
2007 [154]Japan
Overweight individuals (n = 29),
with an average age between 30
and 65 years
Capsinoids at 3 or 10 mg/kg for 4 weeks
Placebo
Promoted fat oxidation, and this positively
correlated with the body mass index; further
analysis showed that treatment enhanced energy
expenditure and oxygen consumption
Snitker et al.,
2008 [70]United States
Overweight subjects (n = 41), with
an average age between 30 and 60
years
Capsinoids at 6 mg for 12 weeks Placebo Safe and promoted fat oxidation
Chaiyasit et al.,
2009 [155]Thailand
Individuals subjected to oral
glucose tolerance tests (n = 12),
with an average age of 20–23 years
Capsaicin at 5 g for up to 120 min None Reduced plasma glucose levels and maintained
insulin levels
Josse et al.,
2010 [156]Canada
Healthy subjects cycling at 55%
VO2peak, and for 30 min into
recovery (n = 12), with an age
between 21 and 27 years
Capsules of purified capsinoids at 10 mg,
30 min prior to exercise None
Enhanced adrenergic activity, and energy
expenditure, leading to a shift in substrate
utilization toward lipid at rest but had little effect
during exercise or recovery
Molecules 2023,28, 6569 12 of 24
Table 2. Cont.
Author, Year Country Study Population Intervention Comparator Main Findings
Nieman et al.,
2012 [157]United States
Overweight and obese females
(n = 31), with an average age
between 40 and 75 years
A combination of red pepper spice at 1 g
daily for 4 weeks
Received turmeric
at 2.8 g Did not affect inflammation and oxidative stress
Janssens et al.,
2013 [158]Netherlands
Healthy individuals subjected to
25% negative energy balance
(n = 15), with an average age
between 18 and 50 years
Capsaicin at 2.56 mg (1.03 g of red chili
pepper, 39,050 SHU) with every meal for
36 h
Placebo
Supported negative energy balance by
counteracting the unfavorable negative energy
balance concomitant with a reduction in energy
expenditure
Janssens et al.,
2014 [159]Netherlands
Healthy individuals (n = 15), with
an average age between 18 and
50 years
Red chili pepper (containing capsaicin
2484 µ/g, nordihydrocapsaicin 278µ/g,
and dihydrocapsaicin 1440 µ/g) at
2.56 mg with every meal, mounting to
daily total dose of 7.68 mg
None
Increased satiety and fullness, and partially
prevented overeating when food intake was ad
libitum; after dinner, treatment prevented the
negative energy balance and desire to eat
Galgani et al.,
2015 [160]United States
Healthy subjects (n = 13), with an
average age between 27 and
30 years
Gel capsules (containing capsinoids at 1,
3, 6 and 12 mg) up to 72 h Placebo
Did not affect metabolic rate, non-protein
respiratory quotient, blood pressure, or axillary
temperature
Yuan et al.,
2016 [161]China
Women with gestational diabetes
(n = 20), with an average age
between 27 and 34 years
Capsaicin at 5 mg daily for 4 weeks Placebo
Improved postprandial hyperglycemia and
hyperinsulinemia, as well as fasting lipid
metabolic disorders; in addition, the fasting serum
levels of apolipoprotein B and calcitonin
gene-related peptide increased compared to
changes in glucose and insulin in the plasma
Joseph et al.,
2021 [162]India
Overweight subjects (n = 12), with
an average age between 35 and
41 years
Capsifen (with 4 mg capsaicinoids/day)
at 200 mg for 28 days Placebo
Reduced body weight, body mass index, and
appetite; results also affirmed the safety and
tolerability of capsifen at the investigational
dosage
Giuriato et al.,
2022 [163]Italy
Healthy males subjected to
constant-load cycling exercise
time-to-exhaustion trials (n = 10),
with an average age between 19
and 26 years
Two capsules of capsaicin at 390 mg,
during 72 h between sessions Placebo
Alleviated neuromuscular fatigue through
alterations in afferent signaling or neuromuscular
relaxation kinetics
Silva-Santana
et al., 2022
[164]
Brazil
Patients undergoing hemodialysis
(n = 24), with an average age
between 20 and 75 years
A combination of turmeric at 3 g and
piperine at 2 mg daily for 12 weeks Turmeric at 3 g/day
Combination treatment was superior in effectively
modulating the status of oxidation and
inflammation by reducing malonaldehyde and
ferritin levels
Molecules 2023,28, 6569 13 of 24
6.2. Evidence of the Effects of Pepper on Overweight and Obese Individuals
Overweight and obesity remain the major contributors to the development of diverse
metabolic complications [
7
,
165
]. Overnutrition consistent with reduced physical activity is
considered the underlying factor driving the development and progression of obesity [
166
].
