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November 09, 2012

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International Journal of Obesity (****) **, **** *556

www.nature.com/ijo

ORIGINAL ARTICLE

Multinutrient supplement containing ephedra and

caffeine causes weight loss and improves metabolic

risk factors in obese women: a randomized controlled

trial

RM Hackman1, PJ Havel1, HJ Schwartz2, JC Rutledge2, MR Watnik3, EM Noceti1, SJ Stohs4,

JS Stern1,2 and CL Keen1,2

Department of Nutrition, University of California, Davis, CA, USA; 2Department of Internal Medicine, University of

California, Davis, CA, USA; 3Department of Statistics, California State University, East Bay, CA, USA and 4Department of

Pharmacy Science, Creighton University, Omaha, USA

Objective: To determine the safety and efficacy of a dietary supplement with a low dose of ephedra and caffeine in overweight/

obese premenopausal female subjects.

Design: A 9-month, double-blind, randomized control study compared the efficacy and safety of a dietary supplement with

ephedra and caffeine to a control supplement.

Subjects: Sixty-one healthy, premenopausal women with body mass index (BMI) from 27 to 39 kg/m2 were randomly assigned

and received a dietary supplement (40 mg/day ephedra alkaloids, 100 mg/day caffeine, high potency mixture of vitamins,

minerals, omega-3 fatty acids) or a control supplement for 9 months.

Measurements: Efficacy: changes in body weight, body composition, lipids, insulin, leptin, adiponectin, ghrelin, and self-reports

of physical activity, diet and quality of life indices. Safety: blood pressure, heart rate, electrocardiograms, urinalysis, blood

histology, serum chemistry measures and self-reported symptoms.

Results: Forty-one women completed the study. The treatment group lost significantly more body weight ( 7.18 kg) and body

fat ( 5.33 kg) than the control group ( 2.25 and 0.99 kg, respectively), and showed significant declines in heart rate, serum

cholesterol, triglycerides, cholesterol to high-density lipoprotein ratio, glucose, fasting insulin, and leptin. Blood pressure,

electrocardiograms, other clinical chemistry measures, blood histology, urinalysis, and self-reported physical activity were similar

in the groups. Minor symptoms included dry mouth, insomnia, nervousness and palpitations. The treatment group reported

more energy and decreased appetite compared to controls and scored higher on a quality of life domain assessing vitality.

Conclusion: A dietary supplement containing a low potency ephedra/caffeine mixture appeared safe and effective in causing

loss of weight and body fat, and improving several metabolic parameters, including insulin sensitivity and lipid profiles when

tested under physician supervision. Such supplements could be a useful tool to assist with weight loss.

International Journal of Obesity (2006) 30, 1545 1556. doi:10.1038/sj.ijo.0803283; published online 21 March 2006

Keywords: (MeSH) ephedra; weight loss; dietary supplement; lipids; insulin; leptin

contributes to at least 300 000 deaths per year,2 and

Introduction

conservatively costs an estimated $75 billion annually in

health care and related costs in the US.3

An estimated 64% of American adults are overweight or

obese (body mass index (BMI) in kg/m2X25.0).1 Obesity is Physicians tend to underreport obesity, and less than half

of obese persons are advised to lose weight or offered a

associated with a number of chronic health problems,

supervised diet or exercise program by their doctor.4,5 These

trends may encourage people seeking weight loss to respond

Correspondence: Dr RM Hackman, Department of Nutrition, University of to heavily marketed products such as nutrition supplements,

California, One Shields Avenue, Davis, CA 95616-8669, USA.

many of which have limited evidence of safety or efficacy.

