The effect of Capsaicinoids or Capsinoids in red pepper on thermogenesis in healthy adults: A systematic review and meta‐analysis

Abstract

The outcomes of the earlier trials are controversial concerning the effect of Capsaicinoids/Capsinoids on thermogenesis. We carried out this systematic review and meta‐analysis to examine the effect of Capsaicinoids/Capsinoids on thermogenesis indices including resting metabolic rate (RMR) and respiratory quotient (RQ) in healthy adults. An electronic literature search was conducted between 1990 and 2019, using the following databases: PubMed, Web of Sciences, Scopus, Cochrane Central Register of Controlled Trials, and EMBASE. Placebo‐controlled clinical trials were considered as eligible papers. Effect sizes were pooled using weighted mean difference (WMD), with a random‐effects model. Of the 4,092 articles, 13 studies were included in the meta‐analysis. Pooled effect sizes revealed that compared with placebo, Capsaicinoids/Capsinoids significantly increased RMR (WMD: 33.99 Kcal/day, 95% CI: 15.95, 52.03; I²: 0%, p = .94), energy expenditure, and fat oxidation. It also significantly lessened RQ (WMD: −0.01, 95% CI: −0.02, −0.01; I²: 5.4%, p = .39) and carbohydrate oxidation. Moreover, intervention in capsule form for longer duration had a more considerable influence on RMR than comparative groups. We observed moderate improvement in RMR, RQ, and fat oxidation following supplementation with Capsaicinoids/Capsinoids. However, further high‐quality studies are required to clarify the thermogenic properties of Capsaicinoids/Capsinoids.

Full text

REVIEW
The effect of Capsaicinoids or Capsinoids in red pepper
on thermogenesis in healthy adults: A systematic review
and meta-analysis
Pardis Irandoost
1
| Neda Lotfi Yagin
2
| Nazli Namazi
3
|
Abbasali Keshtkar
4
| Farnaz Farsi
1,5
| Naimeh Mesri Alamdari
1
|
Mohammadreza Vafa
1,5
1
Department of Nutrition, School of Public
Health, Iran University of Medical Sciences,
Tehran, Iran
2
Nutrition Research Center, Student Research
Committee, School of Nutrition and Food
Sciences, Tabriz University of Medical
Sciences, Tabriz, Iran
3
Diabetes Research Center, Endocrinology and
Metabolism Clinical Sciences Institute, Tehran
University of Medical Sciences, Tehran, Iran
4
Department of Health Sciences Education
Development, School of Public Health, Tehran
University of Medical Sciences, Tehran, Iran
5
Colorectal Research Center, Iran University of
Medical Sciences, Tehran, Iran
Correspondence
Mohammadreza Vafa, Junction of Shahid
Hemmat & Shahid Chamran, Department of
Nutrition, School of Public Healt, Iran
University of Medical Sciences and Health
Services, Tehran, Iran.
Email: rezavafa@yahoo.com
The outcomes of the earlier trials are controversial concerning the effect of
Capsaicinoids/Capsinoids on thermogenesis. We carried out this systematic review
and meta-analysis to examine the effect of Capsaicinoids/Capsinoids on thermogen-
esis indices including resting metabolic rate (RMR) and respiratory quotient (RQ) in
healthy adults. An electronic literature search was conducted between 1990 and
2019, using the following databases: PubMed, Web of Sciences, Scopus, Cochrane
Central Register of Controlled Trials, and EMBASE. Placebo-controlled clinical trials
were considered as eligible papers. Effect sizes were pooled using weighted mean
difference (WMD), with a random-effects model. Of the 4,092 articles, 13 studies
were included in the meta-analysis. Pooled effect sizes revealed that compared with
placebo, Capsaicinoids/Capsinoids significantly increased RMR (WMD: 33.99 Kcal/
day, 95% CI: 15.95, 52.03; I
2
: 0%, p= .94), energy expenditure, and fat oxidation. It
also significantly lessened RQ (WMD: −0.01, 95% CI: −0.02, −0.01; I
2
: 5.4%, p= .39)
and carbohydrate oxidation. Moreover, intervention in capsule form for longer dura-
tion had a more considerable influence on RMR than comparative groups. We
observed moderate improvement in RMR, RQ, and fat oxidation following supple-
mentation with Capsaicinoids/Capsinoids. However, further high-quality studies are
required to clarify the thermogenic properties of Capsaicinoids/Capsinoids.
KEYWORDS
Capsaicinoids, Capsinoids, metabolic rate, obesity, red pepper, respiratory quotient
1|INTRODUCTION
Thermogenesis is a biological factor which plays an important role in
pointed equilibrium of energy intake (EI) and energy expenditure
(EE) by increasing EE (Inoue, Matsunaga, Satoh, & Takahashi, 2007;
Wijers, Saris, & van Marken Lichtenbelt, 2009). Diet-induced thermo-
genesis is a contributing factor in metabolism hemostasis. In addition
to obligatory diet-induced thermogenesis, which refers to the thermo-
genic response to food absorption, digestion, and storage, the
facultative kind of thermogenesis is related to the intake of some
kinds of foods which elevates thermogenesis and EE (Saito,
Matsushita, Yoneshiro, & Okamatsu-Ogura, 2020; von Essen,
Lindsund, Cannon, & Nedergaard, 2017).
Nowadays, elevation of thermogenesis and EE by nutraceutical
foods specially plant-based ingredients, has attracted a great deal
of attention for regulating the energy balance (Bonet, Oliver, &
Palou, 2013; Mele et al., 2017; Wang, Pan, Hung, Tung, &
Ho, 2019).
Received: 15 April 2020 Revised: 3 September 2020 Accepted: 20 September 2020
DOI: 10.1002/ptr.6897
Phytotherapy Research. 2020;1–20. wileyonlinelibrary.com/journal/ptr © 2020 John Wiley & Sons Ltd 1

