Conclusions

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August 31, 2004
Page 1
Canada
August 31, 2004
Todd Norton
Sabinsa
Corporation
121 Ethel Road West, Unit #6
Piscataway,
NJ
08854
Dear Mr. Norton:
At the request of Sabinsa Corporation, CANTOX Health Sciences
International (CANTOX) has reviewed the safety of Forslean®, a root
extract of Coleus forskohlii containing 10% forskolin, under the conditions
of intended use as a dietary supplement for marketing in the United States.
We have evaluated scientific information and data, provided by Sabinsa
Corporation and obtained from literature searches, pertaining to the safety
of Forslean®. The purpose of this review is to provide an independent
expert opinion on whether Forslean® is safe for its intended level of intake
of oral intake of 500 mg/day.
Introduction
Forslean® is composed of a powdered extract from the root of the Coleus
forskohlii plant. The extract is standardized to contain 10% forskolin, the
active ingredient. The intended dose of Forslean® is one 250 mg capsule
to be taken twice daily, providing a total daily dose of 500 mg/day, as an
aid for weight loss. This dose provides 50 mg forskolin/day.
C. forskohlii is cultivated commercially in India where the roots are used as
a spice in pickles (de Souza et al., 1983). Its root also has been used
traditionally in Hindu and Ayurvedic traditional medicine for the treatment of
heart diseases, abdominal colic, respiratory disorders, painful micturition,
insomnia, and convulsions (Ammon and MOiier, 1985; Shah, 1985; Murray,
1995). In addition, the raw roots of the plant have been consumed for the
treatment of cough (Shah, 1985).
August 31, 2004
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Review of the Safety Studies of Forslean® Acute
Toxicity Studies
In an acute toxicity study, male and female Wistar rats were given a single oral
dose of 2,000 mg ForsLean®/kg body weight (Graver, 2000).
No deaths
occurred; however, diarrhea, soiling of the anogenital area, and wetness of the
mouth and anogenital area were reported. No histopathological lesions were
observed following necropsy. The LD50 was reported to be >2,000 mg/kg body
weight. Earlier studies by de Sousa et al (1983) showed the acute LD50 of
forskolin to be 3,100 and 2,550 mg/kg by oral administration and 105 and 92
mg/kg body weight when administered intraperitoneally, in mice and rats,
respectively.
Subchronic Toxicity Study in Rats
Groups of 5 Sprague-Dawley rats/sex were administered doses of C. forskohlii
10% extract of 0, 100, 300, or 1,000 mg/kg body weight/day by gavage for a
period of 28 days (Bhide, 2004). Two additional groups of rats (5/sex/group)
were administered the extract at doses of 0 or 1,000 mg/kg body weight/day
for 28 days, and were observed for a 14- day recovery period thereafter to
assess the reversibility of any possible effects. Daily observations of clinical
signs and mortality, and weekly measurements of body weight and food
consumption were conducted. Ophthalmoscopic examinations were
conducted at the beginning and end of the dosing period and at the end of the
recovery period.
Hematological, biochemical, and urinary parameters were assessed at the
end of the dosing and recovery periods. All animals were subjected to
necropsy, and histopathological examinations of the organs were conducted.
No toxicological effects were observed in any of the measured parameters at
any dose. The no-observed-effect level (NOEL) of C. forskohlii 10% extract
was considered to be 1,000 mg/kg body weight/day, the highest dose tested.
This NOEL represents an appropriate high multiple of the intended human
dose.
Mutagenicity Study
ForsLean® was reported not to be mutagenic in the bacterial reverse
mutation assay with an independent repeat assay using Salmonella
August 31, 2004
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typhimurium strains TA98, TA100, TA1535, and TA1537, and Escherichia
coli strain WP2 uvrA, both in the presence and absence of metabolic
activation, at doses of up to 5,000 µg/plate (Wagner and Klug, 2001).
Clinical Studies
A number of clinical studies investigating the efficacy of ForsLean® for
weight loss have been conducted and are summarized in Table 1. It is
important to note, although efficacy was the primary purpose of these trials,
that parameters related to safety were also monitored.
Open field studies 8 to 12 weeks in length have reported significant decreases
in mean body weight and body fat with no significant adverse effects in
overweight men and women who consumed 125 to 250 mg Forslean® twice
daily (providing 250 to 500 mg Forslean®/day or 25 to 50 mg forskolin/day)
(Tsuguyoshi, 2001; Badmaev et al., 2002).