E-mail: abo92q@r.postjobfree.com

Studies in the early 1990s found that a combination of

Received 24 June 2005; revised 6 January 2006; accepted 19 January 2006;

ephedrine and caffeine significantly reduced body weight

published online 21 March 2006

Multinutrient supplement with low-dose ephedra and caffeine

RM Hackman et al

1546

and fat in humans over a 6-month period.6 Subsequent Table 1 Baseline characteristics of the subjectsa

2- and 6-month studies using combinations of ephedra (Ma

Control (N 32) Treatment (N 29)

Characteristic

Huang) and caffeine reported similar weight loss findings.7,8

The US Food and Drug Administration (FDA) banned the sale Race or ethnic group

African American 1 2

of dietary supplements containing ephedrine alkaloids in

Filipino American 2 0

2004, citing concerns such as consumption of high, Latino American 2 6

unregulated dosages, and use by at-risk populations with Mexican American 0 1

comorbid conditions.9 However, in 2005, a US District Court Asian 1 1

Polynesian 1 0

found insufficient evidence of adverse events related to the

Caucasian 24 19

sale of a dietary supplement containing 10 mg/day ephedra Did not reply 1 0

alkaloids, and ordered the FDA to rewrite its ephedra rule

35.570.9 38.471.1

with consideration for dose response relationships (Nutra- Age (year)

31.670.5 32.470.6

Body mass indexb

ceutical Corp. and Solaray, Inc. vs Lester Crawford, Acting

84.371.7 88.672.4c

Weight (kg)

Commissioner, US FDA et al.). 10571.4 10771.7

Systolic blood pressure (mm Hg)

Intake of vitamins, minerals, and omega-3 fatty acids may 6871.2 7071.3

Diastolic blood pressure (mm Hg)

69.571.5 67.171.4

be compromised in overweight and obese individuals due to Heart rate

improper dietary choices, and a multinutrient supplement

Cholesterol (mg/dl)

may be valuable in providing basic micronutrient support. 197.476.4 182.475.8

Total

We tested the hypothesis that a high-potency multivitamin 124.975.7 113.775.1

Low-density lipoprotein

48.571.9 47.272.1

and mineral formula, plus additional omega-3 fatty acids High-density lipoprotein

105.8711.7 107.8711.0

Triglycerides (mg/dl)

and botanical extracts including a low level of ephedra

alkaloids and caffeine would have a greater effect in Plus-minus values are means7s.e.m. bBody mass index is the weight in

kilograms divided by the square of the height in meters. cA significant

reducing body weight and body fat than a control formula

difference (Po0.05) in body weight existed between the two groups after

containing a lower potency multivitamin and mineral

randomization at baseline.

formula devoid of omega-3 fatty acids, botanical extracts,

ephedra alkaloids, and caffeine over a 9-month period. We

further evaluated the effects of these two types of supple-

Study design

ments on cardiovascular and metabolic indices, serum

chemistry, self-reported symptoms, and behavioral and Randomization of an equal proportion of subjects to one of

psychosocial measures. two groups was conducted with a random number generator

in multiples of 20.10 Subjects and research staff were blinded

to group assignment throughout the intervention. A sealed

Methods copy of the code was available to the study physicians for

emergency purposes. The statistician was the only person

Subjects with access to the code until completion of the study and

Sixty-one healthy pre-menopausal women, aged 25 47 years data verification.

old, with BMI from 27 to 39 kg/m2 were enrolled in the study The control group received a supplement containing

(Table 1). During an enrollment period from February to vitamins and minerals at 100% Daily Value, a small amount

August 2002, 216 prospective volunteers responded to of lutein, a corn oil capsule, and a cellulose tablet (Table 2).

recruitment. Ninety-four passed a telephone-based health The treatment group received a high-potency multivitamin

screening and were further evaluated by a health interview, and mineral formula, an omega-3 fatty acid capsule and a

physical exam, and clinical chemistry. Exclusion criteria botanical supplement containing Garcinia cambogia extract,

included resting systolic blood pressure greater than green tea extract, ephedra (Ephedra sinica) extract, guarana

140 mm Hg or diastolic blood pressure greater than (Paullinia cupana) extract (a source of caffeine), and other

90 mm Hg, history of, or existence of, any medical condition, botanical extracts (Table 2). The treatment group received a

total of 40 mg of ephedra alkaloids per day, provided as

use of prescription medications (except birth control pills),

use of antihistamines or other medications used for mild 20 mg prior to breakfast and 20 mg prior to lunch, and

asthma, coughs, colds, and allergies for 30 days prior to 100 mg of caffeine per day, provided as 50 mg prior to

randomization and for the duration of the study, caffeine breakfast and 50 mg prior to lunch. Independent analysis

intake greater than 150 mg/day, smoking presently or at least conducted at the Department of Pharmacy Science, Creight-