Chile peppers (Capsicum spp.) are valued as a source of a group
of alkaloids called Capsaicinoids especially N-vanillylamides that are
responsible for the spicy flavor of the red pepper (Diepvens,
Westerterp, & Westerterp-Plantenga, 2007; Gonzalez-Zamora
et al., 2013). The fruit is used extensively as a natural food due to its
thermogenic ingredients mainly Capsaicin, a noncaloric ingredient
which can elevate EE and substrate oxidation (Janssens, Hursel,
Martens, & Westerterp-Plantenga, 2013).
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) and dihydrocapsaicin
(8-methyl-Nvanillylnonanamide) comprise about 77%–98% of peppers
Capsaicinoids (Barbero et al., 2014; Keyhaninejad, Curry, Romero, &
O'Connell, 2014). In addition, Capsinoids, the nonpungent Capsaicinoid
analogs, are more palatable and preferred more than the pungent form,
which are obtained from CH-19 Sweet (Capsicum annuum L.) (Yoneshiro,
Aita, Kawai, Iwanaga, & Saito, 2012). The thermogenic properties of
Capsaicinoids and Capsinoids have been the objective of several investi-
gations and have been evaluated in numerous trials (Josse et al., 2010;
Kawabata et al., 2006; Lee, Li, Zerlin, & Heber, 2010; Lejeune, Kovacs, &
Westerterp-Plantenga, 2003; Yoshioka et al., 1995). Thermogenesis
properties of Capsaicin and Capsiate could stem from the stimulation of
the Transient Receptor Potential Vanilloid receptor1 (Hanson, Newstead,
Swartz, & Sansom, 2015; Yoneshiro et al., 2012). To the best of our
knowledge, two meta-analyses have been published to date, considering
the effect of Capsaicinoids/Capsinoids on EE and thermogenesis (Ludy,
Moore, & Mattes, 2012; Whiting, Derbyshire, & Tiwari, 2012; Zsiboras
et al., 2018). As the main limitation, it should be noted that the method-
ologies of the aforementioned meta-analyses did not examine clinical tri-
als systematically. The meta-analysis that was done by Ludy et al. was
published only as a critical review and no systematic review was carried
out in the article. In addition, the databases used for meta-analysis are
not known (Ludy et al., 2012). Besides, in another meta-analysis, the
assessment was not performed as a systematic review and the used
databases were limited. Moreover, quality assessment was not per-
formed for included studies (Zsiboras et al., 2018).
Accordingly, the present study was conducted as both systematic
review and meta-analysis with extensive database searches to exam-
ine the effect of Capsaicinoids/Capsinoids on thermogenesis including
resting metabolic rate (RMR) and respiratory quotient (RQ). It is sup-
posed that current study might reach comprehensive conclusion
about the effect of Capsaicinoids/Capsinoids on thermogenesis and
energy balance.
2|MATERIALS AND METHODS
For current systematic review and meta-analysis, the preferred
reporting items for systematic reviews and meta-analyses (PRISMA)
guidelines were followed (Moher, Liberati, Tetzlaff, & Altman, 2009).
Different phases of the study such as the number of articles included
and excluded have been depicted in PRISMA flow diagram (Figure 1).
The protocol of this systematic review has been registered on PROS-
PERO 2017 (PROSPERO; Registration No CRD42017056933; http://
www.crd.york. ac.uk/PROSPERO).
2.1 |Study characteristics
In this systematic review, we included all randomized placebo-
controlled clinical trials with at least two intervention and control
groups that had parallel or cross over design. These trials were open
labeled or had different levels of blindness such as single blind or dou-
ble blind. In our search, studies which had assessed animal models,
review articles, studies with internal control group (before–after stud-
ies), proceedings, case studies and case reports were excluded. We
did not restrict the language for the selection of primary articles.
2.2 |Participants
Adult subjects, women or men genders (or both genders) with BMI
=18–35 kg/m
2
were included in our systematic review. All of the par-
ticipants were drawn from healthy population and were free from any
allergies to red pepper and chronic diseases such as gastrointestinal
disease, endocrine disease, cardiovascular disease, and cancer. Sub-
jects were supposed not to be athlete and not participate in regular
resistance exercise.
2.3 |Intervention
Interventions with red pepper or its effective components
(Capsaicinoids/Capsinoids) in any dose and in the form of red pepper
powder or capsule were included. Duration of the intervention could
have varied from a single dose to more. Intervention could have been
accompanied with any form of diets if the diets were identical in both
intervention and control groups. The studies that had assessed the
effect of Capsaicinoids/Capsinoids with exercise or had compared the
effect of them with any other drugs were excluded.
2.4 |Comparator or control
Studies which had compared the intervention group with placebo
were eligible. Trials with standard intervention were excluded from
our research.
2.5 |Outcomes
Trials that had assessed the effect of Capsaicinoids/Capsinoids on ther-
mogenesis as a primary outcome via at least one of the effective ways
on thermogenesis (including RMR and RQ) were included in our study.
We assessed some extra data that at least one of them had been
reported in eligible trials as secondary outcomes including EE, volume
of oxygen (Vo2), heart rate (HR), fat and carbohydrate oxidation, body
temperature (BT), blood pressure, and EI. Furthermore, evaluation of
the heterogeneity and its potential sources in primary studies were a
secondary outcome in our systematic review and meta-analysis.
2IRANDOOST ET AL.

2.6 |Information sources
An electronic systematic search was conducted between 1990 and
August 31, 2019, using the following five databases: PubMed, Web of
Sciences, Scopus, Cochrane Central Register of Controlled Trials and
Embase. In addition, the reference lists of all relevant studies and
reviews as sources of further probable eligible studies were reviewed.
Key journals were searched manually as well. Table 1 shows the PICO
criteria.
2.7 |Search strategy
Following keywords have been used to conduct the search:
“Capsicum,”“Capsaicinoid,”“Capsaicin,”“thermogenesis,”“energy
expenditure,”“metabolic rate,”and “respiration quotient.”MeSH and
EMTREE were considered in the development of the mentioned sea-
rch terms. For each electronic database, search strategy was adopted
and presented in online supplementary Appendix. Screening and
selection process were conducted by two independent reviewers (PI,
FF). In the case of discrepancies in the inclusion or exclusion of some
trials, which could not have been resolved through consensus, they
were referred to a third person. In this step, the reason for the exclu-
sion of articles were recorded.
TABLE 1 The PICO criteria used for the present systematic
review
PICO
criteria Description
Population Healthy subjects with normal to high BMI
Exposure Red pepper, Capsaicinoids, Capsinoids, Capsicum,
Capsaicin
Comparison Not using pepper
Outcomes Thermogenesis (EE, RMR, RQ, fat oxidation,
carbohydrate oxidation, heart rate, Vo2 max, body
temperature) energy intake, SBP, DBP
Abbreviations: BMI, body mass index; DBP: diastolic blood pressure; EE,
energy expenditure; RMR, resting metabolic rate; RQ, respiratory quotient;
SBP, systolic blood pressure; Vo2, volume of oxygen.
gnineercS
ytilib
igilE
Records identied through database
searching
(n =4092)
Additional records identied
through other sources
(n =0)
Records after duplicates removed
(n =2401)
Studies included in
quantitative synthesis
(meta-analysis)
(n =13)
Papers with no necessary data
(n = 5)
Records screened
(n =2401)
Records excluded
(n =2348)
Full-text articles assessed
for eligibility
(n =53)
Full-text articles excluded, with reasons
(n =35):
-Irrelevant (n=12)
-Athletes (n=2)
-Don’t have placebo (n=9)
-Intervention with cold exposure (n=6)
-In combination with other
component (n= 6)
Relevant papers
(n =18)
noitacifitnedI
Included
FIGURE 1 Flowchart for study
identification and selection [Colour
figure can be viewed at
wileyonlinelibrary.com]
IRANDOOST ET AL.3

2.8 |Data collection process
Data extraction form was designed and two coauthors (PI, NLY)
extracted necessary data from the full texts of the included papers
independently. The list of data used in the extraction form was as
follows: study characteristics, participants' characteristics (age, sex,
and BMI), and intervention (duration, type including pepper powder
or Capsaicinoids/Capsinoids capsule, dosage), outcomes and other
information that was necessary for the assessment of the risk
of bias.
Statistics for meta-analysis were mean, standard deviation (SD),
standard error of mean, confidence interval (CI), and sample size. If
the favorite results were reported in more than two time periods,
only the baseline data and the end of intervention data were
extracted. In addition, when more than two groups were in the stud-
ies, only data for Capsaicinoids/Capsinoids and placebo groups were
considered. In some cases, with different dosages, to avoid multiple
inclusions, each quantity was regarded as an independent trial by
dividing the sample size into the numbers of evaluated dosage. For
papers with insufficient data, the corresponding authors were con-
tacted by emails for three times in specific and reasonable intervals.
In cases of no response to our emails, the entire paper or variable
with inadequate information was excluded from our systematic
review.
2.9 |Assessment of risk of bias in individual
studies and confidence on the estimates
Methodological quality of each paper was evaluated by two authors inde-
pendently (PI, NM) based on the Cochrane Collaboration's tool for
assessing risk of bias (Higgins et al., 2011). Six types of bias in this tool
including selection (Random sequence generation and Allocation conceal-
ment), performance (Blinding of participants and personnel), detection
(Blinding of outcome assessment), attrition (Incomplete outcome data),
reporting (Selective reporting), and any other apparent sources of bias
were assessed and reported for each trial (Figure 2). Grading of recom-
mendations assessment, development, and evaluation (GRADE) approach
was used for the quality of evidence assessment of thermogenesis indi-
ces based on study limitations, inconsistency of results, indirectness of
evidence, imprecision and publication bias by (PI, NN). The quality of evi-
dence was rated as high, moderate, low, and very low (Table 4). In the
Low Risk: +
High risk: -
)saibnoitceleS(noitarenegecneuqesmodnaR
Allocation concealment (Selection bias)
Blinding of participants and personnel
(Performance bias)
)saibnoitceteD(
tne
mssessa
e
moc
tu
ofogni
dn
ilB
Incomplete outcome data(Attrition bias)
Selective reporting (Reporting bias)
)saibrehtO(deificepserpyllaedi,eslegnihtynA
Ahuja et al 2007
+
-
-
-
+
+
+
Ahuja et al 2006
+
-
-
-
+
+
+
Snitker et al 2009
+
-
+
-
-
+
+
Galgani et al 2010
-
-
+
-
-
+
+
Galgani et al 2010
-
-
+
-
-
+
+
Janssens et al 2013
+
+
-
-
-
+
+
Kawabata et al 2006
-
-
-
-
+
+
+
Kroff et al 2015
+
-
-
-
-
+
+
Lee et al 2010
-
+
+
+
-
+
+
Lejeune et al 2003
-
-
-
-
-
+
+
Ludy et al 2010
-
+
-
-
-
+
+
Schwarz et al 2013
-
-
+
+
+
+
+
Smeets et al 2013
-
+
-
-
+
+
+
Smeets and Westerterp-Plantenga 2009
-
-
-
-
+
+
+
Ang et al 2017
-
-
+
-
+
+
+
Shin and Moritani 2007
-
-
-
-
+
+
+
Inoue et al 2007
-
+
-
-
+
+
+
Yoshioka et al 1998
+
-
-
-
+
+
+
FIGURE 2 Risk of bias assessment of included
studies [Colour figure can be viewed at
wileyonlinelibrary.com]
4IRANDOOST ET AL.

