increased morbidity from diabetes , hypertension , cardiovascular disease , and inflammatory disorders is common in developing and developed countries [ 2 , 3 ] .
more than one - quarter of health care costs related to obesity and associated disorders . promoting weight loss ,
decreasing body fat , maintenance of negative energy balance , reducing energy intake , and increasing energy expenditure through physical activity reduce body weight .
the interest in natural herb supplements such as gymnema sylvestre , green tea , sphaeranthus indicus , garcinia mangostana , dolichos biflorus , and piper betle leaves for treatment of obesity was rapidly growing because of their minimal side effects .
the spicy varieties of capsicum were investigated for their effects on weight loss and thermogenesis . commonly called chili peppers , or simply  chilies ,  capsicum is used as a food additive in many regions due to its pungency , aroma , and color .
it was safely consumed in large amounts in many countries , especially in mexico and korea , where per capita consumption reaches 15 grams per day .
more moderate consumption up to 5 grams daily per capita of capsicum was reported in thailand and india . in u.s .
, consumption of all peppers increased , from an average of 6.94  kg per person in 2005 to 8.66  kg per person in 2012 and consumption of bell peppers grew from 4.17  kg to 5.03  kg , while chili pepper consumption grew from 2.77  kg to 3.36  kg .
the daily consumption of all peppers was approximately 24  g / person and chili pepper was 9  g / person .
capsicum ( capsicum annuum l. or capsicum frutescens l. ) and paprika ( capsicum annuum l. ) were generally recognized as safe ( gras ) for their intended use in food ( 21 cfr 182.10 ; 582.10 ; 21 cfr 182.20 ; 582.20 ; 21 cfr 73.340 ) .
the most abundant forms of capsaicinoids found in hot red peppers are capsaicin ( trans-8-methyl - n - vanillyl-6-nonenamide ) , dihydrocapsaicin , and nordihydrocapsaicin . about 70% of the burning sensation experienced from consumption of chili red peppers
capsaicinoids ( caps ) are detected rapidly using gas chromatography or supercritical fluid extraction and supercritical fluid chromatography ( sfe / sfc ) .
approximately 3  mg of capsaicinoids is present within 1  g of dried red pepper .
evidences showed that capsaicin has effects on digestive tract , regulating homeostasis and other deleterious effects .
capsicum and capsaicinoids improve metabolism and hormone function , stabilize blood glucose [ 9 , 10 ] , reduce insulin and leptin resistance   and endothelial function , inhibiting ldl - cholesterol oxidation , and prevent cancer due to antioxidant activity [ 1416 ] .
spicy food consumption showed highly consistent inverse associations with total mortality among both men and women after adjustment with potential risk factors .
the adjusted hazard ratios for death were 0.90 ( 95% confidence interval 0.84 to 0.96 ) , 0.86 ( 0.80 to 0.92 ) , and 0.86 ( 0.82 to 0.90 ) for those who ate spicy food 1 or 2 , 3 to 5 , and 6 or 7 days a week , respectively .
people consuming spicy foods 6 or 7 days a week showed a 14% relative risk reduction in total mortality .
inverse associations were also observed for deaths due to cancer , ischemic heart diseases , and respiratory diseases .
capsaicinoids ( caps ) , potential ingredient to support body weight , reduce ad libitum energy intake [ 1719 ] , increase thermogenesis and energy expenditure [ 7 , 9 , 2022 ] , and increase lipolysis [ 7 , 9 , 20 , 21 , 2326 ] . since studies have used a variety of treatments ( chilies and dietary supplements ) within the research design , the results for a given outcome measure the ingested treatment , dose , and product quality .
however , assuming the overall effects as noted above , epidemiological data seem to support an association between consumption of caps containing foods and a lower incidence of obesity and associated disorders [ 15 , 27 ] .
caps are major naturally occurring pungent principles in red - hot pepper ( figure 1 ) .