6 months prior to the study, involvement in any weight loss on University, confirmed the ephedrine and caffeine con-

program or diet presently or at least 6 months prior to the tent. Study supplements were provided in daily strip packs

study, and women who were pregnant, lactating or planning and were of similar size, shape and color. Subjects were

a pregnancy during the study period. All subjects provided instructed to take the botanical caplets or placebo 30 45 min

written informed consent, and the University of California, prior to breakfast and again prior to lunch, and to take the

multivitamin-mineral caplets and omega-3 fatty acid or corn

Davis Institutional Review Board approved the study protocol.

International Journal of Obesity

Multinutrient supplement with low-dose ephedra and caffeine

RM Hackman et al

1547

oil capsule with either lunch or dinner. Compliance was

Table 2 Composition of supplements for control and treatment groups

assessed at each clinic visit and by scheduled telephone

Ingredient U/day DRI Amount

interviews weekly, then monthly.

Women were instructed to refrain from eating or drinking

Control Treatment

beverages containing caffeine or alcohol for at least 12 h, and

Vitamin A (palmitate) mg 700-****-***

to refrain from heavy physical activity for 3 h, prior to the

Vitamin A (beta-carotene)a mg 700-***-****

clinic visits. Normal hydration was maintained during the

Vitamin C mg 75 60 1200

Vitamin Db mg 5 10 10 testing. Body weight was measured to the nearest 0.1 kg

Vitamin Ec mg 15 13.5 70.5

while wearing light clothing and without shoes using an

Vitamin K mg 90 25 0

electronic scale (Scale-Tronix 6002). Height was measured to

Thiamin mg 1.1 1.5 9

the nearest 0.5 cm without shoes using a wall-mounted

Riboflavin mg 1.1 1.7 10.2

Niacind mg 14 20 160 stadiometer (Ayrton S100). Body composition was assessed

Vitamin B6 mg 1.3 2 16

with a Xitron Hydra 4200 bioelectrical impedance spectro-

Folatee mg 400 400 800

meter (Xitron Technologies, San Diego, CA, USA) in a supine

Vitamin B12 mg 2.4 6 36

position 30 min after voiding.11 The manufacturer s software

Biotin mg 30 30 100

Pantothenic Acid mg 5 10 40 was used to calculate body composition. Body weight and

Calcium mg 100*-***-*** body composition were measured at baseline and at months

Iron mg 18 18 0

1.5, 3, 6, and 9 after beginning the supplement regimens.

Phosphorus mg 700 109 100

With the subject remaining supine after measurement of

Iodine mg 150 150 0

Magnesium mg 320 100 200 body composition, a 12-lead resting electrocardiograph

Zinc mg 8 15 15 (ECG) (Welch Allyn) was recorded and subsequently read

Selenium mg 55 20 80

by a board-certified cardiologist (JCR). Electrocardiograph s

Copper mg 900-****-****

were recorded at baseline, weeks 1, 2, and 4, and at months

Manganese mg 1.8 2 4

Chromium mg 25 120 200 1.5, 3, 6, and 9.

Molybdenum mg 45 75 50

Blood pressure was measured three times in a resting,

Chloride mg 72 0

seated position with an aneroid sphygmomanometer (Welch

Potassium mg 80 300

Allyn), according to standardized methods.12 A 1-min rest

Boron mg 150 300

Nickel mg 5 0 period was observed between each measurement. The last

Silicon mg 2 500

two readings were averaged for the final measurement.

