Phytotherapy Review & Commentaryby Kerry Bone, FNIMH, FNHAAwww. medi herb, com

Coleus: A New Development in theFight Against Metabolic Syndrome X

Metabolic Syndrome X is now a recognized medicalcondition. The clinical features of this disordertypically include abdominal obesity and visceralfat, fatty liver, elevated hepatic transaminases (liverenzymes), dysllpidemia, and, eventually, hypertension.Sufferers of Metabolic Syndrome have a much greaterrisk of developing type 2 diabetes and usually exhibithigh insulin levels and insulin resistance.'- In the US.the incidence of Metabolic Syndrome has reachedepidemic proportions, with somewhere between 30%to 40% of adults said to suffer from this condition.-^''Insulin resistance is probably the most significantunderlying event in Metabolic Syndrome, and this,in turn, is thought to be closely linked to abdominalobesity and visceral fat.'̂ '' Hence, any agent capable ofaddressing this fundamental issue of excess body fatwill be a useful tool in the management of MetabolicSyndrome (together with other treatments andappropriate dietary and lifestyle modification).

Recent research on the Ayurvedic herb Coleusforskohlii suggests it could be such an agent. Controlledclinical trials with a standardized extract of Coleushave shown that it particularly seems to address theissue of excess body fat, as well as causing modestreductions in total body weight. This article provides ageneral review of the research on Coleus and its activecomponent forskolin, inciuding a summary of theresults of the weight loss trials.

BackgroundAn assumption of many in the scientific community

is that non-toxic medicinal plants have little to offer tothe development of new medicinal agents. However,recent events in natural products research, coupledwith an ever-increasing refinement in pharmacologicalmodels, are beginning to reveal the subtle and relativelyuntapped therapeutic wealth of the plant kingdom.One notable development is Ginkgo biloba and PAFantagonism. Another is forskolin from the Indian plantColeus forskohlii.

Since ancient times, preparations of Coleus specieshave been used in traditional Ayurvedic medicine.However, the use of Coleus forskohlii was only knownto folk medicine. A large-scale screening of medicinalplants by the Indian Central Drug Research Institutein 1974 revealed the presence of a hypotensive andspasmolytic component of C. forskohlii, which wasnamed coieonol/ Concurrent research by HoeschtIndia identified the same compound as forskolin.'* Sincethe Hoescht scientists correctly assigned the chemicalstructure, their name generally has been adopted.

In 1981, it was shown that forskolin can activate,in a unique manner, the enzyme that produces cyclicadenosine monophosphate (AMP).'' The promisingnew drug suddenly generated immense interest asa research tool for the study of biochemical systemsinvolving cyclic AMP. From this point, there was anexponential increase in research on forskolin, andaround 20,000 papers have been published to date.

Although this article will review much of thechemical and pharmacological information onforskolin, emphasis will also be given in the later stagesto the clinical implications for the use of C. forskohlii.At present, the research indicates that Coleus will be ofvalue in the treatment of hypertension, mild congestiveheart failure, asthma, hypothyroidism, psoriasis,digestive weakness, and glaucoma. Coleus may also beused as an antiplatelet herb, and, of course, to assistwith a reduction of body fat.

DefinitionColeus forskohlii is a small member of the Lamiaceae

(Labiatae or mint family), which grows as a perennialon the Indian plains and lower Himalayas. It is alsocultivated as a garden ornamental, and the root isused as a condiment. The root contains an essential oiland diterpenes, especially 0.2 to 0.3% of the labdanediterpene forskolin. No other species of Coleus containsforskolin.

56 TOWNSEND LETTER - MAY 2007

Cyclic AMPAdenylate Cyclase Activation

Cyclic AMP (cAMP) was discovered in 1956, andits production is now known to be the final commonpathway for many hormones and transmitter agents. Inother words, the hormones or neurotransmitters do notenter the cell. They instead activate a receptor on thecell surface that is part of the adenylate cyclase enzymecomplex.'" This complex catalyses the production ofcAMP in a cell. The cyclic AMP then activates c-AMP-dependent protein kinase (PKA), which results inchanges in the cell's function.'"

Figure 1 gives a schematic model of hormone-sensitive adenylate cyclase. The enzyme complexis composed of at least five different subunits, asshown. A stimulatory hormone binds to its receptorin the cell membrane. This results in activation of thecatalytic subunit via coupling with the stimulatoryguanine nucleotide regulatory component, and cAMPproduction is thereby increased. Similarly, an inhibitoryhormone binding to its receptor results in deactivationof the catalytic subunit and decreased cAMPproduction. Forskolin appears to directly activate thecatalytic subunit, an action that is unique. It may alsoactivate the stimulatory Ns component. Research hasshown that forskolin is able to markedly potentiate theeffects of many hormones on biological responses in asynergistic fashion, suggesting that its activation of thecatalytic subunit amplifies hormonal effects.

Cyclic AMP: The Second MessengerA hormone is a chemical messenger, and the

recognition that cAMP participates in many hormonalactivities has led to its being described as a "secondmessenger." Adenylate cyclase is incorporated intoall cell membranes, and only the specificity of thereceptor determines the hormone that will activate it inany particular cell. The physiological and biochemicaleffects of raised intracellular cAMP are many andinclude inhibition of platelet activation, increased forceof contraction of heart muscle, relaxation of smoothmuscle, increased insulin secretion, increased ACTHrelease by the pituitary, increased thyroid function,and increased Hpolysis in adipocytes (fat cells). Manyof the actions of the sympathetic nervous systemare ultimately mediated by cAMP. Given this, it is notsurprising that forskolin has attracted widespreadattention.

The Pharmacology of ForskolinBecause of the fundamental effects of cAMP, the

pharmacology of forskolin is extremely diverse.However, the therapeutic consequences of many ofthese pharmacological actions are unclear, and so thisreview will concentrate on those more likely to be ofclinical significance.

Hemodynamics and Cardiac FunctionForskoiin lowers normal or elevated blood pressure

in different animal species by relaxing arteriolar smoothmuscle." It is active orally and has been scheduled forclinical trials. Despite a decrease in blood pressure,forskolin increased cerebral blood flow in rabbits, aneffect thought to be due to vasodilation.'^ Forskolin hasa positive inotropic action on heart muscle (increasesthe force of contraction).'^ A review concluded thatforskolin reduces preload and afterload of the heartdue to its vasodilating action, and its positive inotropiceffect does not affect myocardiai oxygen consumption.'"'Hence, it was considered to be a promising treatmentfor congestive heart failure. Forskolin was shown tobe a potent inhibitor of human platelet aggregation.''^It also acts synergistically with ajoene from garlic andwith prostacyclin."*

Platelets are thought to play an important rolein malignant tumour metastasis, and thrombusformation is considered to be a significant event in theestablishment of tumor colonies. Forskolin significantlyreduced the number of tumor colonies in mice injectedwith malignant cells.'^ Tumor foci in treated mice werealso smaller and more superficial."

Bronchial Smooth MuscleForskolin relaxed bronchial smooth muscle and

prevented bronchospasm."* It protected sensitizedguinea pigs during antigen challenge and reduced someof the inflammatory reactions that may contribute toasthma, e.g., histamine release, leukotriene production,and white cell activation.'^

Figure 1Model of Hormone-Sensitive Adenylate Cyclase

ATP CAMP

Forskolin

Ni

I I

Inhibitory

Catalytic subunit

Guanine nucleotideregulatorycomponent

Receptor

Hormone

The multkomponent adenylate cyclase complex

TOWNSEND LETTER - MAY 2007

Coleus forskohlii

Adipocytes and LipolysisLipolysis, the hydrolysis of stored fat to free

fatty acids and glycerol, is regulated by cAMP.Forskolin stimulated lipolysis in adipocytes.^" It actssynergistically with adrenaline and glucogon andis countered by insulin.'^ Forskolin inhibits glucoseuptake by adipocytes, but this is due to binding offorskolin with glucose transport protein and is notmediated by cAMP.̂ ' The ability of catecholaminessuch as adrenaline to activate lipolysis in rats declinesas rats grow older. The presence of forskolin countersthis decreased response."

Thyroid FunctionForskolin has similar effects on the thyroid gland

to TSH (Thyroid-stimulating hormone). In an animalmodel, it produced an eightfold increase in thesecretion of thyroid hormones.^^ It also increasesthyroid hormone production.

Pancreatic FunctionForskolin does not initiate secretion of insulin

from pancreatic beta cells, but it does potentiate thesecretagogue effects of glucose.^'' it also potentiates therelease of somatostatin and glucagon.̂ '̂

Hypothalamus and Anterior Pituitary FunctionForskolin stimulates ACTH, prolactin, and growth

hormone from pituitary tissue preparations.'"However, the relationship between cAMP levels andgonadotrophin release is controversial, although onestudy has demonstrated that forskolin increased LHproduction in female rats.̂ '̂ Forskolin increases LH-RHrelease from the hypothalamus of female

Upper Gastrointestinal FunctionThe stimulatory effects of forskolin on upper GI

function are consistent with the traditional use ofColeus forskohlii as a condiment. Forskolin stimulatedamylase secretion from the rat parotid gland,'** andit acts synergistically with choiecystokinin (CCK)in stimulating amylase release from the exocrinepancreas.^'*

Forskolin stimulated acid and pepsinogen releasefrom gastric glands of rabbits, however, the effect onacid release is more potent.-^" This effect is not blockedby atropine or the histamine H., antagonist cimetidine,although it is weakened by the latter. Forskolin andhistamine synergistically increase acid secretion.Another study confirmed the strong gastric secretoryactivity of forskolin.-*'

Maturation of OocytesForskolin stimulated the maturation of follicle-

enclosed oocytes, which may be due to forskolin-induced release of an agent from follicular cells thatpromotes maturation.^^

Smooth MuscieElevated cAMP levels in smooth muscle are generally

associated with relaxation. Vascular smooth musclepreparations appear to be more sensitive to relaxationby forskolin than non-vascular preparations.''' Non-vascular preparations relaxed by forskolin includerabbit small intestine, rat and rabbit uterus, guineapig colon, and rabbit detrusor smooth muscle (urinarytract).'^

Steroid Hormone ProductionForskolin stimulated steroid hormone production

in luteal cells, granulosa cells, testicular interstitialcells, Leydig cells, and the adrenal cortex.'^ It actssynergistically with FSH and LH on oestrogenand progesterone production and, with ACTH, oncorticosteroid production.'^

Recommended CombinationsColeus can be combined with the following:• 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 cerebrovascular disease

• Crataegus for hypertension

• Gymnema and Panax ginseng for insulin resistance and Metabolic Syndrome

• Fucus and Withania to support thyroid function

TOWNSEND LETTER - MAY 2007

Nervous SystemLong-term administration of forskolin caused

an increased rate of regeneration in damagedsensory nerves in frogs.̂ ^ Forskolin injected intothe cerebrospinal fluid (CSF) of mice depressedspontaneous activity, which suggests that increases inbrain cAMP levels may be associated with a reductionin excitability.''' It is possible that forskoiin may havesedative and anticonvulsant activity.

Antidepressant activity may also be linked toenhanced cAMP availability within brain effector cells.While forskolin decreased temperature and inhibitedactivity in normal mice, in mice depleted of brainmonoamines by administration of reserpine, it reversedthe consequent hypothermia and hypokinesia.^^ This issuggestive of antidepressant activity.

Intra-Ocular PressureTopical administration of forskolin lowers intra-

ocular pressure in the eyes of rabbits and healthyhumans.''' It appears to act by reducing aqueous inflow,and its activity may be indirect via its influence on thefunction of the sympathetic nervous system.'^

Coleus forskohlii

Immuue FuuctionForskolin inhibited igE-mediated release of

inflammatory mediators from human basopblls andlung mast cells.*'̂ Human fi-lymphocyte activation ispartly inhibited by forskolin.̂ ^

Calcium MetabolismForskolin acts synergistically with calcitonin

in inhibiting osteoclast function,^" but it does notpotentiate parathyroid hormone-induced boneresorption in

PiiarmacokineticsOral doses result in complete absorption, and blood

levels reached a maximum after one hour. In the rat,blood levels reached a maximum eight to 32 hours afteradministration. Excretion was complete after three orfour days." Forskolin has a low solubility in water, andwater-soluble derivatives have been prepared, not onlyto assist biochemical research but also for improveduptake.

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TOWNSEND LETTER - MAY 2007

Coleus forskohlii

Clinical StudiesHemodynamics and Cardiac Function

Initial studies on patients with congestivecardiomyopathy and coronary artery diseaseconfirmed that forskolin improved cardiac functionand myocardial contractility/" However, another studyon patients with congestive cardiomyopathy found noincrease in myocardial contractility at the tested dose."Left ventricular function was improved, but this waslargely via a reduction in preload due to vasodilation.'"Preliminary tests also found that while higher dosesof forskolin did increase myocardial contractility, theaccompanying large reduction in blood pressure maypreclude such doses in congestive heart failure.^'

Bronchodilatory EffectsInhaled forskolin countered methacholine-induced

bronchoconstriction in extrinsic asthmatics.''^ It alsocountered acetylcholine-induced bronchoconstrictionin a double-blind, placebo-controlled trial in healthyhumans."

intra-Ocular PressureTopical application of 0.5 mg of forskolin lowered

intra-ocular pressure in healthy humans.-"^ A long-liveddecrease in outflow pressure was produced."''' Theunique pharmacology of forskolin confers an effectthat can be additive with other drugs for glaucoma,such as acetazolamide.'-'' Preliminary trials in patientswith open-angle glaucoma demonstrated that topicalforskolin is well-tolerated, although it does causetransient irritation.^'^ Topical forskolin is thought tohave potential advantages in glaucoma therapy; '"*

• unlike lS-b!ockers, it increases intraocular bloodflow; and

• it has no systemic effects.A topical preparation of forskolin is being developed

in India for the treatment of glaucoma."^

Weight LossIn 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 fatcontent. Lean body mass was significantly increased.In an open, 12-week trial conducted in Japan involving14 overweight volunteers (13 women, 1 man; BMI: 29.9),there was a significant decrease in body weight, bodymass index (BMI), and body fat from Coleus extract(containing 25 mg/day of forskolin). Lean body masswas preserved.'*'*

In the United States, a randomized, double-blind,12-week trial observed that although there was no

difference in food intake, overweight women (BMI25-35) taking Coleus extract (containing 50 mg/dayof forskolin) experienced weight loss (mean; 0.7 kg/1.5lbs), while the placebo group gained weight (mean: 1kg/2.2 lbs). The difference between the groups wasnot statistically significant. A trend towards reducedtotal scanned mass occurred (mean loss of 0.2 kg/0.4lbs in Coleus group, gain of 1.7 kg/3.7 lbs for placebo).This suggests that Coleus tended to prevent weightgain. There was no effect on other body compositionparameters, including lean body mass. Heart rate,blood pressure, and blood lipids were unaffected. Noclinically significant side effects were observed."*''

A trial ol similar design conducted in India withobese men and women (BMI: 28-40 and/or body fat> 30% [males], > 40% [females]) found that that thedifference in body weight between the groups wassignificant.''** Coleus-treated patients lost an averageof 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 theplacebo group. Also statistically significant was theeffect on body fat and lean body mass. The loss of bodyfat in the Coleus-treated group was replaced with leanbody mass, while those on placebo gained body fat andexperienced a decrease in lean body mass. Serum HDL-cholesterol significantly increased in those receivingColeus (compared to baseline values and comparedto placebo). Thyroid hormones remained within thenormal range in both groups. In each of these trials,blood pressure did not change significantly, althougha trend towards lower blood pressure was noted in thefirst open trial noted above.'"'"'

In the most significant of all the trials to date, theeffect of forskolin on body composition was also studiedin a double-blind clinical trial conducted in the US andpublished in August 2005. Thirty overweight/obesemale volunteers (BMI > 25) were randomized to receiveColeus extract (containing 50 mg/day of forskolin) orplacebo for a period of 12 weeks. Administration ofColeus resulted in a significant decrease in fat mass andbody fat percentage from baseline, and tbe differencewas also significant compared with the placebo group.For those receiving Coleus, the change in fat mass frombaseline was 4.5 kg/9.9 lbs. There was also a trendtoward a significant increase for lean body mass inthe Coleus group compared with the placebo group.The average change in weight for those treated withColeus was a loss of 0.07 kg/0.15 lbs, in contrast to anaverage gain of 1.57 kg/3.5 lbs for the placebo group.This extensive trial also found that treatment withColeus significantly increased bone mass from baselinevalues. Mean resting metabolic rate did not significantlychange throughout the treatment period for eithergroup. (Resting metabolic rate is synonymous withresting energy expenditure and is closely associatedwith basal metabolic rate.)^'

TOWNSEND LETTER - MAY 2007

What this last trial demonstrates is that the mostprofound effect of Coleus was a large loss of body fat,with only a modest loss of overall body weight. Putsimply, fat was being replaced with muscle. This trialunderlines the significant potential of Coleus in themanagement of Metabolic Syndrome X.

PsoriasisPsoriasis is a skin disorder characterized by

proliferation of epidermal keratinocytes and a failureof maturation of these cells. A feature of epidermalcells in psoriasis is that there is a decrease in thecAMP to cGMP ratio compared to normal skin cells.^^Increased cAMP levels are associated with improvedmaturation and decreased cell turnover. Hence, topicaland systemic use of Coleus may improve psoriasisby raising cAMP levels in affected epidermal cells.Consistent with this hypothesis, forskolin was found toinhibit mitosis in vitro in pig epidermis^^ and also wasreported to improve symptoms in four patients withpsoriasis

Coleus forskohlii

54

Therapeutic Applications of CoieusThe impressive and diverse pharmacological

properties of forskolin are not necessarily all relevantto herbal therapy using Coleus forskohlii. For example,normal oral doses of Coleus may not produce sufficientquantities of forskolin in tissues to reproduce knownpharmacological actions. Another reason is that manyactivities have only been demonstrated in isolated cellor enzyme systems, and the final result of such effectsin a complex living organism is uncertain. A goodexample is the effect of forskolin on blood sugar levels.On the one hand, it potentiates insulin release, but onthe other, it potentiates glucagonand corticosteroid release andinhibits glucose uptake by fatcells. The net effect on blood sugarlevels is not predictable from thispharmacological information andmay, in fact, be insignificant orvariable.

The wide range ofpharmacological propertiesof forskolin may also give theimpression that therapeutic useof Coleus carries a high risk ofside effects. This is probably notthe case, as the activity of normaldoses of Coleus will be mild. Coleusis best regarded as a potentiatorthat can often act synergisticallywith other herbs or the body'sfunctions to correct an imbalanceor symptom complex. This conceptis based on the pharmacology offorskolin, which, via its action on the

catalytic sub-unit, greatly potentiates the stimulation ofcAMP production by hormones and other agonists, butgenerally does not potentiate the effect of antagonists.For example, the antiplatelet action of forskolin actssynergistically with ajoene from garlic. Hence, theuse of Coleus with garlic will produce a more potentantiplatelet activity than either agent alone. It is alsolikely that Coleus will act synergistically with bitters tostimulate upper gastrointestinal function. See Sidebar:Recommended Combinations for other examples.

Coleus will also act synergistically with thecardiovascular actions of Crataegus through adifferent mechanism. Crataegus is thought to inhibitphosphodiesterase," which is the enzyme thatbreaks down cAMP Its inhibition leads to cAMPaccumulation in the cell. Hence, the combined useof Coleus and Crataegus will see cAMP levels raisedby both stimulation of production and inhibition ofdecomposition.

The main therapeutic uses of Coleus can besummarized 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

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TOWNSEND LETTER - MAV 2007

Coleus forskohlii

• To assist weight loss and reduction of body fat inobesity and Metabolic Syndrome X

• To support thyroid function• As part of a protocol for psoriasis• To treat glaucoma (topically)

Contraindications and CautionsColeus is contraindicated in cases of low blood

pressure and peptic ulcers. Since forskolin has theability to potentiate many drugs, Coleus should be usedcautiously in patients taking prescribed medication.This applies especially to hypotensive and antiplateletdrugs.

Dosage and Dosage FormsA fundamental concept in herbal medicine is that the

use of the chemically complex plant is therapeuticallysuperior to the use of its isolated chemical components.One reason is that some chemical components mayimprove the solubilization, absorption, distribution,and utilization of other components. Another is thatsome components may counter the side effects ofothers.

Pharmacokinetic considerations indicate thatwater-soiuble derivatives of forskolin may be moreactive in vivo, and it appears that clinical research willconcentrate on these derivatives. At first glance, thisconsideration appears to downgrade the therapeuticpotential of Coleus. However, an early study implies theopposite. Oral administration of 50 mg/kg of an ethanolextract of Coleus (containing a small percentageof forskolin) was as active as 10 mg/kg forskolin inreducing blood pressure in rats.""' Yet a forskolin-freeextract of Coleus was inactive. Hence, the activity of theplant extract is at least an order of magnitude higherthan would be expected from its forskolin content. Toherbalists, this is not a pharmacological aberration andis readily explained by the reasons suggested above.

Based on these considerations, the adult therapeuticdoes of Coleus is expected to be in the range of 8 g to12g/dayor 8mLto 12mLofa 1:1 fluid extract preparedwith 50% ethanol. Preparations should be standardizedfor forskolin content. The aqueous-ethanolic extract isnot suitable for topical application to the eye.

ConclusionsIn 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, haveconsiderably added to its significance. The incidence ofMetabolic Syndrome X has reached alarming epidemicproportions. The evidence suggests that Coleus has akey role to play in the management of this condition.

Acknowiedgment: Thanks to Michelle Morgan forcontributing to the weight loss section of this article.

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