In fact, there is an increasing need to investigate the therapeutic effects of pepper against
obesity and its associated complications in human subjects. Evidence summarized in this
review indicates that several clinical studies have been completed to test the beneficial
effects of pepper, including its active ingredients, piperine and capsaicin, on obesity and its
related metabolic complications (Table 1). Starting with evidence on black pepper, 3 months
of administration of a formulation containing its main ingredient, pure piperine (at 15 mg),
together with Camellia sinensis soy distearoylphosphatidylcholine was shown to reduce
body weight and fat mass in obese subjects [
143
]. Captivatingly, reviewed evidence already
supports the notion that epigallocatechin, which is one of the major active ingredients
of Camellia sinensis, could potentially neutralize oxidative stress and inflammation to
amend complications of metabolic syndrome [
165
]. The 8-week administration of two
capsules containing a combination of piper nigrum dry extract (3 mg), capsicum annum
(7.5 mg), and decaffeinated dried Camellia sinensis extract (150 mg) could ameliorate obesity-
related complications, including insulin resistance, leptin/adiponectin ratio, and low-
density lipoprotein (LDL) cholesterol levels, while blocking inflammation in overweight
individuals [
91
]. Similarly, a four-hour administration of a capsule containing a combination
of spices (at 2 or 14.5 g) consisting of black pepper, cinnamon, cloves, garlic, ginger, oregano,
paprika, rosemary, and turmeric could reduce the levels of triglycerides while alleviating
high-fat-meal-induced postprandial interleukin (IL)-1
β
secretion in overweight and obese
subjects [
141
,
147
]. Interestingly, an additional study also showed that the beneficial effects
of pepper-containing formulations were associated with improved lipid profiles, as seen
with reductions in total cholesterol, low-density lipopolysaccharide, and triglyceride levels
when individuals with hypercholesterolemia were given capsules comprising different
active ingredients such as bioflavonoids, vitamins, omega-3 fatty acids, and black pepper
for 30 days [
139
]. Summarized evidence on the potential therapeutic effects of black pepper
against obesity and its associated complications appeared to be more pronounced when
used in combination with other active ingredients, with enhanced effects on improving
lipid profiles through the reduction of total cholesterol and triglyceride levels, while also
lowering pro-inflammatory markers in overweight and obese subjects (Table 1; Figure 4).
Summarized evidence also reported the therapeutic potential of red pepper against
obesity and its related complications (Table 2). Here, it was shown that the 7-day admin-
istration of a tablet containing an active ingredient of red pepper, capsaicin (at
0.2 mg
),
together with green tea extract (at 250 mg), tyrosine (at 203 mg), and anhydrous caffeine
(at 25.4 mg) could promote a thermogenic effect and enhance energy expenditure in over-
weight and obese individuals [
152
]. This is of great importance since it has been estimated
that both common therapies like metformin and prominent bioactive compounds can
improve metabolic function by promoting thermogenesis and increasing energy expen-
diture [
167
,
168
]. Interestingly, a 4-week administration of capsinoids (at 3 or 10 mg/kg)
could also promote fat oxidation, which was positively correlated with enhanced energy
expenditure in overweight subjects [
154
]. Other studies supported the beneficial effects of
capsinoids against obesity-related complications, indicating that consuming these bioactive
compounds (at doses between 4–6 mg) for 1 to 3 months could promote fat oxidation
while reducing body weight, body mass index, and appetite in overweight subjects [
70
,
162
].
Moreover, overweight individuals receiving a 4-week chili blend (at 30 g/d; 55%) inter-
vention displayed reduced postprandial hyperinsulinemia [
153
]. However, administration
of a combination of red pepper spices (at 1 g daily for 4 weeks) did not have a significant
effect in improving markers of oxidative stress and inflammation in overweight and obese
subjects [
157
]. Individuals subjected to high-fat and high-carbohydrate meals rich in red
pepper (at 10 g) exhibited reduced appetite and subsequently reduced protein and fat
intakes, while also limiting energy intake [
150
]. This may indicate that the therapeutic