case of discrepancies between two reviewers, a third investigator made
the final decision (AAK).
2.10 |Statistical analysis and data synthesis
Data was analyzed using STATA V.12 software(StataCorp,CollegeStation,
TX). In case of the adequate number of studies (at least two clinical trials),
meta-analysis was performed. To evaluate the effect size of Capsaicinoids/
Capsinoids on thermogenesis indices, all data were measured as weighted
mean differences (WMD) and 95% CI. To check the severity of the effect,
the standard mean differences (SMD) was used. To determine the pooled
WMD, random-effects model was adopted (DerSimonian & Kacker, 2007).
Intragroup changes and corresponding SD were calculated if not reported in
the study. SD was estimated according the formula: SD = square root [(SD
pretreatment)
2
+ (SD posttreatment)
2
–(2R ×SD pretreatment ×SD post-
treatment)], and R= 0.5 was assumed as a correlation coefficient (Higgins &
Green, 2008).
SD was calculated based on the following formula, if an SEM was
stated instead of SD: SD = SEM×square root (n), in which “n”showed
the sample size in each group (Hozo, Djulbegovic, & Hozo, 2005). For the
results presented only in the graphic form, Plot digitizer was employed to
attain the data. Through Isquare (I
2
) index, the heterogeneity was
assessed and if I
2
values were less than 25%, between 25%–50% and
over 50%, low, moderate and severe heterogeneity was considered,
respectively (Patsopoulos, Evangelou, & Ioannidis, 2008).
To detect the factors which were responsible for high heteroge-
neity, subgroup analysis was carried out when possible. Mean age
(less or ≥35 years), dosage of supplementation (less or ≥25 mg),
duration (one dose or more than one dose), BMI of participants (less
or ≥25 mg), geographic area (eastern and western countries), type of
intervention (capsule or powder), type of Capsaicinoids/Capsinoids
and quality assessment (low or high quality) were regarded as the
parameters for the subgroup analysis. We considered the values of
more or less than the median as cut-off values for quantitative param-
eter for subgroup analysis. Regarding the BMI, normal BMI (less than
25 mg/kg) was considered for subgroup analysis.
In cases where the effect size was not sufficient for subgrouping,
we used meta-regression analysis for quantitative data. The sensitivity
analysis was made using the leave-one-out method to study the
impact of every single trial on the pooled effect size. For publication
bias assessment, funnel plots were initially used, followed by Begg's
rank correlation method and Egger's regression method for more and
less than 10 studies, respectively. In the case of high publication bias,
we corrected our results with Trim and Fill method.
3|RESULTS
3.1 |Literature search
After searching PubMed, Scopus, Web of science, Embase, and
Cochrane electronic databases, 4,092 articles (containing 1,691
duplicates) were retrieved. After screening, the papers based on title
and abstracts, 2,348 irrelevant publications were removed. In the next
step, the full texts of the remaining articles were reviewed carefully
and 35 papers were excluded based on the mentioned reasons in
Figure 1. Eventually, we reached 18 papers. However, due to insuffi-
cient data in five studies (Ahuja, Robertson, Geraghty, & Ball, 2006,
2007; Galgani, Ryan, & Ravussin, 2010; Janssens et al., 2013; Smeets,
Janssens, & Westerterp-Plantenga, 2013), the meta-analysis was per-
formed on 13 studies (including 18 effect sizes).
3.2 |Study characteristics
Characteristics of the 18 eligible clinical trials for systematic review
are represented in Table 2. The publication date of trials was from
1998 to 2016. Participants in one study were women (Yoshioka
et al., 1998), in six studies were men (Ang et al., 2017; Galgani
et al., 2010; Galgani & Ravussin, 2010; Kawabata et al., 2006;
Schwarz et al., 2013; Shin & Moritani, 2007) and 11 studies included
both genders (Ahuja et al., 2006, 2007; Inoue et al., 2007; Janssens
et al., 2013; Kroff et al., 2017; Lee et al., 2010; Lejeune et al., 2003;
Ludy & Mattes, 2011; Smeets et al., 2013; Smeets & Westerterp-
Plantenga, 2009; Snitker et al., 2009). The design of 11 studies was
crossover (Ahuja et al., 2006, 2007; Ang et al., 2017; Galgani
et al., 2010; Janssens et al., 2013; Kroff et al., 2017; Ludy &
Mattes, 2011; Schwarz et al., 2013; Smeets et al., 2013; Smeets &
Westerterp-Plantenga, 2009; Yoshioka et al., 1998), while the
remaining (n = 7) had parallel design (Galgani & Ravussin, 2010; Inoue
et al., 2007; Kawabata et al., 2006; Lee et al., 2010; Lejeune
et al., 2003; Shin & Moritani, 2007; Snitker et al., 2009). Participants'
mean age ranged from 20.4 to 53.9 years. Participants' BMI were
from 20.4 to 31.3 kg/m
2
. Regarding sample size, it should be stated
that included eligible studies had sample size range from 10 to 91 sub-
jects. According to the reported data in the included studies, four tri-
als were single blind (Janssens et al., 2013; Shin & Moritani, 2007;
Smeets et al., 2013; Smeets & Westerterp-Plantenga, 2009), eight
were double blind (Ang et al., 2017; Galgani et al., 2010; Galgani &
Ravussin, 2010; Inoue et al., 2007; Lee et al., 2010; Lejeune
et al., 2003; Schwarz et al., 2013; Snitker et al., 2009) and the
remaining (n = 6) (Ahuja et al., 2006, 2007; Kawabata et al., 2006;
Kroff et al., 2017; Ludy & Mattes, 2011; Yoshioka et al., 1998) did not
reported any level of blindness. In 11 studies (Ang et al., 2017; Galgani
et al., 2010; Galgani & Ravussin, 2010; Inoue et al., 2007; Lee et al.,
2010; Lejeune et al., 2003; Ludy & Mattes, 2011; Schwarz
et al., 2013; Shin & Moritani, 2007; Smeets et al., 2013; Snitker
et al., 2009), Capsaicinoids/Capsinoids were consumed in the capsule
form and in seven studies (Ahuja et al., 2006, 2007; Janssens
et al., 2013; Kawabata et al., 2006; Kroff et al., 2017; Smeets &
Westerterp-Plantenga, 2009; Yoshioka et al., 1998) the powder form
was preferred. Capsaicinoids were the main consumed ingredient in
11 trials (Ahuja et al., 2006, 2007; Janssens et al., 2013; Kroff
et al., 2017; Lejeune et al., 2003; Ludy & Mattes, 2011; Schwarz
et al., 2013; Shin & Moritani, 2007; Smeets et al., 2013; Smeets &
IRANDOOST ET AL.5

TABLE 2 Characteristics of the included studies in the systematic review and meta-analysis
No Author Subject (gender)
Mean
age (year)
Sample
size
Study design
(blinding) Other intervention Dosage (g/day)
Duration
(day)
Side effects
(withdrawal) Quality
1 Yoshioka,
St-Pierre, Suzuki,
and
Tremblay (1998)
(Japan)
Healthy subject
(Female: 13)
25.8 ± 2.8 13 Randomized
crossover study
HFD (45% of
energy)
HCD (60% of
energy)
Hot red pepper (10 g) 1 –Low
2 Lejeune et al.
(2003)
(Netherlands)
Overweight
(Female: 68
Male: 23)
18–60 91 Randomized
double-blind
placebo-
controlled
Phase 1: VLCD
Phase 2: Weight
maintenance
period
and
Physical activity
controlled
Capsaicin: (135 mg) Phase 1 30
Phase 2 90
–Low
3
a
Ahuja et al. (2006)
(Australia)
Healthy (Female:
22 Male: 14)
46 ± 12 36 Randomized
crossover
Usual diet “Freshly chopped
Chilli”: 30 g/day
Capsaicin: (33 mg)
In 28 days
study,
assessing 2
meal in
120 min
–Low
4 Kawabata
et al. (2006)
(Japan)
Normal weight or
over
weight (Male:
12)
Intervention:
32.29 ± 11.4
Placebo:
27.8 ± 7.66
Mean: 30.77
12 Controlled trial Controlled energy
intake
CH-19 Sweet;
Capsiate: (0.4 g/kg)
14 –Low
5 Shin and Moritani
(2007) (Japan)
Healthy subjects
(Male: 10)
24.4 ± 6 10 Single blind,
randomized,
placebo-
controlled
Controlled meal
and activity
before testing
Capsaicin: (150 mg) 1 –Low
6
a
Ahuja et al. (2007)
(Australia)
Healthy (Female:
22 Male: 14)
46 ± 12 36 Randomized
crossover
Usual diet “Freshly chopped
Chilli”: 30 g/day
Capsaicin: (33 mg)
28 Any side-effects
participants
reported that
regular ingestion
of higher
amounts would
not be possible
over a long
period
Low
7 Inoue et al. (2007)
(Japan)
Healthy subjects
(Female: 9 Male:
39)
30–65 44 Randomized
double-blind
Habitual diet and
activity (no
significant
difference)
Capsinoids: (3 and
9 mg/kg)
28 –Low
6IRANDOOST ET AL.

TABLE 2 (Continued)
No Author Subject (gender)
Mean
age (year)
Sample
size
Study design
(blinding) Other intervention Dosage (g/day)
Duration
(day)
Side effects
(withdrawal) Quality
8
a
Galgani et al.
(2010) (USA)
Healthy (Male: 13) 271 ± 3.6 13 Double blind,
placebo-
controlled,
randomized,
crossover clinical
trial
Controlled diet and
physical activity
before the
intervention
Capsinoids (12 mg) 5 –Low
9 Smeets and
Westerterp-
Plantenga (2009)
(Netherlands)
Healthy subjects
(Female: 19
Male: 11)
31 ± 14 30 Single blind,
randomized,
crossover design
Controlled meal
before testing
Red pepper,
Capsaicin:
(1,030 mg)
1–Low
10 Snitker
et al. (2009)
(USA)
Over weight and
obese (Female:
40 Male: 40)
Intervention:
43 ± 8
Placebo:
41 ± 8
Mean: 42
67 Placebo-controlled,
double-blind,
randomized
study
Mild energy deficit
of
300–600 kcal/
day
and
Activity monitored
Purified Capsinoids:
(6 mg) consisted
of capsiate,
dihydrocapsiate,
and
nordihydrocapsiate
in a 63:27:10
84 Dyspepsia (n = 2),
Bowel
irregularities
(n = 1),
diarrhea (n = 1),
skin rash (n = 1)
Low
11 Galgani
et al. (2010)
(USA)
Over weight (Male:
78)
Intervention
(3 mg):
33.4 ± 9.5
Intervention
(9 mg):
37.6 ± 13
Placebo:
39 ± 10.58
Mean:
36.75
78 Double-blind,
placebo-
controlled,
randomized,
clinical trial
Controlled diet and
physical activity
before the
intervention
Capsinoids (3 and
9 mg)
28
and
Acute effect
in 120 min
Dry mouth leg
cramps (in 9 mg)
Low
12 Lee et al. (2010)
(USA)
Healthy men and
postmenopausal
women, over
weight and
obese (Female:
25 Male: 26)
Intervention
(3 mg):
51.3 ± 10.6
Intervention
(9 mg):
53.9 ± 10
Placebo:
49.6 ± 8.9
Mean: 51.52
33 Randomized
double-blinded
trial
VLCD (800 kcal/
day providing
120 g/day
protein)
Dihydrocapsiate (3
and 9 mg)
28 –Low
(Continues)
IRANDOOST ET AL.7

TABLE 2 (Continued)
No Author Subject (gender)
Mean
age (year)
Sample
size
Study design
(blinding) Other intervention Dosage (g/day)
Duration
(day)
Side effects
(withdrawal) Quality
13 Ludy and Mattes
(2011) (USA)
Healthy, lean
individuals
(Female: 11
Male: 14)
23.0 ± 3.25 25 Randomized
crossover
Adhered to HFD (2
visits), HCD (2
visits), or their
customary diet
(2 visits) for
3 days before
study and
Avoid strenuous
physical activity
for 2 days before
study visits
Red pepper (1 g/
meal)
6 visit Vomiting Low
14
a
Janssens
et al. (2013)
(Netherlands)
Healthy, normal
weight or over
weight (Female:
7 Male: 8)
29.7 ± 10.8 15 Single-blind,
randomized
crossover design
Subject received
100% or 75% of
their daily energy
requirements
and
Habitual activity
level on the
2 days before
each visit
Red chili pepper:
3.09 g
Capsaicin: (7.68 mg)
1–Low
15 Schwarz
et al. (2013)
(USA)
Healthy and active
subjects (Male:
11)
20 ± 2 11 Randomized
uniform-
balanced,
double-blind,
crossover design
Habitual diet and
physical activity
were recorded
(no significant
difference
between group)
Cayenne pepper:
500 mg
Capsaicin: (1.25 mg)
1–Low
16
a
Smeets
et al. (2013)
(Netherlands)
Healthy
participants
(Female: 12
Male: 12)
27 ± 4 24 Single blind,
randomized,
crossover design
100% or 80% of
daily energy
requirements
and
Activity was
monitored
Red pepper,
Capsaicin:
(1,030 mg)
1–Low
17 Kroff et al. (2017)
(South Africa)
Overweight but
apparently
healthy
individuals
(Female: 18
Male: 16)
32.8 ± 7.2 34 Randomized
crossover
intervention trial
Avoid alcohol, fried
food, and
vigorous exercise
for 24 hr before
each visits
Capsaicinoids:
(5.82 mg)
1–Low
18 Ang et al. (2017)
(Singapore)
Lean volunteers
(Male: 24)
23 ± 1.95 24 Double-blinded,
placebo-
controlled,
randomized
crossover
Controlled meal
and activity
before testing
Capsinoids: (9 mg) 1 –Low
Abbreviations: HCD, high carbohydrate diet; HFD, high fat diet; VLCD, very low-calorie diet.
a
Studies that did not include to meta-analysis.
8IRANDOOST ET AL.

Westerterp-Plantenga, 2009; Yoshioka et al., 1998), while Capsinoids
were ingested in seven trials (Ang et al., 2017; Galgani et al., 2010;
Galgani & Ravussin, 2010; Inoue et al., 2007; Kawabata et al., 2006;
Lee et al., 2010; Snitker et al., 2009). The capsule dosage varied
between 3 to 150 mg/day and powder dosage was between 500 mg
to 27.8 g per day; also, consumption duration of either form was from
1 day to 12 weeks. Different side effects related to Capsaicinoids/
Capsinoids consumption such as dyspepsia, bowel irregularities, and
diarrhea skin rash (Snitker et al., 2009), dry mouth, leg cramps
(Galgani & Ravussin, 2010) vomiting (Ludy & Mattes, 2011) were also
reported.
According to the Cochrane Risk of Bias Tool for Randomized
Controlled Trials, the methodological quality in all eligible studies was
low. Concerning the Cochrane criteria, since the risk of bias was high
in all trials, findings should be interpreted more cautiously.
3.3 |Systematic review
In a clinical trial by Ahuja et al. (2006) and (2007), Capsaicin did not
show any significant effect on basal metabolic rate and RQ. In addi-
tion, RMR did not change following the Capsinoids consumption in
the study by Galgani et al. (2010). The intake of Capsaicin was evalu-
ated in two groups: low calorie and normal diet consumers by
Janssens et al. (2013) and Smeets et al. (2013). Capsaicin did not
affect RQ in Janssens et al. (2013) study, whereas EE was boosted
and RQ was diminished significantly by Capsaicin compared with con-
trol group in Smeets et al. (2013), trial.
Moreover, Schwarz et al. (2013), indicated that increased in HR
was less than 1 beats per minute (bpm) after 60 min of 1.25 mg Cap-
saicin consumption. However, in the study by Shin and
Moritani (2007), there was no significant difference in HR, neither in
Capsaicin nor in placebo groups during 30 min rest. In another trial by
Inoue et al. (2007), 3 and 10 mg Capsaicin for 4 weeks led to an incre-
ment in HR to less than 1 and 4 bpm, respectively, and significant
increase was observed in 10 mg dosage when compared with the
baseline values. In addition, based on Schwarz et al. (2013), Capsaicin
usage did not influence core-BT in 1 hr after consumption. Kroff
et al. (2017), found that 5.28 mg Capsinoids did not have significant
effect on BT. On the other hand, 1 g of red pepper increased core-BT
significantly by 2C in 270 min of consumption (Ludy &
Mattes, 2011). With regard to Vo2 max, Inoue et al. (2007), revealed
that 3 and 10 mg Capsaicin increased Vo2 max 0.002 and 0.004 L/
min, respectively. Furthermore, Capsinoids consumption for 2 weeks
boosted Vo2 max in comparison to placebo group in Kawabata
et al. (2006), although it was not significant. Due to the limited studies
on HR, BT, and Vo2 max, meta-analysis was not carried out in this
regard. It should also be noted that EI was reported in three effect
FIGURE 3 Forest plot of weighted mean difference (WMD) in resting metabolic rate (RMR) in intervention and control groups [Colour figure
can be viewed at wileyonlinelibrary.com]
IRANDOOST ET AL.9

FIGURE 4 Forest plot of weighted mean difference (WMD) in respiratory quotient (RQ) in intervention and control groups [Colour figure can
be viewed at wileyonlinelibrary.com]
FIGURE 5 Forest plot of weighted mean difference (WMD) in energy expenditure (EE) in intervention and control groups [Colour figure can
be viewed at wileyonlinelibrary.com]
10 IRANDOOST ET AL.

FIGURE 6 Forest plot of weighted mean difference (WMD) in fat oxidation in intervention and control groups [Colour figure can be viewed
at wileyonlinelibrary.com]
FIGURE 7 Forest plot of weighted mean difference (WMD) in carbohydrate oxidation in intervention and control groups [Colour figure can
be viewed at wileyonlinelibrary.com]
IRANDOOST ET AL.11

sizes and two studies and since the baseline values was not available
in three effect sizes performing meta-analysis was not possible.
Lejeune et al. (2003) showed that 135 mg Capsaicin enhanced EI
more than placebo after 3-month weight-maintenance period
followed by 4 weeks very low-calorie diet, though it did not reach to
significant level. Besides, EI did not have significant changes in Inoue
et al. (2007), study.
3.4 |Meta-analysis for the effects of Capsaicinoids
or Capsinoids on thermogenesis indices
Forest plots for the effects of Capsaicinoids/Capsinoids on thermo-
genesis indices are displayed in Figures 3–7. Table 2 shows 13 studies
(including 18 effect sizes) on which the meta-analysis has been
performed.
3.4.1 |Resting metabolic rate
Data about the effects of Capsaicinoids/Capsinoids on RMR have
been provided in 10 RCTs containing 15 effect sizes. The pooled
estimates indicated that RMR rose up significantly 34 kcal/day by
Capsaicinoids/Capsinoids consumption compared with placebo,
(WMD: 33.99 kcal/day, 95% CI: 15.95, 52.03; I
2
:0%,p= .94)
(Figure 3) and this effect in RMR increase is mild to moderate
(SMD: 0.22, 95% CI: 0.06, 0.38) (Appendix 2). Although heteroge-
neity was at the lowest level, subgroup analysis was performed
for understanding the effects of factors on effect size (Table 3).
Forest plots for the corresponding subgroups are listed in Appen-
dix 3–18.
3.4.2 |Respiratory quotient
The pooled estimates of RQ (9 studies, 13 effect sizes) indicated that
in participants who consumed Capsaicinoids/Capsinoids, RQ declined
significantly in comparison to those who consumed placebo (WMD:
−0.01, 95% CI: −0.02, −0.01; I
2
: 5.4%, p= .39) (Figure 4); also, this
effect was moderate (SMD: −0.41, 95% CI: −0.59, −0.22) (Appendix
19). As it is seen, heterogeneity was not substantial; however, sub-
grouping was performed for discovering the effects of other factors
on effect size (Table 3). Forest plots for the corresponding subgroups
are listed in Appendix 20–35.
3.4.3 |Energy expenditure
Meta-analysis of four studies and seven effect sizes that assessed
the effect of Capsaicinoids/Capsinoids on EE showed an elevation
in EE. Pooled effect sizes revealed that in comparison to placebo,
Capsaicinoids/Capsinoids significantly increased EE (WMD: 4.88
Kcal/day, 95% CI: 1.75, 7.96; I
2
:0%,p= .54) (Figure 5). It is worth
pointing out that due to the limited studies in this case, few studies
have been pooled in each subgroup. Consequently, meta-regression
analysis was used to evaluate the effects of factors including age,
dose, duration, and BMI on EE. A positive relation with EE was rev-
ealed following the meta-regression for dose and duration, and by
an increment in both factors a rise in EE also happened, although
not statistically significant. In addition, the coefficient for age and
BMI was negative and statistically insignificant meaning that with an
elevation in age and BMI, EE diminished. The dosage of
Capsaicinoids/Capsinoids was one the strongest and age was one of
the weakest coefficients, respectively. The results have been shown
in Appendix 36.
3.4.4 |Fat oxidation
Regarding the results of meta-analysis on eight trials including
12 effect sizes, Capsaicinoids/Capsinoids supplementation led to a
significant rise in fat oxidation (WMD: 0.18 g/hr, 95% CI: 0.07, 0.29;
I
2
:55.1%,p= .01), with moderate to severe heterogeneity (Figure 6),
though this effect is moderate (SMD: 0.56, 95% CI: 0.26, 0.86). A
subgroup analysis was carried out to determine the source of the
heterogeneity. As presented in Table 3, after stratification by BMI
the heterogeneity was decreased or totally removed. In participants
with BMI ≥25 kg/m
2
(WMD: 0.59 g/hr, 95% CI: 0.29, 0.89; I
2
:
15.4%, p= .31), fat oxidation increased significantly after
Capsaicinoids/Capsinoids consumption compared with individuals
with BMI < 25 kg/m
2
(WMD: 0.50 g/hr, 95% CI: −0.27, 1.26; I
2
:0%,
p=.72).ButstratificationbyBMIledtoanincreaseineffectsize
and a decrease in heterogeneity in both groups (BMI < 25 kg/m
2
or
BMI > 25 kg/m
2
), which might stem from the exclusion of Yoshiaka
et al. study that had not reported the baseline value of BMI. After
excluding this study, pooled estimate changed considerably from
0.18 to 0.59 g/hr (WMD: 0.59 g/hr, 95% CI: 0.34, 0.85; I
2
:0%,
p= .60). In addition, after removing this trial, the heterogeneity was
totally removed.
It was also observed that stratification by duration attenuated
the heterogeneity. Usage of Capsaicinoids/Capsinoids for long
duration (WMD: 0.60 g/hr, 95% CI: 0.34, 0.87; I
2
:0%,p= .43)
boosted fat oxidation significantly more than the short duration
(WMD: 0.1 g/hr, 95% CI: 0.05, 0.14; I
2
: 17.2%, p= .30). Subgroup
analysis revealed that in addition to the reduction in heterogeneity
to its lowest value, older subjects (>35 years old) (WMD: 0.81 g/hr,
95% CI: 0.48, 1.14; I
2
:0%,p= .69) experienced significant increase
in fat oxidation in comparison to younger ones (<35 years old)
(WMD: 0.1 g/hr, 95% CI: 0.06, 0.14; I
2
:9.4%,p= .35). Further-
more, ingestion of Capsaicinoids/Capsinoids in capsule form
(WMD: 0.60 g/hr, 95% CI: 0.34, 0.87; I
2
:0%,p= .45) significantly
improved fat oxidation more than the ingestion of Capsaicinoids/
Capsinoids in powder form (WMD: 0.10 g/hr, 95% CI: 0.05, 0.14;
I
2
: 22.9%, p= .27). The result of subgroup analysis for remaining
factors including geographic area, dose, type of effective compo-
nent of red pepper, and weight was represented in Table 3.
12 IRANDOOST ET AL.