Tin mg 10 0

Heart rate was measured in beats per minute after the second

Vanadium mg 10 50

blood pressure reading. Blood pressure and heart rates

Lutein mg 250 0

Eicosapentaenoic acid mg 0 0 180 were recorded at baseline, weeks 1, 2, and 4, and monthly

Docosahexaenoic acid mg 0 0 120 thereafter. Accepted values for normal blood pressure at the

Choline mg 0 0 60

time of the study (130/85 mm Hg) were used.13

Coenzyme Q-10 mg 0 0 150

Blood collected from the antecubital vein and urine

Garlic extract mg 0 0 50

L-Glutathione mg 0 0 5 samples were obtained at baseline and at months 1.5, 3, 6,

L-Methionine mg 0 0 100 and 9. Serum levels of sodium, potassium, bicarbonate,

Bioflavonoids mg 0 0 100

chloride, magnesium, carbon dioxide, urea nitrogen, creati-

L-Carnitine mg 0 0 25

nine, glucose, phosphorus, calcium, protein, albumin, alka-

Taurine mg 0 50

Beta-sitosterol mg 0 25 line phosphatase, aspartate transaminase (AST/SGOT), total

Gingko biloba extract mg 0 10

bilirubin, alanine transaminase (ALT/SGPT), creatinine

Silymarin extract mg 0 5

kinase, lactate dehydrogenase, ketone bodies, cholesterol,

Red wine polyphenols mg 0 5

high-density lipoprotein (HDL) cholesterol, and triglycerides

Garcinia cambogia extract mg 0 2000

Tulsi extract mg 0 50 were determined by chemistry analyzers (Beckman LXI

Gymnema sylvestre extract mg 0 10

and LX20 Pro). Low-density lipoprotein (LDL) cholesterol

Green tea extract mg 0 20

was calculated (TChol HDL TG/5 Calculated LDL). Insulin,

Oolong tea extract mg 0 200

thyroxine, and thyroid stimulating hormone were assessed

Eleutherococcus senticosis extract mg 0 50

550g

Guarana extract mg 0 by chemiluminescent immunoassay (Bayer Advia Centaur).

500h

Ephedra extract mg 0

The above tests, as well as blood histology, were performed

by the Department of Pathology at the University of

As retinol activity equivalents. bAs cholecalciferol. cAs alpha-tocopherol. dAs

niacin equivalents. eAs dietary folate equivalents. fNo DRI established. California Davis Medical Center. Urinalyses by dipstick and

Contains 100 mg caffeine. hContains 40 mg ephedrine group alkaloids. urine pregnancy tests were performed at our clinic.

Plasma glucose concentrations were measured with a

YSI Glucose Analyzer Model STAT 2300 (Yellow Springs

Instruments, Yellow Springs, OH, USA). Free fatty acids

were assayed with an enzymatic colorimetric assay (Wako

International Journal of Obesity

Multinutrient supplement with low-dose ephedra and caffeine

RM Hackman et al

1548

Chemicals USA, Richmond, VA, USA) adapted to a microtiter response terms (e.g. blood pressure above normal values).

plate reader. Intra- and interassay coefficients of variation in our Reported P-values were two-sided and a P-value of 0.05 or

laboratory are 4.7 and 7.5%, respectively. Insulin was assayed less was considered statistically significant. Analyses were

as described elsewhere,14 using human insulin standards performed with SAS software (version 9.1).23

(Linco Research, St Charles, MO, USA), (3-125I) insulin

(human recombinant) (Amersham Biosciences, Piscataway,

NJ, USA) and antiinsulin antisera (Radioassay Systems Results

Laboratories, Carson, CA, USA). Intra- and interassay varia-

tions are 5.5 and 8.9%, respectively. Leptin was measured Attrition

with a radioimmunoassay kit using an I-125-iodinated Of the 61 subjects enrolled, 41 (67%) completed the 9-

human leptin tracer and human leptin standards (Linco month study. Figure 1 depicts the randomization flow and

Research, St Charles, MO, USA). Intra- and interassay reasons for attrition. The study code never needed to be

variations are 5.8 and 5.7%, respectively. Adiponectin was broken for emergency purposes. No subjects were removed

determined with a radioimmunoassay kit using an I-125- from the study due to clinically abnormal changes in serum

iodinated murine adiponectin tracer, a multispecies adipo- chemistry, hematology, urinalysis, pregnancy, or ECG read-

nectin rabbit antiserum, and human adiponectin standards ings. No subjects were removed by the study physicians due