the current study was a pilot study designed to study the safety and tolerability of capsaicinoids from capsicum extract fruit in a beadlet form , administered to a group of 12 healthy overweight female subjects to escalating dosages of caps from capsicum extract fruit ( i.e. , 210  mg capsaicinoids ) .
daily diary data was maintained by subjects to show general tolerability and record adverse events .
the study is designed to test different doses of caps product ( 2  mg caps , 4  mg caps , 6  mg caps , 8  mg caps , and 10  mg caps ) on tolerability , safety , and anthropometric and metabolic measures in overweight healthy subjects .
the study was a single center , dose - finding , open - label , and adaptive study design with twelve ( 12 ) overweight women taking escalating doses of the study product , each dose for six ( 6 ) weeks .
an ascending dose protocol evaluated a total dose of up to 10  mg daily given in different doses ( 2  mg , 4  mg , 6  mg , 8  mg , and 10  mg of caps ) .
safety and tolerability are assessed by recording vital signs , electrocardiograms , clinical chemistry parameters , urinalysis , and adverse events .
institutional review board ( irb ) approval was received ( copernicus group , irb , cary , nc ) .
all participants completed a detailed medical history , prior and concomitant medications , and physical activity questionnaire . 

healthy female subjects between 25 and 55 years of age and with body mass index ( bmi ) between 25 and 34.9  kg / m were included .
subjects were excluded based on regular ingestion of chili peppers ( raw or powdered form ) , black pepper , or ginger or foods known to contain chili peppers , black pepper , or ginger more than 3 times per week .
subjects were excluded for any prescribed medications for chronic diseases such as inflammatory disorders , metabolic disorders , diabetes , cardiovascular disease , cancer , hiv / aids , and obesity .
subjects with recent history of alcoholism ( within 12 months ) or drug abuse were excluded .
study design and number of visits of participants are reported in figure 2 . medical history , review of concomitant medications , vital signs , demographic assessments , anthropometric measurements ,
physical examination , and laboratory assessments including urine collection for pregnancy and blood draws for cbc and cmp were assessed .
subjects returned to the site every week and tolerability reviews were conducted using open - ended questions .
subjects were given 2  mg caps ( 100  mg capsimax ) , 4  mg caps ( 200  mg capsimax ) , 6  mg caps ( 300  mg capsimax ) , 8  mg caps ( 400  mg capsimax ) , and 10  mg caps ( 500  mg capsimax ) during each visit .
vital signs , medical history , and tolerability survey were recorded for subjects at each visit .
blood samples were analyzed for safety markers such as complete blood count ( cbc ) and comprehensive metabolic panel ( white blood cells , red blood cells , hemoglobin ( hb ) , hematocrit , mean platelet volume ( mpv ) , mean corpuscular volume ( mcv ) , red cell distribution width ( rdw ) , platelet count , mean corpuscular hemoglobin , neutrophil , lymphocyte , monocytes , eosinophil , basophil , total protein , albumin , globulin , ratio of albumin and globulin , calcium , chloride , sodium potassium , and anion gap ) and liver , lung , and kidney function tests ( serum glutamic - oxaloacetic transaminase ( sgot ) , serum glutamic - pyruvic transaminase ( sgpt ) , alkaline phosphatase , bilirubin , carbon dioxide , blood urea nitrogen ( bun ) , and creatinine blood urea nitrogen ) . frequency and intensity of adverse event ( ae ) and serious aes were recorded based on the diaries and interviews during each visit .
capsimax , a proprietary product , consists of capsaicinoids ( caps ) obtained from dried red fruits of capsicum annuum l. the capsicum extract was standardized into a beadlet form with food grade carbohydrates useful for food applications .
capsimax is a faint , pinkish - white colored , free - flowing , uniform spheroidal beadlet with a spicy odor characteristic of dried ripe fruits of capsicum .
the product was standardized to 2% capsaicinoids , of which 1.21.35% is capsaicin , 0.60.8% is dihydrocapsaicin , and 0.10.2% is nordihydrocapsaicin .
