Coleus forskohlii

Coleus forskohlii is an herb used in traditional medicine that may boost Testosterone and induce fat loss, particularly in men.

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Coleus forskohlii is an herb historically used in Ayurveda medicine.

Today, Coleus forskohlii is used as a fat burning supplement.

The main bioactive ingredient in Coleus forskohlii is called forskolin. Through forskolin, Coleus forskohlii supplementation may increase testosterone, and protect against cancer and inflammation. Further research is needed to confirm these effects, since forskolin is most often used as a research tool in vitro, or outside the body, like in a test tube or petri dish. Forskolin may act differently inside the body.

Forskolin increases cellular levels of an enzyme called cyclic adenosine monophosphate (cAMP). Elevated cAMP levels are associated with increased rates of fat loss, and can improve the effects of other fat burning compounds.

Forskolin is still being researched for its effects on testosterone and fat loss, but preliminary evidence is promising.

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Also Known As

Forskolin, Coleonol, 7beta-acetoxy-1alpha,6beta,9alpha-trihydroxy-8,13-epoxy-labd-14-en-11-one


Is a Form of


Goes Well With


Does Not Go Well With

  • Alpha(2)adrenoreceptor agonism

Caution Notice

Examine.com Medical Disclaimer

To supplement Coleus forskohlii, take 250 mg of a supplement that contains 10% forskolin, twice a day, for a 500 mg total daily dose.

Further research is needed to determine the optimal Coleus forskohlii dose.


The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Coleus forskohlii has in your body, and how strong these effects are.
GradeLevel of Evidence
ARobust research conducted with repeated double blind clinical trials
BMultiple studies where at least two are double-blind and placebo controlled
CSingle double blind study or multiple cohort studies
DUncontrolled or observational studies only
Level of Evidence
EffectChange
Magnitude of Effect Size
Scientific ConsensusComments
CBlood Pressure

No significant influence on blood pressure was noted with coleus supplementation

CWeight

Minor

Mixed effects on overall weight, may be more effective in men rather than women. Overall, it requires more evidence to see if it has a role in weight loss regimens.

CAsthma

Notable

Although more evidence is required, it appears to be more effective at suppressing asthmatic symptoms than other nutraceuticals. Mechanisms may be related to beta-adrenergic... show

CIntraocular Pressure

Minor

Somewhat effective as ocular eyedrops in reducing ocular pressure.

CFatigue

Minor

Less fatigue reported as a side-effect, no comparator or ability to assess potency.

CTestosterone

Minor

Increase of testosterone observed in men not overly potent and is highly variable.

CBone Mineral Density

Notable

Definitely requires more evidence, but a DXA confirmed increase in bone mass in men over 12 weeks makes this notable (rather than an increase in bone mass in osteoporotic... show

CLean Mass

Minor

Somewhat effective (2lbs over 12 weeks relative to placebo) although somewhat confounded with the increase in bone mass, as lean mass is inclusive of bone and skeletal muscle.

CFat Mass

Minor

Somewhat effective in reducing fat mass in obese and overweight persons.

DHDL-C

Notable

Needs to be replicated in larger trials, but the degree of increase was quite remarkable.


Disagree? Join the Coleus forskohlii Discussion

Table of Contents:


Edit1. Source and Composition

1.1. Source

Coleus Forskohlii of the family Lamiaceae (alternate name of Plectranthus barbatus) is an Ayurvetic medicine traditionally used for various cardiovascular, gastrointestinal, and central nervous system ailments.[1] It also has some implications in lung health and urinary health.[2]

Other names of coleus include 'falso boldo' (in brazil[3])

1.2. Composition

The aerial parts of coleus forskohlii (leafs and stem) include:

  • The forskolin series of related compounds (A,G,H,I,J)and isoforskolin[4][5][6][7] The main forskolin compound used in research has the technical name 7beta-acetoxy-1alpha,6beta,9alpha-trihydroxy-8,13-epoxy-labd-14-en-11-one.[8]
  • The Forskoditerpenoside series (A,C,D,E) of diterpene structures.[9][10]
  • (16S)-Coleon E[3]
  • 4beta,7beta,11-enantioeudesmantriol[10]
  • Rosmarinic Acid (leaves)[11]
  • Abietane diterpenoids[12]
  • Chamaecydin[4]
  • Scutellarein as 4′-methyl ether 7-O-glucuronide[3]
  • Luteolin as 7-O-Glucuronide[12]
  • Apigenin as 7-O-glucuronide[12]
  • Acacetin as 7-O-glucuronide[12]
  • Alpha-cedrene[4]
  • Oleanolic Acid[4] and Betulinic acid[4]
  • Beta-sitosterol[4]

Whereas the root portion contains:

  • 14-deoxycoleon U[13]
  • Demethylcryptojapnol[13]
  • Alpha-Amyrin and Alpha-Cedrol[13]
  • Betulinic acid[13]
  • Beta-sitosterol[13]

It is typically used for its active component, Forskolin, which is a direct activator of a cellular intermediate called Adenylate Cyclase.[14] Also called coleonol, Forskolin is found in varying concentrations in different plants of Coleus Forskohlii.[2] It is a yellowish brown powder when supplemented, and has a pleasing aroma yet bitter taste; when supplementing the whole plant the color is more brown in appearance.[2] Forskolin has poor solubility in water but is otherwise quite stable.[15]

1.3. Variants and Formulations

Forskolin itself has poor water solubility, and activates 8 out of 9 isoforms of Adenylate Cyclase. This is seen as undesirable by some, as increasing cAMP in other organs aside from the target organ can give rise to unforeseen side-effects.[16]

Derivates of Forskolin have been developed, FD-1 (6-{N-{2-isothiocyanatoethyl}aminocarbonyl}forskolin) has affinity for type II receptors and also III, V to lesser degrees. 5,6-dehydroxy-7-deacetyl-7-nicotinoylforskolin (FD-4) appears to have high affinity for type III receptors and no difference between II and V. Finally, 6-{3-(Dimethylamino)propionyl}14,15-dihydroforskolin appears to have great affinity for type V over type II, with lesser effects on type III.[16] This information is relevant as type II are ubiquitous (everywhere), type III are more located to olfactory tissues, atria and brown fat, and type V is the major isoform of the adult cardiac tissue.[17][16] Potencies of some of these isoforms relative to parent forskolin range from 100-300%.[16]


Edit2. Molecular Targets

2.1. Adenylyl Cyclase

Forskolin is an adenylyl cyclase (synonymous with adenylate cyclase) stimulator, which increases levels of cyclic adenosine monophosphate (cAMP) in cells.[18][14] It is a highly reliable and effective cAMP increasing agent, and is routinely used as a research tool to investigate the effects of cAMP increases in a cell.[8]

This increase in cAMP does not increase lipolysis per se at low concentrations of 0.1-1µM, but when it surpasses 10µM it can induce lipolysis on its own.[18] Low concentrations are effective at increasing lipolysis when paired with β2-adrenergic agonists, suggesting the fat burning effects of forskolin are dependent on either high dosages or costimulation with other agents (exogenous and/or endogenous).[18] Similar to the costimulatory effect with agents that would normally stimulate adenylyl cyclase, pharmacological targets that can inherently suppress adenylyl cyclase activity such as α2-adrenergic stimulation or insulin can suppress the activity of forskolin in increasing cAMP.[19]

Forskolin can activate adenylyl cyclase to increase cAMP concentrations in a cell, and is additive with other agents that eventually increase cAMP. Endogenous molecules or supplements that exert a suppressive action on cAMP (via suppression of adenylyl cyclase) can suppress the activity of forskolin

2.2. Increasing cAMP

This mechanism of increasing cAMP is similar to exercise in regards to increasing activity of some enzymes, downstream of mitochondrial biogenesis (also, a non-significant increase in mitochondrial density at 4uM forskolin).[20] This cAMP increasing ability by Forskolin also appeared to non-significantly activate AMPK.[20]


Edit3. Pharmacology

3.1. Absorption

Coleus Forskohlii is well absorbed in the cat gastrointestinal tract after oral administration[21] and can be absorbed in all areas of the intestines and colon (in rats) although the duodenum seems to have highest uptake.[22]

Forskolin appears to be subject to P-Glycoprotein efflux in the intestines, and coingestion of a P-glycoprotein inhibitor may increase oral bioavailability.[22]


Edit4. Neurology

4.1. Mechanisms

Coleus leaves appear to have acetylcholineaster inhibiting properties with an IC50 value of 1.02+/-0.02mg/mL in vitro[12][3] which appears to survive simulated gastric digestion[12] and has been noted to be relevant following oral ingestion of 600mg/kg in rats.[11] These effects are thought to be secondary to Rosmarinic Acid which has an IC50 value of 0.44mg/mL, and the inhibition appears to be reversible.[11][3] Rosmarinic acid has been detected in the brain (20.4-24.1μM 30-60 minutes after intraperitoneal injection of 1g/kg) following ingestion of coleus leaf tea and acetylcholinesterase activity has been noted to be decreased by 5.5-10% (60 minute and 30 minutes, respectively).[11] Acetylcholineasterase inhibition has also been noted with isolated rosmarinic acid to the level of 12.8-13.5% following ingestion of 550μmol/kg.[11]

Coleus forskohlii leaves (not commonly supplemented, as many supplements contain the root) appear to have acetylcholinesterase inhibiting properties due to the rosmarinic acid content. These effects are confirmed in vivo


Edit5. Interactions with Obesity

5.1. Human studies

In regards to human in vivo studies, they appear to be promising but limited in numbers and power. One study in overweight women noted that two doses of 250mg 10% extract reduced weight gain.[23] There was not significant weight loss in the experimental group, but there was a significant difference between the experimental (slight loss) and control (weight gain).[23] In overweight men, the same dose appears to cause favorable changes in body composition over a period of 12 weeks.[24] Testosterone and bone mass were also increased in the Coleus Forskohlii group. One study that did not investigate weight changes primarily noted that over a period of 2 months with 500-700mg Coleus Forskohlii there was a 2.38-2.6% reduction in BMI.[25]

There may be notable differences between obese and normal weight humans, as obese persons seem to have lower activity adenylate cyclase enzymes in fat cells, which is partially corrected upon weight loss via caloric restriction.[26] Also, men may have more benefit than women as testosterone can act as a fat burner/muscle preserving agent, although only one study has been conducted on men so far.[24]

5.2. Metabolic Rate

One study on overweight men consuming 250mg of Coleus Forskohlii twice daily found no significant effect on increasing the Metabolic Rate.[24]


Edit6. Interactions with Skeletal Muscle

6.1. Muscle Protein Synthesis

Forskolin is able to increase activity of Adenylate Cyclase in skeletal muscle.[27] Through increasing cAMP, it has been speculated that Forskolin can increase muscle protein synthesis by activating PI3K and Akt, independent of the insulin receptor[28] and that this reaction is subject to desensitization.[29]

6.2. Muscle contractility

Forskolin, in vitro at concentrations of 1uM, has been shown to increase electical-stimulated skeletal muscle contractility in the mouse diaphragm.[30][31] The theorized mechanims of this is increasing cAMP levels, inducing PKA activity which acts on the ryanodine receptor and increases Ca2+ efflux from the sarcoplasmic reticulum. [32]

Although biological plausibility exists, no studies have been conducted on Coleus Forskohlii and muscle contraction in vivo.

6.3. Nutrients and Muscle cells

Forskolin has been implicated in vivo in reducing insulin's effects on the mTOR/Akt pathway in skeletal muscle.[33] Specifically, Forskolin appeared to reduce insulin's ability to phosphorylate Akt (with no affect on total Akt) and similar results were seen when looking at 4EBP1, with mTOR and S6K1 unaffected by all treatments.[33]

Forskolin is also able to inhibit myocyte GLUT4 translocation in vitro, and GLUT1 to a lesser degree.[34] This may also be downstream of cAMP, as it is seen in adipocytes as cAMP is known to adversely influence GLUT4 translocation via its promoter,[35][36] and also in muscle cells.[37]

In regards to fat metabolism, the activation of cAMP/PKA in myocytes seems to improve lipid metabolism,[38] and is one of the junction points of exercise and health in muscle cells.[39][40][41] Possibly through a myokine called Myonectin.[42]


Edit7. Interactions with Heart Health

7.1. Blood Pressure

The active compound of Coleus Forskohlii, Forskolin, appears to either relax blood vessels and depress blood pressure or to have no overall effect on blood pressure.

It does not appear to reduce blood pressure via cholinergic or histamine means,[21] and provides a sustained reduction in blood pressure at 0.1-1mg/kg bodyweight in anathesized cats; with more reduction seen in those with higher baseline blood pressures.[21] Higher dosages do not increase potency of the blood pressure decrease, but instead prolong the time it can act; a parallel to the effects of forskolin on intraocular pressure.[21]

This vasorelaxant ability of forskohlii may be synergystic with Prostaglandin E1.[43]

7.2. Cardiac tissue

Forskolin is able to activate Adenylate Cyclase in the myocardium, and exerts a positive ionotropic effect which may be beneficial to failing hearts.[44] This has been observed in vivo with cat and rabbit hearts.[21]


Edit8. Interactions with Organs

8.1. Eyes and Intraocular pressure

One study noted decreases in Intra-Ocular Pressure (IOP) with forskohlii in man[45] via its effects as an adenylate cyclate activator.[46][47] That being said, past studies have used a topical method of delivery (eye drops). Recently, this effect has been seen after oral ingestion of a Forskohlii/Rutin/Thiamin/Riboflavin combination by about 20% after 40 days of treatment in persons with Primary Open Angle Glaucoma.[48]

8.2. Liver

Coleus Forskohlii extract at 0.5% of feed intake in rats results in induction of various enzyme systems in the liver, alongside an increase in liver weight. Dose dependent increases in transcription for Cyp2b10, Cyp2c29, Cyp3a11, and Gstm2 were noted.[49] These changes were seen after 1 week, and ceased upon cessation of Coleus intake. This intake was estimated to be 740mg/kg bodyweight of Coleus daily; 24mg in total for the rats.[49] The CYP2C induction is of clinical relevance, as it is the enzyme that metabolizes warfarin.

Isolated forskolin has weaker induction of CYP3A and Glutathione enzymes, and does not increase liver weight at 0.05% of the diet.[49] This induction may be mediated by agonism of the Pregnane X receptor, which is independent of its activities on Adenylate Cyclase.[50]


Edit9. Interactions with Hormones

9.1. Testosterone

One intervention in overweight men noted increases in testosterone with 250mg Coleus Forskohlii (10% Forskolin by weight) over the course of 12 weeks.[24] Although there were significant differences at baseline (5.06+/-1.21ng versus 4.12+/-0.82ng Total Test, 15.90+/-13.39pg v. 13.28+/-7.26pg free test; higher values in Coleus group) increases were still at 6 weeks and 12 weeks in Coleus while no changes occurred in control. Total test increased by 16.77+/-33.77% and free test by 3.47+/-8.10 after 12 weeks, with high inter-individual variance.[24]

The hypothesized mechanism of action is via increasing intra-testicular cAMP levels, which mimick the mechanisms of action of luteinizing hormone in the testicles.[51] LH normally increases cAMP itself, but circumventing LH to increase cAMP can increased steroidogenesis per se.[52][53] Even some other studies investigating herbs like Cordyceps in the testes will use forskolin as a standard by which to compare the efficacy of the newer drugs.[54]

Coleus extract may also induce CYP3A4 in the liver, which theoretically should lead to increased metabolism of testosterone.[49] However, testosterone was not measured in this rat study; isolated forskolin had a much lesser effect.

9.2. Insulin

Forskolin has been shown, in vitro, to be able to release insulin (as well as glucagon and somatostatin) when incubated in pancreatic cells.[55]


Edit10. Nutrient-Nutrient Interactions

10.1. Beta-Adrenergic Agonists

Its is able to potentiate the effects of the beta-adrenergic agonist isoproterenol, and seems to be highly effective until isoproterenol reaches concentrations of 1uM (in which afterwards, descending returns are seen),[18] forskolin showed dose dependent benefits in increasing cAMP alongside isoproterenol.

In situations where beta-adrenergic agonists do not stimulate (hyporesponsiveness), low doses of forskolin are able to rescue the effectiveness of beta-adrenergic agonists.[56] Additionally, 1uM forskolin (although not lesser concentrations) are able to rescue beta-adrenergic desensitization.[57]

This synergy has been noted in vivo using isoproterenol and forskolin, via IV.[58]

Beta-Adrenergic agonists incluce Synephrine, Ephedrine, Capsaicin and possibly raspberry ketones; as well as endogenous adrenaline secretion.

10.2. Methylxanthines

Forskolin is synergistic with methylxanthines, as methylxanthines have the ability to reduce adenosine's suppressive influence on elevated cAMP levels in adipocytes via acting as adenosine inhibitors.[59][18] This combination of Forskolin and the Methylxanthine Aminophylline is even more synergistic with the addition of a beta-adrenergic agonist, such as Ephedrine.

Some methylxanthines, such as theophylline and Caffeine, also possess phosphodiesterase inhibitory properties. PDE inhibition results in increased cAMP by alleviating degradation, and forskolin does not influence PDEs.[18] The combination of methylxanthines and forskolin can increase production of and alleviate degradation of cAMP to promote synergism in vitro.

Forskolin has also been shown to increase sarcoplasmic loading of Calcium and modulate Calcium spikes from the sarcoplasmic reticulum (via phospholambin)[60] which augments caffeine's ability to induce calcium release.[61]

Methylxanthines include theophylline, theobromine, and Caffeine. These can be found in high amounts in tea, chocolate, and coffee; respectively.

10.3. Alpha-Adrenergic Antagonists

When coincubated (in the cell at the same time), and alpha-adrenergic agonism by insulin or agonists can inhibit the increases in cAMP seen by forskolin.[62] Co-incubation of an alpha-adrenergic antagonist with the agonist and forskolin can rescue some of the effects by negating the inhibition.[62]

Interestingly, sensitizing cells (in this study, colonic carcinoma cells) by incubating with an alpha-adrenergic agonist [62] After exposure to an agonist for 30+ minutes, cells have 20-fold increases in forskolin-stimulated cAMP for a short time (20-40 minutes).[62][63]


Edit11. Safety and Toxicity

11.1. General

Coleus Forskohlii supplementation can cause an increase in stomach acid levels, and may be a bad idea for those currently suffering from stomach ulcers.[64]

In cats, the LD50 appears to be 68mg/kg bodyweight forskolin.[21]

11.2. Tolerance

Aortic cells normally increase calcium uptake in response to cAMP, although it appears that a 20 hour incubation of 25µM forskolin can desensitize these cells to stimulation from cAMP despite adenylyl cyclase not being desensitized, suggesting refractory adaptation on another level.[65] Other cells have noted refractoriness at the level of protein synthesis and can be mimicked by isoproterenol (β2-adrenergic agonist).[66]

It seems that while adenylyl cyclase itself is not desensitized or altered in function with exposure to forskolin, prolonged elevations of cAMP cause proteins to be synthesized in an attempt to normalize intracellular cAMP levels.

References

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  2. Pharmacognostic Evaluation of Coleus forskohlii
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  65. Krall JF, Jamgotchian N. Forskolin refractoriness. Exposure to the diterpene alters guanine nucleotide-dependent adenylate cyclase and calcium-uptake activity of cells cultured from the rat aorta. Biochem J. (1987)
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  71. González-Sánchez R, et al. Forskolin versus sodium cromoglycate for prevention of asthma attacks: a single-blinded clinical trial. J Int Med Res. (2006)

(Common misspellings for Coleus forskohlii include forskolhii, forshkolii, forskholii, forskoli, forsholii, forsholi, forshkohli)

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