EAL

EE: Ephedra (2005)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To assess the acute thermogenic effects of chewing gum containing different doses of nicotine and caffeine, separately and in combination, and to compare their effects with those of placebo chewing gum in healthy, normal-weight men.

Inclusion Criteria:

Understand and give written consent
Healthy men, aged 18 to 45, with BMI values of 18.5 to 25
Smoker group: smoking more than 15 cigarettes a day for more than a year
Non-smokers group: Never smoke on a regular daily basis
No history of substance use
No current healthy problems or medication used.

Exclusion Criteria:

Refusal to consent
Not meeting inclusion criteria.

Description of Study Protocol:

Recruitment

Subjects were students at the Royal Veterinary and Agricultural University.

Design

Randomized, double-blind,crossover, placebo-controlled trial.

Blinding

Double-blind.

Statistical Analysis

Power analysis was used to determine number of subjects in the study
Analysis of variance (ANOVA) with interaction analysis of covariance to analyze energy expenditure and RQ. Covariates included:
- Baseline values [i.e., resting energy expenditure (EE) and resting respiratory quotient (RQ)]
- Smoking status
- Period (on which week the subject was given the different types of gum)
- Carry-over (which type of gum the subjects were given the previous time)
- Age
- Height
- Weight
- Percentage body fat
Bonferroni's correction for multiple test was applied for multiple post-hoc comparisons
Two-sided P values <0.05 were considered statistically significant.

Data Collection Summary:

Timing of Measurements

A randomized, double-blinded, crossover, placebo-controlled trial that tested seven different chewing gums
Each subject underwent seven three-hour sessions in a within-subject design of total of six REE measurements with two pieces of gum per day
Protocol for each test day: The first piece of gum was given 30 minutes after the test started and the second piece was given after an additional 60 minutes. The subjects chewed each piece of gum for 25 minutes.
The meal was consumed after the final (sixth) measurement (180 minutes)
A washout period of two or more than two days elapsed between test days for each subject.

Dependent Variables

Measured REE [(VO₂, L per minute), VCO₂ (L per minute; ml per kg per minute), RQ, ventilation (L per minute)].
- IC type: Open-circuit IC
- Equipment of Calibration: 5% CO₂ and 95% O₂
- Coefficient of variation using std gases: Yes
- Rest before measure (state length of time rested if available): 10 minutes
- Measurement length: 25 minutes each, 150 minutes total (180 - 30 = 150)
- Steady state: Not addressed
- Fasting length: Post-absorptive
- Exercise restrictions XX hour prior to test? 48 hours
- Room temp: Not addressed
- Number of measures within the measurement period: Six 25-minute measurements
- Were some measures eliminated? No
- Were a set of measurements averaged? No
- Coefficient of variation in subjects measures? Not addressed
- Training of measurer? Not addressed
- Subject training of measuring process? Not addressed.
- Monitored heart rate? Not addressed
- Body temperature? Not addressed
- Medications administered? No.

Independent Variables

Seven types of gum containing following doses of nicotine-to-caffeine (mg-to-mg): 0/0, 1/0 2/0, 1/50, 2/50, 1/100, and 2/100.

Control Variables

Baseline values (resting EE and resting RQ)
Smoking status (non-smoker or smoker)
Period (on which week the subjects were given the different types of gum)
Carry-over (which type of gum the subjects were given the previous time)
Age
Height: Measured to nearest 0.001m
Weight: Measured using a digital scale accurate to 0.01kg
Percentage body fat: Electrical impedance.

Description of Actual Data Sample:

Final N

N=12 males (6 smokers, 6 non-smokers).

Age:

Smokers: 25±3.0 years
Non-smokers: 24±2.5 years
NS.

Ethnicity

Danish.

Anthropometrics

	Smokers	Nonsmokers
Weight (kg)	82.8±10.0	79.9±7.6
Height (m)	1.88±0.08	1.86±0.03
BMI	22.9±1.53	23.1±2.9
Percent of body fat	16.0±4.7	17.2±4.9

Location

Denmark.

Summary of Results:

Energy Expenditure

Thermogenic response was significantly affected by both nicotine (P<0.001) and caffeine (P<0.001)
There was an interaction between nicotine and caffeine (P<0.05). The responses were not influenced by smoking status.
The thermogenic responses (increases over response to placebo) were 3.7%, 4.9%, 7.9%, 6.3%, 8.5% and 9.8 %, respectively, for the gums containing 1/0, 2/0, 1/50, 2/50, 1/100, 2/100mg nicotine per mg caffeine (P<0.05 for all).
Nicotine: The thermogenic responses were higher after 1.0mg nicotine (P<0.001) and 2.0mg nicotine (P<0.001) than after 0mg nicotine. However, there were no significant difference between 1.0mg nicotine and 2.0mg nicotine (P>0.05).
Caffeine: There was a greater thermogenic effect of 50mg caffeine (P<0.05) and 100mg caffeine (P<0.01) compared with 0mg caffeine. However, there was no significant difference between 50mg caffeine and 100mg caffeine (P>0.05).
Adding caffeine to either 1.0 or 2.0mg nicotine significantly enhanced the thermogenic response, but there was not significant difference between the thermogenic effects of adding 50 or 100mg caffeine to nicotine.

There was no significant interaction between nicotine and caffeine in the effect of treatment on RQ
Caffeine had a significant treatment effect on RQ (P<0.05), but nicotine did not
The post-dose RQ was influence by the covarites baseline RQ (P<0.001), body weight (P<0.01) and EE (P<0.05) (analysis of covariance).

Side Effect

No side effects were reported with placebo gum or the gums that contained 1.0mg nicotine with zero, 50, or 100mg caffeine
Side effects were only reported with the gums that contained 2.0mg nicotine
The side effects were headache, unpleasant taste in mouth, dizziness, vision problems and nausea.

Author Conclusion:

In conclusion, we found that 1.0mg nicotine has a pronounced thermogenic effect, which is increased by approximately 100% when it is combined with 100mg caffeine. Increasing nicotine dose from 1.0 to 2.0mg did not increase the thermogenic effects but produced side effects in most subjects.

Funding Source:

Industry:

Fertin Pharma (Denmark)

Pharmaceutical/Dietary Supplement Company:

Reviewer Comments:

Strengths

Randomized, double-blinded, cross-over control trails. Systematic error or bias is unlikely.
Effects of nicotine/caffeine gum were both assessed on smoker and non-smokers
Study protocol and statistics was carefully designed to avoid possible errors or bias, such as two-day washout period, restricted physical activity, accounting covariates in analysis.

Generalizability/Weaknesses

Relatively small sample size, although a power calculation was done
Apply to only healthy young men. Would be enhancing its generalizability if the sample population includes females.
Limitations of study were not addressed.

[Analyst note: This study was accepted even though it DID NOT meet sorting criteria of N=10 for each group due to interest in chewing gum therapy for smoking cessation and weight loss. Any evidence will be qualified by noting the smaller sample size. It should also be noted that the sample size was determined using a power calculation on the basis of a resting oxygen consumption of 250 ml per minute, a CV of 5.8% in measurement of resting metabolic rate and a 95% probability of detecting a 3% difference in thermogenic response between two treatments.]

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?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	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?	Yes
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.)	Yes
	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?		No
	4.1.	Were follow-up methods described and the same for all groups?	N/A
	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%.)	No
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	???
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	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?	N/A
	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)?	Yes
	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?	N/A
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?	No
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes