EE: Caffeine and Other Stimulants (2014)


Greenway FL, De Jonge L, Blanchard D, Frisard M, Smith SR. Effect of a dietary herbal supplement containing caffeine and ephedra on weight, metabolic rate, and body composition. Obes Res. 2004; 12(7): 1,152-1,127.

PubMed ID: 15292480
Study Design:
Randomized Crossover Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
  • To evaluate the effect of a dietary supplement containing herbal caffeine and ephedra on:
    • Metabolic rate
    • Weight loss
    • Body composition
    • Safety parameters. 
  • This study involved three phases:
    • Phase One: Tested the effect of the supplement containing caffeine and ephedra on metabolic rate compared to a placebo
    • Phase Two: Tested the safety and efficacy of the supplement
    • Phase Three: Observed the safety and weight loss over a six-month period. 
Inclusion Criteria:
  • Subjects 18 to 65 years old
  • BMI between 25 and 35kg/m2.
Exclusion Criteria:
  • Pregnant or nursing
  • Smokers
  • Taking regular medications except birth control or HRT
  • Taking MAOIs or methyldopa
  • Taking drugs for Parkinson's disease
  • Taking products containing ephedrine alkaloids
  • Diseases such as:
    • Thyroid disease
    • Diabetes
    • Blood pressure higher than 140/90mm Hg
    • Depression
    • Psychiatric disorders
    • Glaucoma
    • Prostatism
    • Seizure disorders.
Description of Study Protocol:


Recruitment was not specified. But the 12 subjects who participated in Phase One also participated in Phases Two and Three.   


  • Phase One: Double-blind, randomized, crossover trial where subjects received either the placebo or the oral supplement containing caffeine and ephedra
  • Phase Two: Double-blind, randomized controlled trial where subjects received either the supplement (C&E) or placebo
  • Phase Three: All subjects received the supplement with caffeine and ephedra for six months. 

Blinding Used

Phases One and Two were double-blinded. In Phase Three, blinding was not applicable as all subjects received the C&E supplement. 


  • Phase One: On two separate days,12 subjects were randomly assigned into either a placebo or supplement group (C&E) containing caffeine and ephedra. Resting metabolic rate was measured at baseline and then after ingestion of the pill and their RMR was measured for 30 minutes of each hour for two hours. Subjects then repeated the protocol on their second visit, the order was balanced and the assignment made randomly.
  • Phase Two: The initial 12 subjects plus 28 additional ones were randomly assigned to the herbal product containing caffeine and ephedra (C&E) or a placebo (20 subjects per group). All took two pills three times per day for three months with measurements at baseline and at three and six months. 
  • Phase Three: At the end of Phase two, all subjects were placed on the dietary herbal supplement and took two pills three times per day for six months. Subjects were seen monthly for measurements of variables. 

Statistical Analysis

  • Phase One: The difference in the area under the curves above baseline for energy expenditure during the two hours was analyzed using a Student T-test for paired samples with subjects serving as their own controls
  • Phase Two: Weight, pulse and blood pressure (BP) were compared using the mixed model with repeated measures analysis. Body composition by DXA and lipids were compared using the Student T-test. Adverse events, demographic data and dropouts were compared by X2.
  • Phase Three: Used descriptive statistics due to lack of a control group. 
Data Collection Summary:

Timing of Measurements

All subjects who participated in all three phases underwent the following tests at screening for participation into the study:

  • Medical history and physical examination
  • ECG
  • Blood tests:
    • Glucose
    • Creatinine
    • Potassium
    • Uric acid
    • Albumin
    • Calcium
    • Magnesium
    • Creatine phosphokinase
    • Alanine leucine transpeptidase
    • Alk. phos.
    • TSH
    • Total cholesterol, and LDL, HDL cholesterol
    • TG
    • Hgb/HCT
    • MCV
    • Platelet
    • WBC
    • Neutrophil
    • Eosinophil
    • Basophil
    • Urine analysis (UA).  

Measurements in the different phases included:

  • Phase One: On two separate occasions subjects reported to the laboratory after a 12-hour fast, refrained from strenuous physical activity for 24 hours and consumed their usual diet for the preceding three days. Subjects rested for 30 minutes, and then RMR was measured for 30 minutes. After ingesting the placebo or supplement, the RMR was measured for 30 minutes of each hour for two hours. 
  • Phase Two: 20 subjects were randomly assigned to the placebo group and 20 subjects were assigned to the supplement group. Measurements were obtained at baseline and monthly during the three-month trial. Instruction on a balanced 1,200kcal per day diet (women) or 1,500kcal per day (men) took place at baseline. Subjects were also asked to walk five minutes three times per day and gradually increase to 10 minutes four times per day over the length of the study.
  • Phase Three: All subjects from study two were placed on the supplement of two pills three times per day and were seen monthly for six months for recording of adverse events, BP, weight and pulse rate. At the end of the six months, blood tests for TSH, ECG and UA were repeated. 