TABLE 3 Subgroup analysis for the effects of Capsaicinoids/ Capsinoids on RMR, RQ and fat oxidation
NO. ES Pooled effect size (95%CI) I
2
(%) P (Heterogeneity) P (Between)
RMR (kcal/day)
Age
<35 yr 6 28.90 (6.55,51.24) 0.0% 0.094
≥35 yr 7 43.39 (10.18,76.00) 0.0% 0.541 0.750
Not reported 2 44.44 (-34.36,123.24)
BMI
<25 kg/m
2
2 40.85 (-60.42,142.12) 0.0% 0.976
≥25 kg/m
2
11 40.50 (10.69, 70.32) 0.0% 0.792 0.846
Not Reported 2 29.66 (6.41,52.92) 0.0% 0.665
Weight
<70 kg 4 30.23 (7.56,52.89) 0.0% 0.972
≥70 kg 11 40.50 (10.69,70.32) 0.0% 0.792 0.591
Duration
Short term 5 28.85 (6.48,51.22) 0.0% 0.880
Long term 10 43.57 (13.04,74.10) 0.0% 0.832 0.446
Dose
<25 mg 10 35.25 (4.46,66.03) 0.0% 0.911
≥25 mg 4 33.30 (11.00,55.60) 0.0% 0.428 0.993
Not Reported 1 47.51 (-403.68,498.70) --- ---
Geographic area
Eastern 7 26.57 (5.08,48.06) 0.0% 0.955 0.212
Western 8 51.74 (18.51,84.97) 0.0% 0.818
Type
Capsule 11 43.47 (14.34,72.61) 0.0% 0.889
Powder 4 28.09 (5.10,51.07) 0.0% 0.778 0.854
Type2
Capsaicinoids 6 31.92 (9.94,53.91) 0.0% 0.580
Capsinoids 9 38.25 (6.67,69.83) 0.0% 0.941 0.680
Double blindness
Yes 3 -27.23 (-176.47, 122) 0.0% 0.671
No 12 34.90 (16.72, 53.08) 0.0% 0.914 0.951
Randomization
Yes 4 33.70 (13.39, 54.01) 0.0% 0.544
No 11 35.08 (-4.27, 74.43) 0.0% 0.913 0.418
RQ
Age
<35 yr 7 -0.01 (-0.02,0.00) 0.0% 0.993
≥35 yr 6 -0.02 (-0.03,-0.01) 49.2% 0.080 0.151
BMI
<25 kg/m
2
4 -0.01 (-0.02,0.00) 0.0% 0.927
≥25 kg/m
2
7 -0.02 (-0.03,-0.01) 39.1% 0.131 0.306
Not Reported 2 -0.01 (-0.02,0.00) 0.0% 1.000
Weight
<70 kg 4 -0.01 (-0.02,0.00) 0.0% 0.926
≥70 kg 8 -0.02 (-0.03,-0.01) 32.3% 0.170 0.354
Not Reported 1 -0.01 (-0.02,0.01) --- ---
Duration
Short term 6 -0.01 (-0.02,-0.00) 0.0% 0.992
Long term 7 -0.02 (-0.03,-0.01) 39.1% 0.131 0.126
(Continues)
IRANDOOST ET AL.13

TABLE 3 (Continued)
NO. ES Pooled effect size (95%CI) I
2
(%) P (Heterogeneity) P (Between)
Dose
<25 mg 7 -0.02 (-0.03,0.01) 24.5% 0.242
≥25 mg 5 -0.01 (-0.02,-0.00) 0.0% 0.417 0.665
Not Reported 1 -0.02 (-0.06,0.02) ---- ---
Geographic area
Eastern 6 -0.01 (-0.02, -0.00) 0.0% 0.998
Western 7 -0.02 (-0.03,-0.01) 45.7% 0.087 0.243
Type
Capsule 8 -0.02 (-0.03,-0.01) 29.8% 0.190
Powder 4 -0.01 (-0.02,-0.00) 0.0% 0.965 0.295
Not Reported 1 -0.01 (-0.02,0.01) --- ---
Type
Capsaicinoids 8 -0.01 (-0.02,-0.00) 0.0% 0.726
Capsinoids 5 -0.02 (-0.04,-0.01) 28.4% 0.232 0.105
Double blindness
Yes 3 -0.04 (-0.05, -0.02) 0.0% 0.633
No 10 -0.01 (-0.02,-0.00) 0.0% 0.879 0.007
Randomization
Yes 2 -0.01 (-0.02, -0.01) 0.0% 1.000
No 11 -0.02 (-0.02, -0.01) 15.2% 0.299 0.345
Fat oxidation (g/h)
Age
<35 yr 6 0.10 (0.06, 0.14) 9.4% 0.356 0.001
≥35 yr 4 0.81 (0.48, 1.14) 0.0% 0.696
Don’t reported 2 0.20 (-0.26, 0.67) 0.0% 0.720
BMI
<25 kg/m
2
4 0.50 (-0.27, 1.26) 0.0% 0.724
≥25 kg/m
2
6 0.59 (0.29, 0.89) 15.4% 0.315 0.001
Not Reported 2 0.09 (0.03, 0.15) 68.6% 0.074
Weight
<70 kg 5 0.10 (0.04, 0.15) 27.2% 0.240
≥70 kg 7 0.58 (0.30, 0.86) 6.5% 0.378 0.001
Duration
Short term 5 0.10 (0.05, 0.14) 17.2% 0.305
Long term 7 0.60 (0.34, 0.87) 0.0% 0.434 0.001
Dose
<25 mg 6 0.30 (-0.06, 0.66) 0.0% 0.865
≥25 mg 5 0.18 (0.05, 0.31) 80.7% 0.000 0.346
Not Reported 1 0.61 (-0.59, 1.81) --- ---
Geographic area
Eastern 7 0.10 (0.05,0.15) 17.6% 0.295
Western 8 0.57 (0.18,0.97) 36.6% 0.177 0.001
Type
Capsule 8 0.60 (0.34,0.87) 0.0% 0.452
Powder 4 0.10 (0.05, 0.14) 22.9% 0.273 0.001
Type2
Capsaicinoids 6 0.17 (0.05, 0.30) 75.9% 0.001
Capsinoids 6 0.34 (-0.01, 0.70) 0.0% 0.858 0.185
Abbreviations: BMI, body mass index; RMR, resting metabolic rate; RQ, respiratory quotient.
14 IRANDOOST ET AL.

FIGURE 8 Forest plot of weighted mean difference (WMD) in systolic blood pressure (SBP) in intervention and control groups [Colour figure
can be viewed at wileyonlinelibrary.com]
FIGURE 9 Forest plot of weighted mean difference (WMD) in diastolic blood pressure (DBP) in intervention and control groups [Colour
figure can be viewed at wileyonlinelibrary.com]
IRANDOOST ET AL.15

3.4.5 |Carbohydrate oxidation
Based on findings, it was revealed that in individuals supplemented
with Capsaicinoids/Capsinoids, carbohydrate oxidation (WMD:
−1.42 g/hr, 95% CI: −2.67, −0.18; I
2
: 28.2%, p= .23) declined signifi-
cantly (Figure 7), and its effect was moderate. In addition, meta-
regression was performed for factors such as age, BMI, intervention
duration and dose; however, for none of them significant correlation
was found. It seems that the strongest correlation was with the inter-
vention duration, and dose had the greatest effect on the heterogene-
ity level. The results were presented in Appendix 36.
3.5 |Other thermogenesis factors
Regarding the HR, due to the small number of studies and high het-
erogeneity, pooling studies and performing meta-analysis were
impossible (I
2
= 67.6%, p= .02). As mentioned in the systematic
review, a significant increase in HR was observed in two studies,
which was related to longer-term studies. Furthermore, meta-
analysis was not performed for BT and Vo2 max due to the small
number of studies.
3.5.1 |Increase in systolic and diastolic pressure
(as a side effect)
The pooled estimates for systolic blood pressure (SBP) and diastolic
blood pressure (DBP) are shown in (Figures 8 and 9). Accordingly, no
significant changes were observed in SBP (WMD: −0.98 mm/Hg, 95%
CI: −5.31, 3.36; I
2
: 0.0%, p= .70) and DBP (WMD: 0.85 mm/Hg, 95%
CI: −2.95, 4.66; I
2
: 19%, p= .29) after Capsaicinoids/Capsinoids
intake, although a small increase occurred in SBP.
3.6 |Publication bias
According to the visual inspection of funnel plots, no publication bias
was found for the effects of Capsaicinoids/Capsinoids on thermogen-
esis parameters. The funnel plots for RMR and RQ have been shown
in Appendix 37–38. They were confirmed by Egger's regression test.
It revealed no evidence of publication bias for EE (p= .35), CHO oxi-
dation (p= .54), SBP (p= .92), and DBP (p= .78). Begg's test demon-
strated no publication bias for RMR (p= .55), fat oxidation (p= .73),
and RQ (p= .16).
3.7 |Quality of evidence assessment
Our evaluation showed moderate evidence for the outcomes RMR,
RQ, carbohydrate oxidation, and EE but low quality evidence for fat
oxidation. The results are shown in Table 4.
3.8 |Sensitivity analysis
Based on sensitivity analysis, elimination of any of the studies did not
have a substantial influence on any of the assessing factors.
TABLE 4 Quality of evidence by GRADE assessment
Summary of findings
Quality assessment Number of participants
Absolute
effect
Number of
studies Limitation Inconsistency Indirectness Imprecision
Publication
bias Quality Intervention Placebo
WMD
(95%CI)
RMR 10
(RCTs)
Serious Not serious Not serious Not serious Undetected LLL
Moderate
273 229 33.99
(15.95,
52.03)
RQ 9 (RCTs) Serious Not serious Not serious Not serious Undetected LLL
Moderate
184 164 −0.01
(−0.02,
−0.01)
Fat oxidation
8 (RCTs)
Serious Serious Not serious Not serious Undetected LL
Low
200 169 0.18
(0.07,
0.29)
Carbohydrate
oxidation 4
(RCTs)
Serious Not serious Not serious Not serious Undetected LLL
Moderate
55 53 −1.42
(−2.67,
−0.18)
EE 4 (RCTs) Serious Not serious Not serious Not serious Undetected LLL
Moderate
114 107 4.86
(1.75,
7.96)
Abbreviations: EE: energy expenditure; RMR: resting metabolic rate; RQ: respiratory quotient; WMD: weighted mean difference.
16 IRANDOOST ET AL.

4|DISCUSSION
Current systematic review and meta-analysis was conducted to assess
the effect of Capsaicinoids/Capsinoids on thermogenesis in healthy
subjects. Regarding recent meta-analysis results, consumption of
Capsaicinoids/Capsinoids elevated thermogenesis significantly via an
increase in RMR, EE, fat oxidation as well as RQ and carbohydrate oxi-
dation reduction. Our findings were in agreement with two previous
meta-analyses that evaluated the effect of red pepper on EE and RQ
(Ludy et al., 2012; Zsiboras et al., 2018).
In a meta-analysis by Ludy et al., Capsiate increased EE
(SMD = 0.40, 95% CI: 0.22, 0.59) significantly but changes in EE fol-
lowing Capsaicin consumption did not reach significant levels
(SMD = 0.11, 95% CI: −0.06, 0.29). In that study, both Capsaicin and
Capsiate improved RQ (SMD = −0.35, 95% CI: −0.54, −0.15) and
(SMD = −0.31, 95% CI = −0.54, −0.07) (Ludy et al., 2012). As our sea-
rch results indicated, the study by Ludy et al. was the first in this field
on EE and RQ data. In another meta-analysis by Zsiboras et al. (2018),
the effect of Capsaicin/Capsiate on EE and RQ were studied in seven
trials. Based on pooling effect estimates in these studies, ingestion of
Capsaicin/Capsiate resulted in 58.56 kcal/day increase in EE (SMD:
0.24; 95% CI: 0.02, 0.46) and a significant reduction in RQ by 0.216
(SMD: −0.21; 95 CI: −0.41, −0.01). However, the studies that were
analyzed in Zsiboras et al. meta-analysis but the variables baseline
values were not reported in them, were not included in current meta-
analysis (Janssens et al., 2013; Smeets et al., 2013). Besides, it seems
that the latter meta-analysis has assessed the changes of EE as RMR
and total EE, while we presented the effect of Capsaicinoids/
Capsinoids separately in two EE and RMR forest plots. Therefore, it is
possible to discuss the effects of red pepper on RMR separately from
other factors that might affect EE. In our study, we also compared the
effect of consumption type including capsule or powder on thermo-
genic outcomes.
Our findings revealed that Capsaicinoids/Capsinoids in red pep-
per increased RMR. This elevation was considerable in those older
than 35 years old as well as in studies with longer duration (not as
one dose) and employing capsule forms. Intervention for long term
and in capsule form designs led to an elevation in RMR by 43.57 and
43.47 Kcal/day, respectively, nevertheless the nature of effective
components in red pepper (Capsaicinoid/Capsinoid) did not play an
important role in RMR changes. Considering duration, it is worth not-
ing that, for every 10 days of increase in intervention duration, RMR
increased by 3.94 kcal, which was close to the significant levels
(p= .17). Another most important effective factor in rising RMR is
geographic area. Our results revealed that Capsaicinoids/Capsinoids
consumption elevated RMR in western rather than eastern areas. Pep-
pers are major ingredients in food products all over the world, but in
eastern area it is more regularly used (Hursel & Westerterp-
Plantenga, 2010). Perhaps adding pepper to nonregular users in west-
ern area triggered more improvement in thermogenesis.
In view of quality scores, it was demonstrated that in randomized
trials, the effect of intervention on RMR was stronger, though double
blindness had a dropping effect on RMR. When subgroup analysis
was carried out for double blindness, the studies which did not have
double blind design caused greater increase in RMR compared with
studies with double blind design. However, in 15 effect sizes from
10 trials where RMR was reported, there were only two double blind
trials (three effect sizes) based on our quality assessment, indicating
the necessity for further studies with double blind design. As men-
tioned, RMR increased a little more in doses of <25 mg compared
with higher doses, although this difference was not considerable.
Since this effect was stronger in higher doses (SMD = 0.42, CI: 0.13,
0.72) than lower doses (SMD = 0.14, CI: −0.05, 0.33), it is possible
that factors such as greater number of the effect sizes in the subgroup
of the dose <25 mg (10 vs. 4) were effective in the results which was
further confirmed by meta-regression results for dosage and RMR. By
an increase in dosage, RMR also increased. We found 10 mg increase
in dose led to 2.98 Kcal increment in RMR. Even if this relationship
was not significant, the direct association of dosage and RMR was
revealed.
In the current study, it has been shown that intervention with
Capsaisinoids/Capsinoid reduced RQ significantly in comparison to
control groups. When the intervention was in capsule form and in
western area, the reduction in RQ was greater and in higher ages and
BMI the reduction was also greater. Intervention duration was
another contributing factor in RQ changes. It was revealed that for
every 10 days of increase in intervention duration, the RQ decreased
about 0.002, which was statistically significant. The decrease in RQ
was considerable in trials with stronger allocation and blindness, and
since the effect of the double blindness was marked, trials with double
blind design are suggested in further studies.
Evidently, RQ is affected by both fat and carbohydrate oxidation
(Patel & Bhardwaj, 2018), and in the current meta-analysis we evalu-
ated the effect of red pepper consumption on either factor individu-
ally. In intervention groups, fat oxidation increased and carbohydrate
oxidation decreased by 0.18 and 1.42 g/hr, respectively. Pooled esti-
mate of Capsaisinoids/Capsinoid supplementation effect on fat oxida-
tion demonstrated moderate to severe heterogeneity. Our finding
indicated that age is one of the most contributing factors in fat oxida-
tion. The heterogeneity totally disappeared in age ≥35 and also fat
oxidation was enhanced noticeably compared with subgrouping for
other factors (from 0.18 to 0.81 g/hr). Perhaps, due to the increase in
fat mass with age, more fat oxidation with negligible heterogeneity
occurred in higher ages following Capsaisinoids/Capsinoid supple-
mentation. Moreover, long duration intervention removed heteroge-
neity thoroughly and elevated fat oxidation. In addition, for every
10 days of increase in intervention duration, fat oxidation increased
0.1 g/hr. This correlation showed the effect of the duration of pepper
consumption on fat oxidation. Furthermore, remarkable higher fat oxi-
dation has been shown in western areas and supplementation in
capsule form.
The number of studies in which carbohydrate oxidation was mea-
sured was limited; consequently, we did not succeed in examining the
effective factors by subgrouping in the final analysis. However, using
meta-regression, a positive link was found between dosage and dura-
tion of intervention with carbohydrates oxidation, although it was not
IRANDOOST ET AL.17