(Linco Research, St Charles, MO, USA). Intra- and interassay to severe or serious symptoms. Of the nine subjects in the

variations are 5.1 and 8.6%, respectively. Ghrelin was treatment group who withdrew, two started a medication

measured with a radioimmunoassay kit using rabbit anti- that was exclusionary for the study, two reported headaches,

serum specific for the synthetic peptide (Phoenix Pharma- one was lost to follow-up, one was noncompliant and one

ceuticals, Belmont, CA, USA). Intra- and interassay variations each reported insomnia, nervousness, and dizziness. Of the

are 5.9 and 13.3%, respectively. The homeostasis assessment nine subjects in the control group who withdrew, four were

model (HOMA-IR) was used to calculate an index of insulin lost to follow-up, three reported personal conflicts, one

resistance/sensitivity.15 refused to participate, and one started a medication that was

Self-reported symptoms were assessed in person at base- contraindicated for study participation.

line, weeks 1, 2, and 4 and monthly hereafter, as well as by

regularly scheduled telephone calls. Events were self-rated

for intensity (mild, moderate, severe, or serious), reviewed Body weight and composition

by the study physicians and classified according to the The treatment group had a slightly higher average body

FDA coding system and thesaurus for adverse events weight (89.0 kg) than the control group (84.0 kg) at baseline.

terminology.16 Body weights were rank transformed prior to statistical

Food intake was assessed by a standardized self-adminis- analysis, and all values from subjects completing 3 months

tered food frequency questionnaire (Block Food Frequency of the intervention were included in the model. Significant

Questionnaire17) at baseline and month 9. Physical activity differences between groups for weight loss occurred at

months 1.5, 3, 6, and 9 (Po0.0001 between groups at each

was assessed by an interview-administered standardized

instrument (Seven-Day Physical Activity Recall18) at baseline time; Figure 2), with the treatment group losing significantly

and at months 1.5, 3, 6, and 9. Psychosocial indices were more body weight than the control group (overall change

determined at baseline and months 1.5, 3, 6, and 9 using a between groups, P 0.0022). Changes in BMI were similar to

self-administered, standardized survey (Medical Outcomes those found for changes in body weight, with the treatment

Study 36-item Health Survey [SF-36 version 2]19) to assess group showing a significant reduction in BMI at months 1.5,

3, 6, and 9 compared to controls (Po0.0001 between groups

domains of general health status, limitations in physical

activities due to health problems, limitations in usual role at each time; P 0.0002 overall). The amount of body fat did

activities due to physical or emotional problems, bodily not differ between groups at baseline (P 0.71). Significant

pain, energy and fatigue levels, social functioning, general reductions in body fat were noted for the treatment group

mental health and general health perception. at months 1.5, 3, 6, and 9 compared to controls at each

time, and was significant overall (P 0.0017; Figure 2). No

differences in fat-free mass were found between the two

Statistical analysis groups at specific visits (P 0.60).

Outcome measures were analyzed using mixed model

analysis of variance. Least squares means comparisons were

Blood pressure, heart rate, and electrocardiograph

performed to determine significant differences between

groups overall and between the groups at specific time Mean systolic and diastolic blood pressure values remained

points. When model assumptions were not met, transforma- fairly constant throughout the intervention and were within

tions were used prior to analysis.20 Missing values were not the normal range at all measurement periods. At the time of

imputed; they were left as missing.21,22 Fisher s exact test was the study, normal blood pressure was defined as systolic

o140 mm Hg and diastolic o90 mm Hg. Using these criteria,

used to determine differences between groups for categorical

International Journal of Obesity

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RM Hackman et al

1549

217 Assessed for Eligibility

123 Excluded

86 Not Meeting Inclusion Criteria

37 Refused to Participate

94 Medically Screened

33 Excluded

33 Not Meeting Inclusion Criteria

61 Randomized

1 Excluded

1 Refused to Participate

29 Assigned to 31 Assigned to

Treatment Group Control Group

3 Excluded

2 Lost to Follow-up

1 Non-compliance

1 Insomnia

1 Nervousness

26 at 6 weeks 29 at 6 weeks

4 Excluded 6 Excluded

1 Lost to Follow-up 2 Lost to Follow-up

1 Dizziness 3 Personal Conflict

1 Headaches 1 Medication

1 Medication

22 at 12 weeks 23 at 12 weeks

2 Excluded

1 Medication

1 Headaches

20 at 24 weeks 23 at 24 weeks

1 Excluded

1 Surgery

23 at 36 weeks

19 at 36 weeks

Figure 1 Randomization flow.

no differences in the number of high values for systolic or were noted for a small number of subjects in each group

diastolic blood pressure were found between groups. By the at various times, but in no case were the readings suffi-

completion of the study, new standards had been adopted to ciently alarming to warrant discontinuation of any subject.

define normal blood pressure as systolic o120 mm Hg and One subject in the treatment group was found to have a

diastolic o80 mm Hg. Using these newer criteria, no differ- heart murmur, confirmed by an echocardiogram, which was

ences in systolic blood pressure were observed between diagnosed by the study cardiologist during the blinded phase

groups except at month 3. No differences in diastolic values of the intervention. The murmur most likely was due to a

were found (Table 3). congenital anomaly and was not considered to be clinically

Heart rates were similar between groups at baseline and significant.

were log transformed for analysis. Following ANOVA, mean

values and 95% confidence intervals were calculated24 and

Serum lipids, chemistry, urinalysis, and histology

are shown in Table 3. Heart rates in the control group

were significantly higher at week 1, month 3, and month 9 Total serum cholesterol levels were significantly higher in

compared to the treatment group. Heart rates for the the control group at baseline than in the treatment group

(P 0.002). Both groups showed a similar decline in

treatment group were significantly higher at week 2 than

cholesterol over the course of the study (P 0.78; Table 4).

the control group. Overall, the treatment group showed a

significant decline in heart rate compared to the control High-density lipoprotein cholesterol was similar at baseline

group (P 0.0003). for the two groups (P 0.49) and was log transformed for

analysis.24 Levels did not differ between groups at any time

Most electrocardiograms (ECGs) were considered within

the normal range. Clinically insignificant deviations in ECGs except month 6, when the treatment group had significantly

International Journal of Obesity

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RM Hackman et al

1550

concentrations were not different after 9 months in control

Change in Body Weight (kg)

1 subjects but decreased by nearly 18% (P 0.017) after 9

months in the treatment group. Insulin sensitivity as

assessed by the HOMA index was unchanged in the control

Change in weight (kg)

-1 *

group, but improved by 23% (P 0.004) in the group

-2

consuming the dietary supplement with ephedra and

-3 Control

* caffeine. The absolute and proportional (percent) changes

Treatment

-4

of plasma glucose, insulin, and insulin sensitivity in the

-5

treatment group were not related to either the absolute or

-6

the percent change of body fat mass by simple regression

-7 analysis. Baseline plasma leptin concentrations averaged

-8 approximately 20 22 ng/ml in both groups. Leptin was

1.5 mo 3 mo 6 mo 9 mo unchanged in the control group, but decreased by

Control 0.02 -0.98 -1.67 -2.25

25.875.2% (P 0.0004) after 9 months in the supplement-

Treatment -0.68 -3.04 -6.31 -7.18

treated subjects (Table 5). The absolute and proportional

changes of leptin were significantly correlated with the

Change in Fat (kg)

absolute and percent changes of BMI (P 0.0005 and 0.001,

respectively). Circulating adiponectin levels at baseline were

similar in the control and treatment groups and remained

0 unchanged after 9 months. Initial concentrations of total

Change in fat (kg)

plasma ghrelin averaged approximately 700 pg/ml in both

-1

the control and supplement-treated groups, and were un-

++ Control

-2

Treatment changed after 9 months in both groups.

-3

-4

-5 Diet, physical activity, and quality of life

++ +++

At the beginning of the study, reported daily energy intake

-6

1.5 mo 3 mo 6 mo 9 mo for the treatment group was 8079 kJ (1930 kcal) compared to

Control 0.8 1.42 -0.35 -0.99 6614 kJ (1580 kcal) for the control group (P 0.005). After 9

Treatment -0.22 -1.58 -5.34 -5.33

months, the reported mean daily energy intake in the

treatment group decreased to 6367 kJ (1521 kcal) (Po0.006

Figure 2 Changes in body weight and body fat in control and treatment

groups.

compared to baseline value), while the mean daily caloric

intake in the control group was 6455 kJ (1542 kcal). Two

subjects reported energy intake o2512 kJ/day (o600 kcal/

higher HDL than the control group (Po0.0001). The ratio of

day) at both the beginning and end of the study, and six

total cholesterol to HDL cholesterol was significantly lower

additional subjects reported energy intakes of o4186 kJ/day

at months 1.5, 3, 6, and 9 for the treatment group compared

(o1,000 kcal/day).

to the control group, as was the trend over time (P 0.004).

