This article originally
appeared in the May 2007 issue of the Townsend
Published online May 2009.
Metabolic syndrome X is now a recognized
medical condition. The clinical features of this disorder typically
include abdominal obesity and visceral fat, fatty liver, elevated
hepatic transaminases (liver enzymes), dyslipidemia, and, eventually,
hypertension. Sufferers of metabolic syndrome have a much greater
risk of developing type 2 diabetes and usually exhibit high insulin
levels and insulin resistance.1,2 In the US, the incidence of metabolic
syndrome has reached epidemic proportions, with between 30% and
40% of adults said to suffer from this condition.3,4 Insulin resistance
is probably the most significant underlying event in metabolic syndrome,
and this, in turn, is thought to be closely linked to abdominal
obesity and visceral fat.5,6 Hence, any agent capable of addressing
this fundamental issue of excess body fat will be a useful tool
in the management of metabolic syndrome (together with other treatments
and appropriate dietary and lifestyle modification).
Recent research on the Ayurvedic herb Coleus forskohlii suggests
that it could be such an agent. Controlled clinical trials with
a standardized extract of Coleus have shown that it particularly
seems to address the issue of excess body fat, as well as causing
modest reductions in total body weight. This article provides a
general review of the research on Coleus and its active component
forskolin, including a summary of the results of the weight loss
An assumption of many in the scientific community is that nontoxic
medicinal plants have little to offer to the development of new
medicinal agents. However, recent events in natural-products research,
coupled with an ever-increasing refinement in pharmacological models,
are beginning to reveal the subtle and relatively untapped therapeutic
wealth of the plant kingdom. One notable development is Ginkgo biloba
and PAF antagonism. Another is forskolin from the Indian plant Coleus
Since ancient times, preparations of Coleus species have been used
in traditional Ayurvedic medicine. However, the use of Coleus forskohlii
was only known to folk medicine. A large-scale screening of medicinal
plants by the Indian Central Drug Research Institute in 1974 revealed
the presence of a hypotensive and spasmolytic component of C. forskohlii,
which was named coleonol.7 Concurrent research by Hoescht India
identified the same compound as forskolin.8 Since the Hoescht scientists
correctly assigned the chemical structure, their name generally
has been adopted.
In 1981, it was shown that forskolin can activate, in a unique manner,
the enzyme that produces cyclic adenosine monophosphate (AMP).9
The promising new drug suddenly generated immense interest as a
research tool for the study of biochemical systems involving cyclic
AMP. From this point, there was an exponential increase in research
on forskolin, and around 20,000 papers have been published to date.
Although this article will review much of the chemical and pharmacological
information on forskolin, emphasis will also be given in the later
stages to the clinical implications for the use of C. forskohlii.
At present, the research indicates that Coleus will be of value
in the treatment of hypertension, mild congestive heart failure,
asthma, hypothyroidism, psoriasis, digestive weakness, and glaucoma.
Coleus may also be used as an antiplatelet herb, and, of course,
to assist with a reduction of body fat.
Coleus forskohlii is a small member of the Lamiaceae (or Labiatae,
also known as the mint) family, which grows as a perennial on the
Indian plains and lower Himalayas. It is also cultivated as a garden
ornamental, and the root is used as a condiment. The root contains
an essential oil and diterpenes, especially 0.2% to 0.3% of the
labdane diterpene forskolin. No other species of Coleus contains
Adenylate Cyclase Activation
Cyclic AMP (cAMP) was discovered in 1956, and its production is
now known to be the final common pathway for many hormones and transmitter
agents. In other words, the hormones or neurotransmitters do not
enter the cell. They instead activate a receptor on the cell surface
that is part of the adenylate cyclase enzyme complex.10 This complex
catalyses the production of cAMP in a cell. The cyclic AMP then
activates cAMP-dependent protein kinase (PKA), which results in
changes in the cell's function.10
Figure 1 gives a schematic model of hormone-sensitive
adenylate cyclase. The enzyme complex is composed of at least
five different subunits, as shown. A stimulatory hormone binds to
its receptor in the cell membrane. This results in activation of
the catalytic subunit via coupling with the stimulatory guanine
nucleotide regulatory component, and cAMP production is thereby
increased. Similarly, an inhibitory hormone binding to its receptor
results in deactivation of the catalytic subunit and decreased cAMP
production. Forskolin appears to directly activate the catalytic
subunit, an action that is unique. It may also activate the stimulatory
Ns component. Research has shown that forskolin is able to markedly
potentiate the effects of many hormones on biological responses
in a synergistic fashion, suggesting that its activation of the
catalytic subunit amplifies hormonal effects.
Cyclic AMP: The
A hormone is a chemical messenger, and the recognition that cAMP
participates in many hormonal activities has led to its being described
as a "second messenger." Adenylate cyclase is incorporated
into all cell membranes, and only the specificity of the receptor
determines the hormone that will activate it in any particular cell.
The physiological and biochemical effects of raised intracellular
cAMP are many and include inhibition of platelet activation, increased
force of contraction of heart muscle, relaxation of smooth muscle,
increased insulin secretion, increased ACTH release by the pituitary,
increased thyroid function, and increased lipolysis in adipocytes
(fat cells). Many of the actions of the sympathetic nervous system
are ultimately mediated by cAMP. Given this, it is not surprising
that forskolin has attracted widespread attention.
Because of the fundamental effects of cAMP, the pharmacology of
forskolin is extremely diverse. However, the therapeutic consequences
of many of these pharmacological actions are unclear, and so this
review will concentrate on those more likely to be of clinical significance.
Forskolin lowers normal or elevated blood pressure in different
animal species by relaxing arteriolar smooth muscle.11 It is active
orally and has been scheduled for clinical trials. Despite a decrease
in blood pressure, forskolin increased cerebral blood flow in rabbits,
an effect thought to be due to vasodilation.12 Forskolin has a positive
inotropic action on heart muscle (increases the force of contraction).13
A review concluded that forskolin reduces preload and afterload
of the heart due to its vasodilating action, and its positive inotropic
effect does not affect myocardial oxygen consumption.14 Hence, it
was considered to be a promising treatment for congestive heart
failure. Forskolin was shown to be a potent inhibitor of human platelet
aggregation.15 It also acts synergistically with ajoene from garlic
and with prostacyclin.16
Platelets are thought to play an important role in malignant tumor
metastasis, and thrombus formation is considered to be a significant
event in the establishment of tumor colonies. Forskolin significantly
reduced the number of tumor colonies in mice injected with malignant
cells.17 Tumor foci in treated mice were also smaller and more superficial.11
Forskolin relaxed bronchial smooth muscle and prevented bronchospasm.18
It protected sensitized guinea pigs during antigen challenge and
reduced some of the inflammatory reactions that may contribute to
asthma; for example, histamine release, leukotriene production,
and white cell activation.19
Lipolysis, the hydrolysis of stored fat to free fatty acids and
glycerol, is regulated by cAMP. Forskolin stimulated lipolysis in
adipocytes.20 It acts synergistically with adrenaline and glucogon
and is countered by insulin.19 Forskolin inhibits glucose uptake
by adipocytes, but this is due to binding of forskolin with glucose
transport protein and is not mediated by cAMP.21 The ability of
catecholamines such as adrenaline to activate lipolysis in rats
declines as rats grow older. The presence of forskolin counters
this decreased response.22
Forskolin has similar effects on the thyroid gland to TSH (thyroid-stimulating
hormone). In an animal model, it produced an eightfold increase
in the secretion of thyroid hormones.23 It also increases thyroid
Forskolin does not initiate secretion of insulin from pancreatic
beta cells, but it does potentiate the secretagogue effects of glucose.24
It also potentiates the release of somatostatin and glucagon.25
Anterior Pituitary Function
Forskolin stimulates ACTH, prolactin, and growth hormone from pituitary
tissue preparations.19 However, the relationship between cAMP levels
and gonadotrophin release is controversial, although one study has
demonstrated that forskolin increased LH production in female rats.26
Forskolin increases LH-RH release from the hypothalamus of female
The stimulatory effects of forskolin on upper GI function are consistent
with the traditional use of Coleus forskohlii as a condiment. Forskolin
stimulated amylase secretion from the rat parotid gland,28 and it
acts synergistically with cholecystokinin (CCK) in stimulating amylase
release from the exocrine pancreas.29
Forskolin stimulated acid and pepsinogen release from gastric glands
of rabbits; however, the effect on acid release is more potent.30
This effect is not blocked by atropine or the histamine H2 antagonist
cimetidine, although it is weakened by the latter. Forskolin and
histamine synergistically increase acid secretion. Another study
con?rmed the strong gastric secretory activity of forskolin.31
Maturation of Oocytes
Forskolin stimulated the maturation of follicle-enclosed oocytes,
which may be due to forskolin-induced release of an agent from follicular
cells that promotes maturation.32
Elevated cAMP levels in smooth muscle are generally associated with
relaxation. Vascular smooth muscle preparations appear to be more
sensitive to relaxation by forskolin than nonvascular preparations.19
Nonvascular preparations relaxed by forskolin include rabbit small
intestine, rat and rabbit uterus, guinea pig colon, and rabbit detrusor
smooth muscle (urinary tract).19
Forskolin stimulated steroid hormone production in luteal cells,
granulosa cells, testicular interstitial cells, Leydig cells, and
the adrenal cortex.19 It acts synergistically with FSH and LH on
estrogen and progesterone production and, with ACTH, on corticosteroid
Long-term administration of forskolin caused an increased rate of
regeneration in damaged sensory nerves in frogs.33 Forskolin injected
into the cerebrospinal fluid (CSF) of mice depressed spontaneous
activity, which suggests that increases in brain cAMP levels may
be associated with a reduction in excitability.34 It is possible
that forskolin may have sedative and anticonvulsant activity.
Antidepressant activity may also be linked to enhanced cAMP availability
within brain effector cells. While forskolin decreased temperature
and inhibited activity in normal mice, in mice depleted of brain
monoamines by administration of reserpine, it reversed the consequent
hypothermia and hypokinesia.35 This is suggestive of antidepressant
Topical administration of forskolin lowers intraocular pressure
in the eyes of rabbits and healthy humans.19 It appears
to act by reducing aqueous inflow, and its activity may be indirect
via its influence on the function of the sympathetic nervous system.19
Forskolin inhibited IgE-mediated release of inflammatory mediators
from human basophils and lung mast cells.36 Human ß-lymphocyte
activation is partly inhibited by forskolin.37
Forskolin acts synergistically with calcitonin in inhibiting osteoclast
function,38 but it does not potentiate parathyroid hormone-induced
bone resorption in vitro.39
Oral doses result in complete absorption, and blood levels reached
a maximum after one hour. In the rat, blood levels reached a maximum
8 to 32 hours after administration. Excretion was complete after
three or four days.14 Forskolin has a low solubility in water, and
water-soluble derivatives have been prepared, not only to assist
biochemical research but also for improved uptake.
Hemodynamics and Cardiac Function
Initial studies on patients with congestive cardiomyopathy and coronary
artery disease confirmed that forskolin improved cardiac function
and myocardial contractility.40 However, another study on patients
with congestive cardiomyopathy found no increase in myocardial contractility
at the tested dose.41 Left ventricular function was improved, but
this was largely via a reduction in preload due to vasodilation.41
Preliminary tests also found that while higher doses of forskolin
did increase myocardial contractility, the accompanying large reduction
in blood pressure may preclude such doses in congestive heart failure.41
Inhaled forskolin countered methacholine-induced bronchoconstriction
in extrinsic asthmatics.42 It also countered acetylcholine-induced
bronchoconstriction in a double-blind, placebo-controlled trial
in healthy humans.43
Topical application of 0.5 mg of forskolin lowered intraocular pressure
in healthy humans.44 A long-lived decrease in outflow pressure was
produced.44 The unique pharmacology of forskolin confers an effect
that can be additive with other drugs for glaucoma, such as acetazolamide.45
Preliminary trials in patients with open-angle glaucoma demonstrated
that topical forskolin is well tolerated, although it does cause
transient irritation.46 Topical forskolin is thought to have potential
advantages in glaucoma therapy:14
• unlike ß-blockers, it increases intraocular blood
• it has no systemic effects.
A topical preparation of forskolin is being developed in India for
the treatment of glaucoma.47
In an open trial of eight weeks' duration, oral administration
of a Coleus extract (containing 50 mg/day of forskolin) to six overweight
women (BMI: > 25) resulted in significant reduction of body weight
and fat content. Lean body mass was significantly increased. In
an open, 12-week trial conducted in Japan involving 14 overweight
volunteers (13 women, 1 man; BMI: 29.9), there was a significant
decrease in body weight, body mass index (BMI), and body fat from
Coleus extract (containing 25 mg/day of forskolin). Lean body mass
In the US, a randomized, double-blind, 12-week trial observed that
although there was no difference in food intake, overweight women
(BMI 25–35) taking Coleus extract (containing 50 mg/day of
forskolin) experienced weight loss (mean: 0.7 kg/1.5 lbs), while
the placebo group gained weight (mean: 1 kg/2.2 lbs). The difference
between the groups was not statistically significant. A trend towards
reduced total scanned mass occurred (mean loss of 0.2 kg/0.4 lbs
in Coleus group, gain of 1.7 kg/3.7 lbs for placebo). This suggests
that Coleus tended to prevent weight gain. There was no effect on
other body composition parameters, including lean body mass. Heart
rate, blood pressure, and blood lipids were unaffected. No clinically
significant side effects were observed.49
A trial of similar design conducted in India with obese men and
women (BMI: 28-40 and/or body fat > 30% [males], > 40% [females])
found that that the difference in body weight between the groups
was significant.50 Coleus-treated patients lost an average of four
percent of total body weight (1.73 kg/3.8 lbs), compared to a gain
of 0.3% (0.25 kg/0.55 lbs) in the placebo group. Also statistically
significant was the effect on body fat and lean body mass. The loss
of body fat in the Coleus-treated group was replaced with lean body
mass, while those on placebo gained body fat and experienced a decrease
in lean body mass. Serum HDL-cholesterol significantly increased
in those receiving Coleus (compared with baseline values and compared
to placebo). Thyroid hormones remained within the normal range in
both groups. In each of these trials, blood pressure did not change
significantly, although a trend towards lower blood pressure was
noted in the first open trial noted above.48,50
In the most significant of all the trials to date, the effect of
forskolin on body composition was also studied in a double-blind
clinical trial conducted in the US and published in August 2005.
Thirty overweight/obese male volunteers (BMI = 25) were randomized
to receive Coleus extract (containing 50 mg/day of forskolin) or
placebo for a period of 12 weeks. Administration of Coleus resulted
in a significant decrease in fat mass and body fat percentage from
baseline, and the difference was also significant compared with
the placebo group. For those receiving Coleus, the change in fat
mass from baseline was 4.5 kg/9.9 lbs. There was also a trend toward
a significant increase for lean body mass in the Coleus group compared
with the placebo group. The average change in weight for those treated
with Coleus was a loss of 0.07 kg/0.15 lbs, in contrast to an average
gain of 1.57 kg/3.5 lbs for the placebo group. This extensive trial
also found that treatment with Coleus significantly increased bone
mass from baseline values. Mean resting metabolic rate did not significantly
change throughout the treatment period for either group. (Resting
metabolic rate is synonymous with resting energy expenditure and
is closely associated with basal metabolic rate.)51
What this last trial demonstrates is that the most profound effect
of Coleus was a large loss of body fat, with only a modest loss
of overall body weight. Put simply, fat was being replaced with
muscle. This trial underlines the significant potential of Coleus
in the management of metabolic syndrome X.
Psoriasis is a skin disorder characterized by proliferation of epidermal
keratinocytes and a failure of maturation of these cells. A feature
of epidermal cells in psoriasis is that there is a decrease in the
cAMP to cGMP ratio compared with normal skin cells.52 Increased
cAMP levels are associated with improved maturation and decreased
cell turnover. Hence, topical and systemic use of Coleus may improve
psoriasis by raising cAMP levels in affected epidermal cells. Consistent
with this hypothesis, forskolin was found to inhibit mitosis in
vitro in pig epidermis53 and also was reported to improve symptoms
in four patients with psoriasis.54
The impressive and diverse pharmacological properties of forskolin
are not necessarily all relevant to herbal therapy using Coleus
forskohlii. For example, normal oral doses of Coleus may not produce
sufficient quantities of forskolin in tissues to reproduce known
pharmacological actions. Another reason is that many activities
have only been demonstrated in isolated cell or enzyme systems,
and the final result of such effects in a complex living organism
is uncertain. A good example is the effect of forskolin on blood
sugar levels. On the one hand, it potentiates insulin release, but
on the other, it potentiates glucagon and corticosteroid release
and inhibits glucose uptake by fat cells. The net effect on blood
sugar levels is not predictable from this pharmacological information
and may, in fact, be insignificant or variable.
The wide range of pharmacological properties of forskolin may also
give the impression that therapeutic use of Coleus carries a high
risk of side effects. This is probably not the case, as the activity
of normal doses of Coleus will be mild. Coleus is best regarded
as a potentiator that can often act synergistically with other herbs
or the body's functions to correct an imbalance or symptom
complex. This concept is based on the pharmacology of forskolin,
which, via its action on the catalytic subunit, greatly potentiates
the stimulation of cAMP production by hormones and other agonists,
but generally does not potentiate the effect of antagonists. For
example, the antiplatelet action of forskolin acts synergistically
with ajoene from garlic. Hence, the use of Coleus with garlic will
produce a more potent antiplatelet activity than either agent alone.
It is also likely that Coleus will act synergistically with bitters
to stimulate upper gastrointestinal function. Other examples include:
· Crataegus, Astragalus or Panax
ginseng for mild congestive heart failure
· Zingiber and/or Curcuma (turmeric) for antiplatelet action
· Gentiana for stimulation of upper digestive function
· Crataegus and or/Salvia miltiorrhiza for compromised cardiac
function in ischemic heart disease
· Ginkgo biloba for hypertension
· Gymnema and Panax ginseng for insulin resistance and metabolic
· Fucus and Withania to support thyroid function
Coleus will also act synergistically
with the cardiovascular actions of Crataegus through a different
mechanism. Crataegus is thought to inhibit phosphodiesterase,55
the enzyme that breaks down cAMP. Its inhibition leads to cAMP accumulation
in the cell. Hence, the combined use of Coleus and Crataegus will
see cAMP levels raised by both stimulation of production and inhibition
The main therapeutic uses of Coleus
can be summarized as follows:
· to treat hypertension
· to treat congestive heart failure
· to treat ischemic heart disease (antiplatelet action)
· to treat cerebrovascular disease (vasodilation)
· to treat asthma and chronic obstructive airways disease
· to improve upper digestive function (the stimulation of
pancreatic enzyme release is a significant property)
· to assist weight loss and reduction of body fat in obesity
and metabolic syndrome X
· to support thyroid function
· as part of a protocol for psoriasis
· to treat glaucoma (topically)
Coleus is contraindicated in cases of low blood pressure and peptic
ulcers. Since forskolin has the ability to potentiate many drugs,
Coleus should be used cautiously in patients taking prescribed medication.
This applies especially to hypotensive and antiplatelet drugs.
Dosage and Dosage
A fundamental concept in herbal medicine is that the use of the
chemically complex plant is therapeutically superior to the use
of its isolated chemical components. One reason is that some chemical
components may improve the solubilization, absorption, distribution,
and utilization of other components. Another is that some components
may counter the side effects of others.
Pharmacokinetic considerations indicate that water-soluble derivatives
of forskolin may be more active in vivo, and it appears that clinical
research will concentrate on these derivatives. At first glance,
this consideration appears to downgrade the therapeutic potential
of Coleus. However, an early study implies the opposite. Oral administration
of 50 mg/kg of an ethanol extract of Coleus (containing a small
percentage of forskolin) was as active as 10 mg/kg forskolin in
reducing blood pressure in rats.56 Yet a forskolin-free extract
of Coleus was inactive. Hence, the activity of the plant extract
is at least an order of magnitude higher than would be expected
from its forskolin content. To herbalists, this is not a pharmacological
aberration and is readily explained by the reasons suggested above.
Based on these considerations, the adult therapeutic dose of Coleus
is expected to be in the range of 8 g to 12 g/day or 8 mL to 12
mL of a 1:1 fluid extract prepared with 50% ethanol. Preparations
should be standardized for forskolin content. The aqueous-ethanolic
extract is not suitable for topical application to the eye.
In the past two decades, Coleus has played a valuable role in the
modern herbal materia medica. However, the recent findings of its
value in assisting weight loss, especially via a pronounced reduction
in body fat, have considerably added to its significance. The incidence
of metabolic syndrome X has reached alarming epidemic proportions.
The evidence suggests that Coleus has a key role to play in the
management of this condition.
Acknowledgment: Thanks to Michelle Morgan for
contributing to the weight loss section of this article.
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