significant. For better results, conducting more trials with carbohy-
drate oxidation assessments is suggested.
We also studied other indices of thermogenesis such as EE, HR,
BT, and Vo2. But since these factors have been considered as second-
ary outcome, the number of studies was insufficient to perform a
meta-analysis in some cases.
It should be noted that there was an elevation in EE following
Capsaicinoids/Capsinoids consumption. Although this amount was
statistically significant, it was too small from clinical point of view. In
addition, by an increase in age, BMI, duration and dosage of interven-
tion, red pepper had greater effect on EE. The increase in EE is less
than an increase in RMR, which can be due to fewer studies on EE
compared with RMR. The data of RMR and TEE were separated in
present meta-analysis to control either the effects of confounding fac-
tors such as physical activity, or to examine the effect of diet-induced
thermogenesis (thermic effect of food) separately from RMR. Possibly,
because of the greater effect of red pepper on RMR, it could be
expected that the effect of red pepper on TEE is more pertinent to
RMR. However, given the small number of studies that have been
evaluated for the effect on EE, it remained inconclusive.
In total, we examined some important components of thermogen-
esis. It seems that Capsaicinoids/Capsinoids consumption have a
moderate effect on thermogenesis, through several pathways men-
tioned above. Type of intervention (capsule or powder) and duration
of intervention are the most important factors.
On the other hand, thermogenic properties of Capsaicinoids/Cap-
sinoid accompanied with weight-loss diets are assessed in two
included studies in our meta-analysis (Lee et al., 2010; Lejeune
et al., 2003). As we know, metabolic adaptation and thermogenesis
reduction occurred following calorie restriction for saving energy
(Davis et al., 2017; Heymsfield et al., 2011; Ochner, Barrios, Lee, & Pi-
Sunyer, 2013). Consumption of Capsaicinoids/Capsinoid along with
calorie restriction diet attenuated decrease in thermogenesis occur-
ring with weight-loss diet. These investigations demonstrated that
Capsaisinoids/Capsinoid improved thermogenic indices during calorie
restriction and maintenance phases more than the placebo did.
However, in the current meta-analysis, due to lack of study in this
regard, stratification by low-calorie diets was impossible. There is a
gap in this area regarding the assessment of the Capsaicinoids/
Capsinoids effects on thermogenesis reduction in weight loss or main-
tenance periods.
Capsaicinoids/Capsinoids act as agonists of TRP channels and
activate sympathetic nervous system (SNS), which in turn trigger
uncoupling protein 1 (UCP1) as a thermogenic genes (TRP-SNS-UCP1
pathway) (Bonet et al., 2013; Hursel & Westerterp-Plantenga, 2010).
Aforementioned pathway causes adipose tissue remodeling and ele-
vate thermogenesis. Therefore, it seems reasonable that long-term
consumption of Capsaicinoids/Capsinoids have stronger effects than
short-term intervention, which are supported by our finding indicating
more thermogenesis indices in “long term”intervention subgroup.
Since Capsaicinoids/Capsinoids exert their thermogenic effect via
SNS stimulation (Bonet et al., 2013) the most serious side effect of
red pepper consumption could be hypertension. However, we
obtained no significant change neither in SBP nor DBP we obtained
no significant change in either SBP or DBP.
Thermogenic properties of red pepper in obese individuals
prompted a closer scrutiny into Capsaicinoids/Capsinoids on weight
loss to elucidate the antiobesity effect. However, concerning the few
studies included in our meta-analysis which reported the effect of red
pepper on weight loss (Inoue et al., 2007; Kawabata et al., 2006;
Lejeune et al., 2003) we could not achieve conclusive results about
the effect of Capsaicinoids/Capsinoids on weight loss.
Overall, our study assessed various dimensions of thermogenesis
following red pepper intake or its ingredients supplementation. In
addition, we adopted GRADE approach to the assessment of confi-
dence on our estimates. Several subgroup analyses which were con-
ducted in current meta-analysis elucidated contributing factors in
thermogenic effects of red pepper. Findings of the present meta-
analysis can be helpful for nutritionists and other clinicians to make a
decision to recommend red pepper supplements, in form of whole
herb or effective components, to improve energy balance considering
individuals' characteristics. Nevertheless, our meta-analysis as a strong
study collected the results of clinical trials and confirmed the thermo-
genic properties of red pepper. However, it is probable that some of
red peppers supplements do not have enough quality, especially in
powder form (Williamson, Liu, & Izzo, 2020).
Besides, according GRADE framework, despite some study limita-
tions such as lack of blindness, the confidence in this estimate for
most thermogenic parameters was still moderate. However, further
research with better designs are suggested to improve our confidence
and confirm our results.
Limitations of our study are as follows: First, due to the limitation
in primary outcome selection, a comprehensive review of weight loss
and other thermogenesis components such as HR and brown adipose
tissue activation was impossible. Second, we did not compare the
effect of red pepper on thermogenesis factors in regular user and
nonuser subjects. It is possible that red pepper ingredients have dif-
ferent effects in the two groups of users. Third, the effect of other
thermogenic items in participants' daily diet such as coffee and green
tea were not evaluated in our study. Fourth, we did not compare the
sole effects of Capsaicinoids/Capsinoids versus its concurrent use
with a low-calorie diet on thermogenesis indices with subgroup analy-
sis, due to the limited studies in this regard. Finally, it should be
pointed that, probably most of the studies included in the present sys-
tematic review and meta-analysis have been not done following rec-
ommendations of a recent consensus document providing a
perspective in best practice in pharmacological investigation on bioac-
tive preparations from plants (Heinrich et al., 2020).
5|CONCLUSION
Generally, consumption of red pepper or supplementation with its
effective ingredients led to a moderate improvement in EE, RMR, fat
oxidation, and reduction in RQ as well as carbohydrate oxidation. It is
required to perform further high-quality studies focusing on
18 IRANDOOST ET AL.

preventive effects of Capsaicinoids/Capsinoids in stopping and decel-
erating weight loss trend following calorie restriction diets. In addition,
studies on their preventive effects on brown adipose tissue activation
can be considerably helpful.
ACKNOWLEDGEMENT
The authors wish to thank to the Iran University of Medical Sciences.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests and no finan-
cial support.
ORCID
Pardis Irandoost https://orcid.org/0000-0002-4063-3879
Neda Lotfi Yagin https://orcid.org/0000-0001-8778-9582
Nazli Namazi https://orcid.org/0000-0002-3119-2805
Abbasali Keshtkar https://orcid.org/0000-0002-7305-8639
Naimeh Mesri Alamdari https://orcid.org/0000-0003-2563-8193
Mohammadreza Vafa https://orcid.org/0000-0001-7052-8810
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of this article.
How to cite this article: Irandoost P, Lotfi Yagin N, Namazi N,
et al. The effect of Capsaicinoids or Capsinoids in red pepper
on thermogenesis in healthy adults: A systematic review
and meta-analysis. Phytotherapy Research. 2020;1–20. https://
doi.org/10.1002/ptr.6897
20 IRANDOOST ET AL.