Dependent Variables

  • Resting metabolic rate (Deltatrac II)
  • Weight, percent body fat/body composition measured by:
    • DXA
    • Cholesterol
    • HR
    • BP
    • TSH.

Independent Variables

Supplement containing caffeine and ephedra and other herbs (C&E: 12mg ephedra and 35mg caffeine per capsule).

Control Variables

  • Physical activity was limited for 24 hours before measurements in Phase One. Physical activity was suggested and encouraged to be controlled in Phases Two and Three.
  • Subjects were fasted for 12 hours prior to RMR measurements
  • Subjects were instructed on healthy lifestyle changes for Phases two and three.  
Description of Actual Data Sample:

Initial N

  • Phase One: Twelve subjects participated and finished the study
  • Phase Two and Three: Forty subjects were recruited to participate in the study. 

Attrition (Final N)

  • Phase One: All 12 subjects finished the study
  • Phase Two: 31 subjects completed the study (12 in the supplement group and 19 in the placebo group)
  • Phase Three: Of the 12 subjects in the group randomized to C&E in Phase One, 11 completed Phase Three. Of the 19 subjects in the group originally randomized to placebo, 13 completed Phase Three. 


  • C&E: 46.8±2.8 years
  • Placebo: 45.3±1.9 years.


  • C&E: Six black, 14 white
  • Placebo: Four black, 16 white.

Other Relevant Demographics

  • BMI (kg/m2):
    • C&E: 29.7±0.5
    • Placebo: 29.6±0.5.
  • Weight (kg):
    • C&E: 82.8±3.2
    • Placebo: 83.2±2.0.


There was no significant difference between the placebo or C&E group at baseline in terms of:

  • Gender
  • Race
  • Age
  • BMI
  • Weight. 


United States.

Summary of Results:

Key Findings

  • Phase One: The RMR was 8%±0.1% (SE) higher when the subjects took the C&E supplement (P<0.01).
  • Phase Two:
    • There was no significant difference in the incidence of adverse events between the two groups
    • The C&E group did not experience the adrenergic symptoms typically associated with caffeine or ephedra in excess of the placebo group
    • There were no serious adverse events and the only arrhythmia was seen in the placebo group
    • The C&E group lost more weight (3.5kg±0.5kg in the supplement group compared to 0.8kg±0.5kg in the placebo group). This was significant (P<0.02) as a treatment effect, a time effect (P<0.001) and a time x treatment interaction (P<0.001).
    • Compliance with pills was 90% on average and did not differ between groups
    • Pulse rate decreased 0.3bpm below baseline in the C&E group compared with a 6.6bpm decrease in the placebo group. This was significant as a treatment effect (P<0.03) and a time effect (P<0.04) but not a time x treatment interaction. 
    • There was no difference in blood pressure between the C&E group and placebo (P>0.1)
    • Total cholesterol, HDL, LDL and TG was not different between the two groups at three months
    • Percent weight loss at three months by DXA was 4.8%±1.5% in the C&E group compared with the 0.9%±0.8% in the placebo group (P<0.02)
    • The percent fat loss at three months by DXA was 7.9%±2.9% and 1.9%±1.1% in the C&E group and the placebo group respectively (P<0.05) 
    • The percent loss of lean tissue was 1.7%±1.1% in the C&E group compared to  0.27%±0.9% in the placebo group (not significant). Less lean tissue was lost as a percentage of total weight loss compared with the placebo group, but this was not significant.
  • Phase Three:
    • At six months, the group that started on C&E lost 7.8%±1.9% body weight. The group that started on placebo and then went to C&E lost 7.3%±1.9%. 
    • There were no serious adverse events and no evidence of toxicity on physical examination, urinalysis or blood testing. 

Other Findings

  • The mean increase in RMR in the C&E group was 8%. This is consistent with other studies that supplemented with 20mg ephedra and 200mg caffeine. 
  • The researchers did not feel that the other herbs included in the C&E supplement would have contributed to its weight loss effects
  • DXA confirmed the loss of body weight as well as a loss of body fat. C&E did not significantly preserve lean body mass in this study, however. 
Author Conclusion:

C&E increased RMR by 8% compared with placebo, promoted more weight and fat loss, and was well tolerated. 


Funding Source:
Science Technology and Toxicology, San Francisco, CA
Reviewer Comments:
  • Small sample size for Phase One for measuring RMR
  • Ephedra no longer approved by FDA.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? No
2. Was the selection of study subjects/patients free from bias? ???
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? No
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? ???
  10.1. Were sources of funding and investigators' affiliations described? ???
  10.2. Was the study free from apparent conflict of interest? ???