the product has 1525% extract from capsicum , 4555% sucrose , and 3035% cellulose gum coatings .
placebo and capsimax capsules ( providing 2  mg , 4  mg , 6  mg , 8  mg , and 10  mg caps ) from capsicum extract in beadlet form are provided by omniactive health technologies ltd . ,
a modified per - protocol analysis was performed including all subjects who had at least one poststudy product exposure visit .
primary endpoints were tolerability assessments and aes and secondary end points were blood safety markers ( complete blood count ( cbc ) and comprehensive metabolic panel ( cmp ) ) .
change in assessments for tolerability and safety measures is assessed by anova in a repeated measures design .
this allowed for an assessment of the main effect of time , dose , and time by dose interaction .
a paired sample t test was used to assess changes over time for each group .
mean , standard deviation and significance and categorical variables are summarized as counts and percentages .
data derived from diary entries , clinical chemistry assessments , questionnaires , and other relevant assessments at baseline and after supplementation . statistical software for social sciences ( spss version 19 ) was used to run all analysis .

 table 1 provides descriptive baseline characteristics of the participants . in the current study , 58% subjects were hispanics and 42% were non - hispanic subjects .
overweight healthy women participated in the study ( mean bmi : 28  kg / m ) .
subjects tolerability survey reports suggest that escalating doses of caps ( 210  mg caps ) had no significant changes in the skin , bowel movements , hair , digestion , urination , mouth or throat , and breathing . at week 2 , only 92% of the subjects reported no changes in their urination .
four incidences of adverse events such as sprained ankle , elevated blood pressure , stomach ache , and increased urination are reported . however , in investigator evaluation , these incidences unrelated to product consumption .
no significant changes were observed for vital signs , body weight , body mass index , and blood pressure over baseline ( sbp / dbp , table 2 ) .
no statistically significant changes were observed in cbc compared to baseline for all markers ( table 3 ) . there were no significant changes in liver , lung , and kidney function test .
repeated measures analysis of variance for all assessments revealed no significant effect of dose on tolerability assessments and safety measures .
capsaicinoids ( caps ) serve as agonists of the transient receptor potential vanilloid subfamily member 1 ( trpv1 ) .
trpv1 releases substance p , which activates the postsynaptic receptor of substance p , neurokinin-1 .
caps are found to have weight loss properties based on their potential mechanism of action ( figure 3 ) .
activation of neurokinin-1 results in an increased activation of the sympathetic nervous system , leading to the release of epinephrine ( epi ) and norepinephrine / noradrenaline ( na ) .
recent systematic review and met analysis [ 30 , 31 ] reported that consumption of 2  mg capsaicinoids increases energy expenditure ( 50  kcal / day ) and would produce clinically significant levels of weight loss in 1 - 2 years .
it was also observed that regular consumption reduced much abdominal adipose tissue levels and reduced appetite and energy intake as part of a weight management program . 
 in vitro dissolution data ( unpublished ) for 500  mg capsimax beadlets is equal to 10  mg caps tested in acidic medium similar to stomach ph .
in addition , caps from capsimax were released in alkaline medium , which is similar to conditions in the upper intestine .
the release of caps in alkaline medium was gradual , over the period of 4 hours . at 4 hours
results from this study showed that 6-week consumption of the study product in increasing doses ( 210  mg / d ) has no significant effect on change in skin color , bowel movements , hair , digestion , mouth or throat , and breathing including urination .
there were no significant changes in anthropometric measures , clinical chemistries , cbc , metabolic measures , and vital signs compared to baseline measurements .
overall , the results of the study indicated that caps supplemented dosages were safe and well tolerated .
the current data supports that higher dose of caps was safe and tolerable for human consumption .
the results reinforce animal and human studies on the acute effects of caps on metabolic measures such as white blood cells ( wbcs ) , neutrophils , eosinophils , basophils , monocytes , lymphocytes , t lymphocytes , b lymphocytes , and nk cells .