Similarly, double blind, randomized, placebo-controlled trials ranging in length
from 8 to 12 weeks have demonstrated no significant adverse effects in
subjects who consumed 250 mg Forslean® twice daily (500 mg Forslean®/day
or 50 mg forskolin/day) (Agena, unpublished; Kreider et al., 2002; Bhagwat et
al., 2004). Measurements of systolic and diastolic blood pressure and pulse
rate in each of the studies also revealed no significant effects as a result of
Forslean® consumption. In addition, Kreider et al. (2002) reported no clinically
significant effects in metabolic markers, blood lipids, muscle and liver enzymes,
electrolytes, red blood cells, white blood cells, hormones (insulin and thyroid
hormones), heart rate, blood pressure, or other side effects. Bhagwat et al.
(2004) also reported no significant changes in liver and kidney function, thyroid
function, as measured by triiodothyrodine {T3), thyroxine (T4), and thyroidstimulating hormone (TSH) levels, nor any significant changes in blood lipid
profile, with the exception of a significant increase in high-density lipoprotein
(HDL) cholesterol and a significant decrease in total cholesterol/HDL ratio.
Other clinical studies have evaluated the effects of C. forskohlii extract on
blood pressure in hypertensive patients. Dubey et al. (1997) conducted 2 trials
in which hypertensive patients were given capsules containing 165 mg of C.
forskohlii extract (5 mg forskolin). In the first trial, 23 hypertensive patients
were instructed to take 1 capsule 3 times daily for a period of 3 weeks (total
daily dose = 495 mg C. forskohlii and 15 mg forskolin). In the second trial, 28
subjects were given the same doses of C. forskohlii extract for a period of 8
weeks, while 9 subjects were given 2 capsules 3 times daily (total daily dose =
990 mg C. forskohlii and 30 mg forskolin) over the same period.
August 31, 2004
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Blood biochemical and hematological parameters were assessed and stool
and urine analyses were performed at the beginning and end of the study
period in both trials. All parameters assessed were reported to remain within
normal ranges; however, serum cholesterol, creatinine, and blood urea were
reported to decrease significantly in both phases of the study. Systolic and
diastolic blood pressure also were reported to significantly decrease over the
course of the study period. Side effects that were reported to diminish over
the course of the study included gastrointestinal disturbances, palpitation,
dyspnea on exertion, insomnia, headache, and anxiety.
These studies represent a significant clinical database since, even though
numbers of subjects are limited as in most such trials with volunteers, results
are consistent and reproducible. Although these trials have been presented at
scientific meetings, complete study data have not been published.
August 31, 2004
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Table 1
Summary of Clinical Studies of Coleus forskohlii Extracts
Number of Subjects
Dose of C. forskohlii
Extract (mg/day)
[dose
of
(mg/day)]
Study Design
Study
Length
Measured Outcome(s)
Reference
12 wk
No significant effects on systolic and diastolic blood
Tsuguyoshi et al.,
pressure or pulse rate. No significant adverse effects.
2001
No significant effects on systolic and diastolic blood
Badmaev et al.,
pressure or pulse rate.
2002
No significant effects on body weight, heart rate, mean
arterial pressure, or systolic and diastolic blood
Agena, unpublished
forskolin
Clinical Studies of Forslean®
14 overweight
250 [25]
Open-field study
subjects (1 male, 13
female)
6 overweight women
16 overweight men
(8/group)
500 [50]
500 [50]
Open-field study
Randomized, doubleblind, placebo-
8 wk
8 wk
controlled study
19 women [n=12
(controls); n=7 (test)]
500 [50]
Randomized, doubleblind, placebo-
pressure.
12 wk
controlled study
60 obese men and
women (30/group)
500 [50]
Randomized, doubleblind, placebo-
No significant differences between groups in
metabolic markers, blood lipids, muscle and liver
Kreider et al., 2004
enzymes, electrolytes, red blood cells, white blood
cells, hormones (insulin, TSHa, T3b, T/}, heart rate,
blood pressure, or reported side effects.
12 wk
No significant effects on blood pressure, liver, kidney,
and thyroid function or blood lipid profile, with the
Bhagwat et al., 2004
exception of increased HDLd cholesterol and
decreased ratio of total:HDL cholesterol.
controlled study
Clinical Studies of Other C. forskohlii Extracts
23 hypertensive
patients
495 [15]
Open-field studies
3 wk
No significant effects on blood biochemical and
hematological parameters, urinalysis.
8 wk
blood urea, and systolic and diastolic blood pressure.
Significant decreases in serum cholesterol, creatinine,
37 hypertensive
495 [15] (n=28)
patients
990 [30] (n=9}
Side effects included: gastrointestinal disturbances,
palpitation, dyspnea, insomnia, headache, anxiety;
side effects diminished over the course of the study.
- Thyroid-stimulating
hormone
b Triiodothyronine
c Thyroxine
d
High-density lipoprotein
Dubey et al., 1997
August 31, 2004
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Pharmacological Effects and Mechanism of Action of Forskolin
Forskolin has been reported to possess antihypertensive activity, positive
inotropic effects, and to inhibit platelet aggregation (de Souza et al., 1983;
Ammon and MOiier, 1985). The mechanism of action of forskolin is thought to
be related to its stimulatory action on adenylate cyclase, increasing the
intracellular level of cyclic adenosine monophosphate (cAMP), which
mediates a number of biological responses (de Souza et al., 1983; Ammon
and MOiier, 1985; Dohadwalla, 1985; Seamon, 1985). Numerous
pharmacological studies on the various effects of forskolin have been
conducted in laboratory animals and humans following topical, intravenous
(i.v.), intraarterial, intraperitoneal (i.p.), intratracheal (i.t.), and inhalation
treatment. Physiological effects of cAMP, which also have been demonstrated
by forskolin, include inhibition of platelet aggregation, increased adipocyte
lipolysis in vitro, positive inotropic effects on heart muscle, potentiation of
insulin secretion by the pancreas, increased secretion of thyroid hormones,
increased
steroidogenesis
by
the
adrenal
glands,
increased
adrenocorticotropic hormone (ACTH) release by the pituitary gland, and
decreased intraocular pressure in topical application (Dubey et al., 1981;
Caprioli and Sears, 1983; Malaisse and Malaisse-Lagae, 1984; Ammon and
MOiier, 1985; Dohadwalla, 1985; Potter et al., 1985). Forskolin also has been
reported to induce bronchodilation in guinea pigs (i.v. doses of 1 ml/kg body
weight for 10 minutes and i.t. administration of 30 µg) and in asthmatic
patients (inhalation of 1 to 10 mg forskolin, as dry powder), with no significant
side effects (Lichey et al., 1984; Kreutner et al., 1985; Bauer et al., 1993).
Conclusions
To put the safety of forskolin, or any substance for that matter, into
perspective, it is important to consider the toxicological principle of dose
response. Any substance at a sufficient dose will be toxic, and there is a dose
for all substances below which no effect will occur. The evidence we have
reviewed for forskolin has not revealed any reason to believe that it is not safe
at the dose levels tested in animal studies and in clinical trials.
The activation of adenylate cyclase and subsequent increase in cAMP
levels in the body are associated with a number of physiological functions.
Although the available toxicological studies in animals and clinical studies at
the intended level of use indicated that C. forskohlii 10% extract is welltolerated and without adverse effects, these studies do not address the
possibility of interactions with other active substances. The 28-day study in
August 31, 2004
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rats provided a NOEL of 1,000 mg/kg body weight/day, the highest dose
tested, which provides a 120-fold margin of safety over the intended dose of
500 mg/person/day (8.3 mg/kg body weight/day for a 60 kg individual). This
margin of safety would likely be more for the intended, overweight user.
Clinical studies in which ForsLean® was administered at doses of up to 500
mg/day for periods of up to 12 weeks have demonstrated no significant
effects on clinical chemistry or hematological parameters, nor any significant
detrimental effects on blood pressure and thyroid function. Based on review
of in vitro studies on the pharmacological actions of forskolin, but without the
benefit of recent toxicological and clinical studies, in 1997 the American
Botanical Council (ABC) indicated that forskolin "has the ability to potentiate
many drugs", and has suggested that caution be exercised in all patients taking
prescription medications. In addition, the ABC contraindicated the use of
forskolin by gastric ulcer patients and hypotensive patients (ABC, 1997). It
should be noted that forskolin's mode of action is not the same (Lindner et al,
1987; Kramer et al, 1987) as sympathomimetic agents which have been a
concern due to their stimulant activity. Nevertheless, as an activator of
adenylate cyclase, possible interaction with other physiologically active
supplements or drugs should be subject to warnings on product labels.
Normally, in the absence of clinical data, a minimum battery of genotoxicity,
reproduction, and subchronic (i.e., 90 days) studies is desirable. The toxicological
database for forskolin is limited, with the longest duration of exposure of 28 days in a rat
study, but a number of longer term clinical studies are available. A bacterial mutation
test showed no genotoxic potential in a microbial system.
In the absence of developmental or reproduction studies, the product should be labeled
with a warning against use by pregnant women. Lack of chronic data can be addressed
by clear labeling that warns against long term use.
The clinical database is supportive of the safety of the intended dosage level (50 mg
forskolin/day). The available studies, of which three are randomized, placebo-controlled
and double-blind, provide evidence that helps to compensate for a limited toxicological
database.
Safe use of forskolin also is supported by a long history of its use as a spice and in
traditional medicine. Although it has been estimated that consumption from spice in
India may amount to 5 mg intake of forskolin per day, there is no specific information
available about dosage levels from Hindu and Ayurvedic traditional medicine. If serious
side effects or adverse events had been suspected to be linked to forskolin, however, it
is logical that there would not be continuing use of such preparations, and one might
expect reports of adverse effects in the literature. In the United States, 10's of millions
of dosages per year have been consumed in recent years without Adverse Effect
Reports (AERs). Although AERs are not a reliable source of information concerning
August 31, 2004
Page 7
safety, the absence of AERs for forskolin is helpful, given the publicity and political
pressure attendant to the AERs reported for other herbals such as ephedra and kava
kava.
In summary, with appropriate labeling to address potentiation, contraindications,
cessation with serious or continuing side effects, period of time of consumption, etc.,
especially considering the intended use for obesity, the available information supports
the safety of Forslean® at the intake level of 500 mg per day resulting in a dose of 50
mg of forskolin per day.
References
ABC. 1997. Coleus forskohlii Monograph. American Botanical Council HerbClip, May
1, 1997.
Agena, S.M. Unpublished. The effect of forskolin supplementation on weight
loss in moderately active overweight males.
Ammon, H.P.T.; MOiier, A.B. 1985. Forskolin: From an ayurvedic remedy to a
modern agent. Planta Med No. 6:473-477.
Badmaev, V.; Majeed, M.; Conte, A.A.; Parker, J.E. 2002. Diterpene forksolin (
Coleus forskohlii, Benth.): A possible new compound for reduction of
body weight by increasing lean body mass. NutraCos 1(2):6-7.
Bauer,
K.; Dietersdorfer, F.; Sertl, K.; Kaik, B.; Kaik, G. 1993.
Pharmacodynamic effects of inhaled dry powder formulations of
fenoterol and colforsin in asthma. Clin Pharmacol Ther 53:76-83.
Bhagwhat, A.M.; Joshi, B. (Principal Investigators); Joshi, A.S.; Jain, A.;
Sawant, N. (Co- Investigators). 2004. A randomized double-blinded
multicenter phase Ill clinical trial to investigate the efficacy and safety of
ForsLean® in increasing lean body mass. Shri C.B. Patel Research
Centre for Chemistry and Biological Sciences; Mumbai, India.
Sponsored by Sarni Labs Limited; Bangalore, India. [Study Protocol
Number: FL-003/2003].
Bhide, R.M. 2004. Subacute oral toxicity study (28 day) of C31971 in the
Sprague- Dawley rat. Indian Institute of Toxicology, Pune, India.
Project No. 9620 unpublished study report.
Caprioli, J.: Sears. M. 1983. Forskolin lowers intraocular pressure in rabbits,
monkeys, and man. Lancet 1:958-960.
de Souza, N.J.; Dohadwalla, A.N.; Reden, J. 1983. Forskolin: A labdane
diterpenoid with antihypertensive, positive inotropic, platelet
aggregation inhibitory, and adenylate cyclase activating properties.
Med Res Rev 3(2):201-219.
Dohadwalla, A.N. 1985. Biological Activities of Forskolin.!.O.: Rupp, R.H.; de
Souza, N.J.; Dohadwalla, A.N. (Eds). 1985. Proceedings of the
International Symposium on Forskolin: its chemical, biological and
medical potential. Hoechst India Limited, Bombay 400 080. p 19-30.
Dubey, M.P.; Srimal, R.C.; Nityanand, S.; Dhawan, B.N. 1981.
Pharmacological studies on coleonol, a hypotensive diterpene from
Coleus forskohlii. J Ethnopharmacol 3(1):1-13.
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