The two groups reported similar levels of physical

Low-density lipoprotein cholesterol was significantly higher

activity at the beginning and end of the study, and no

at baseline in the control group compared to the treatment

differences were found between groups. Six of the seven

group, and both groups showed a decline over the course of

quality of life domains assessed did not differ between

the intervention. Triglyceride values were log transformed

groups. Subjects in the treatment group reported a

for analysis. Values for the treatment group consistently

significantly lower vitality index at baseline compared to

declined over the study, while values in the control group

those in the control group, and the vitality scores rose

increased from baseline to 6 months and then declined at 9

significantly for the treatment group while no change was

months. Differences between groups were significant over

found in the control group.

time (P 0.050).

Among all other clinical chemistry, blood histology and

urinalysis values monitored, no clinically significant changes

Self-reported symptoms

were found.

The treatment group reported significantly more dry mouth,

nervousness, and palpitations than the control group

Endocrine parameters (Table 6). None of the symptoms were severe and no subject

Fasting glucose levels were unchanged in the control group was dropped from the study due to such self-reports. The

over time, while values in the treatment group declined treatment group also reported significantly more increased

significantly (P 0.001) (Table 5). Fasting plasma insulin energy and decreased appetite than the control group.

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Table 3 Blood pressure and heart rate in control and treatment groups

Blood pressure (mm Hg) Control Treatment

7s.e.m. 7s.e.m.

n mean n mean P

Systolic

Baseline 30 105 1.5 29 107 1.7 0.226

Week 1 31 108 1.4 29 108 1.3 0.767

Week 2 30 106 1.5 28 108 1.3 0.252

Week 4 30 108 1.5 28 110 1.5 0.112

Week 6 29 106 3.5 26 107 2.0 0.589

Month 2 26 108 1.4 24 111 2.0 0.113

Month 3 23 107 2.1 22 111 2.1 0.035

Month 4 23 110 1.7 21 111 2.4 0.645

Month 5 23 109 2.7 20 112 2.7 0.350

Month 6 23 110 2.3 19 110 1.6 0.774

Month 7 23 110 1.3 19 112 2.8 0.770

Month 8 23 111 1.9 18 111 2.8 0.814

Month 9 23 112 2.1 17 109 2.2 .075

Overall: Group P 0.609

Group Visit P 0.381

Diastolic Baseline 30 68 1.3 29 70 1.3 0.079

Week 1 31 68 1.3 29 69 1.3 0.309

Week 2 30 68 0.9 28 68 1.1 0.978

Week 4 30 68 1.5 28 68 1.3 0.845

Week 6 29 68 1.5 26 69 1.4 0.322

Month 2 26 68 1.4 24 70 1.4 0.195

Month 3 23 68 1.5 22 70 1.7 0.139

Month 4 23 69 1.3 21 71 1.3 0.375

Month 5 23 68 1.5 20 72 1.8 0.065

Month 6 23 69 1.5 19 69 1.4 0.510

Month 7 23 68 1.3 19 71 1.6 0.074

Month 8 23 70 1.0 18 69 1.7 0.408

Month 9 23 70 1.5 17 71 1.9 0.689

Overall: Group P 0.518

Overall: Group Visit P 0.471

Heart ratea (beats/min) Control Treatment

n Mean Lower 95% CI Upper 95% CI n Mean Lower 95% CI Upper 95% CI P

Baseline 30 68.9 66.7 71.3 29 66.7 64.5 69.0 0.174

Week 1 31 76.9 74.5 79.5 29 72.7 70.3 75.2 0.018

Week 2 30 74.2 71.7 76.7 29 78.6 76.0 81.3 0.016

Week 4 30 75.3

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