capsaicinoids decreased the levels of acquired immunity cells and increased the number of total wbcs and neutrophils without changing the number of monocytes , eosinophils , or basophils .
this indicates that intake of caps does not elicit harmful immune response . 
 in vitro and in vivo studies
the rats showed oral irritation when fed with normal capsicum extract during pilot experiments , because no irritation was noted with caps ( capsimax beadlets ) .
caps and caps plus formulations did not show any adverse effects on body weights or on organs as evaluated by necropsy and histopathological examination .
the caps ( capsimax ) and caps containing formulations were tolerable in experimental animals and without any behavior changes .
in mutagenesis test , no real increase in revertant colony numbers in any of the five tester strains was observed following caps treatment at any concentration , regardless of metabolic activation ( s9 mix ) .
there was also no tendency for higher mutation rates with increasing concentrations in the range below the border of biological relevance .
the results of these investigations revealed that caps did not induce gene mutations by base pair changes or frameshifts in the genome of the strains .
the results of these investigations suggest that caps were nonmutagenic in both the presence and the absence of metabolic activation . in the chromosomal aberration test , caps were tested in human peripheral blood lymphocyte cultures .
caps did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used .
caps were well tolerated , with no observed side effects related to gastric upset or discomfort .
no difference in heart rate and systolic or diastolic blood pressure was noted as compared to placebo at up to 4 hours after dosing .
the current findings suggest that daily consumption of capsaicinoids up to 10  mg was well tolerated and no significant changes in blood chemistries were observed . the limitations of the study were only up to 10  mg capsaicinoids for 7-day intervention for tolerability and safety of the product .
this study is only trying to find the dose of tolerability to use in efficacy studies .
recent studies suggest that capsaicinoids from capsicum extract alone and/or with other ingredients reported no adverse events and further confirmed that caps are safe [ 26 , 3945 ] .
the results of these clinical trials show that 2  mg caps ( capsimax ) were safe and tolerable for human consumption .
furthermore , no serious adverse effects were reported , and the regimen was well tolerated .
the current findings suggest that daily consumption of 2  mg caps and up to 10  mg caps were well tolerated and no significant changes in liver and kidney functions . further long - term safety and efficacy studies are warranted .
the escalating dose levels of caps from capsimax product , a highly concentrated natural capsicum fruit extract , were found tolerable and safe for human consumption .
 a single center , open - label , dose - finding adaptive study was conducted in twelve healthy overweight female subjects . 
 the study was to evaluate the safety and tolerability of the capsaicinoids ( caps ) from capsicum extract in a beadlet form compared to placebo in a healthy overweight population . 
 the investigational product capsaicinoids ( caps ) from capsicum extract in a beadlet form ( capsimax ) a proprietary encapsulated form of capsicum extract in beadlet form supplemented at 2  mg , 4  mg , 6  mg , 8  mg and 10  mg of caps . 
 an ascending dose protocol evaluated a total dose of 10  mg daily given in five divided doses ( 2  mg , 4  mg , 6  mg , 8  mg and 10  mg of caps ) . 
 each dose was given for a week . 
 safety and tolerability were assessed . 
 primary outcomes were tolerability assessments and reports of adverse events . 
 tolerability assessments were observed on skin color and any changes in skin , bowel movement , digestion , mouth or throat , hair color or changes in hair color , urination includes frequency and burning sensations , breathing , any changes in their health . 
 secondary outcomes were body weight , body mass index ( bmi ) , blood pressure ( sbp / dbp ) , vital signs , electrocardiograms , clinical chemistry parameters including liver function tests , lung function tests and kidney function tests and complete blood count ( cbc ) . 
 no dose effective changes were observed . 
 the escalating dose levels of caps in a beadlet form product found was tolerable and safe for weight management studies . 
 tolerability assessments and safety blood markers showed no significant changes from baseline . 
 no significant serious adverse events were reported throughout the duration of the study . 
 further longer term studies are required to explore the tolerability of the product . 
 this trial is registered with isrctn : #  isrctn10975080 . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions