This article originally appeared in the May 2007 issue of the Townsend Letter.
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 trials.

Background
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 forskohlii.

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.

Definition
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 forskolin.

Cyclic AMP
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 Second Messenger
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.

The Pharmacology of Forskolin
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.

Hemodynamics and Cardiac Function
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

Bronchial Smooth Muscle
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

Adipocytes and Lipolysis
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

Thyroid Function
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 hormone production.

Pancreatic Function
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

Hypothalamus and 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 rats.²⁷

Upper Gastrointestinal Function
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

Smooth Muscle
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

Steroid Hormone Production
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 production.¹⁹

Nervous System
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 activity.

Intraocular Pressure
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

Immune Function
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

Calcium Metabolism
Forskolin acts synergistically with calcitonin in inhibiting osteoclast function,³⁸ but it does not potentiate parathyroid hormone-induced bone resorption in vitro.³⁹

Pharmacokinetics
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.

Clinical Studies
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

Bronchodilatory Effects
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

Intraocular Pressure
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 flow; and
• it has no systemic effects.

A topical preparation of forskolin is being developed in India for the treatment of glaucoma.⁴⁷

Weight Loss
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 was preserved.⁴⁸

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
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

Therapeutic Applications of Coleus
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 syndrome
· 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 of decomposition.

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 (bronchodilation)
· 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)

Contraindications and Cautions
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 Forms
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.

Conclusions
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.

Kerry Bone, FNIMH, FNHAA
www.mediherb.com

Notes
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