Forskolin
Coleus forskohlii (Willd.) Briq., Lamiaceae (mint family)
Pashanabhedi , makandi , colforsin , HL-362 , mao hou qiao rui hua . The plant is a component of   Asthma X-5 (Olympian Labs),   Ele-max (Tyler),   Interex ,   Meta-Burn EF (MRM),   Ripped Fuel Extreme (Twinlab),   Fat Busters (Nature's Plus),   GlucoLean (Biochem), and   ForsLean (Sabinsa).
 
Clinical Overview
Uses
Forskolin has been shown to dilate the blood vessels causing a decrease in blood pressure, increase the contractility of the heart, inhibit platelet aggregation, and relax contracted airways in asthma patients. Because of its multiple sites of action, it should be used with caution.

Dosing
Typical dosage is 100 to 300 mg/day of an extract containing 10% to 20% forskolin.

Contraindications
Avoid use in patients on anticoagulants, antihypertensives, and vasodilators because of additive effects. Avoid use with ulcers because of stimulation of gastric acid and in diabetes due to stimulation of lipid release and gluconeogenesis.

Pregnancy/Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.

Interactions
May have additive effects with anticoagulants, antihypertensives, and vasodilators.

Adverse Reactions
Avoid use with ulcers because of stimulation of gastric acid and in diabetes due to stimulation of lipid release and gluconeogenesis.

Toxicology
No data.

 
Botany
Coleus forskohlii is a perennial herb in a large genus of mints. The plant is native to subtropical and tropical regions of India and east Africa. A synonym is C. barbatus (Andrews) Benth.
 
History
This species and other related species were used in Ayurvedic medicine under the name pashanabhedi for heart and lung diseases, intestinal spasms, insomnia, and convulsions. 1 It was studied for cardiovascular activity in 1974 by scientists from Hoechst India and the Central Drug Research Institute of India in screening programs that examined medicinal plants. 2
 
Chemistry
As a result of that screening program, the diterpene forskolin (coleonol) was isolated and elucidated as the major active hypotensive principle of the roots of the plant. 3 The absolute stereochemistry of forskolin was determined by x-ray crystallography. 4 , 5 The other most abundant diterpene, 1,9-dideoxy-forskolin, had no hypotensive activity. 6 Since that time, many closely related diterpenes have been isolated from the roots and aboveground portions of the plant. 6 , 7 , 8 Stigmasterol also was isolated. 9
Because forskolin has been actively pursued as a drug development lead, there have been many analytical chemistry studies. A gas-liquid chromatography (GLC) method was developed for quantitation of forskolin in plant tissues and in dosage forms. 10 Both thin layer and high performance liquid chromatographic (HPLC) methods also have been published. 11 The GLC method was more sensitive but the HPLC method was found to be more rapid. 11 The HPLC method has been used to monitor variation in forskolin content in different germplasm. The content ranged from 0.01% to 0.27% for 38 samples. 12 A monoclonal antibody specific for forskolin has been developed for affinity isolation of forskolin. 13 The same antibody also has been used for extremely sensitive quantitation of forskolin in plant tissues at different stages of development. 14 Nuclear magnetic resonance data and a gas chromatography-mass spectral method also have been published for forskolin and its congeners. 15 , 16 Tissue culture methods for forskolin production also have been successfully explored because the relatively modest content of forskolin in the plant has limited its development as a drug. 17 , 18
 
Uses and Pharmacology
Cardiovascular effects   The principle mechanism by which forskolin exerts its hypotensive activity is by stimulation of adenylate cyclase, thereby increasing cellular concentrations of the second messenger cyclic AMP (cAMP). 19 Of the 9 types of adenylate cyclase in humans, forskolin can activate all but type IX, which is found in spermatozoa. 20 Photoaffinity derivatives of forskolin have been shown to irreversibly react with type I adenylate cyclase, 21 and the structure of forskolin bound to type II cyclase has been determined by x-ray crystallography. 22 Chemical modification of forskolin at the 6- and 7-positions has led to semisynthetic compounds with modest selectivity for particular cyclase isoforms, including the cardiac type V adenylate cyclase. 20 , 23 , 24 Stimulation of adenylate cyclase is thought to be the mechanism by which forskolin relaxes a variety of smooth muscles.
Forskolin also has been found to act through other mechanisms, however. Forskolin binds to the glucose transporter in adipocytes, 25 to the P-glycoprotein drug efflux pump, 26 alters potassium channel activity, 27 decreases GABA receptor chloride flux, 28 and modulates the nicotinic acetylcholine receptor. 29 , 30 The natural diterpene 1,9-dideoxy-forskolin, which has no activity on the cyclase enzyme, shows activity in most of these other systems. Because this compound is a major component of the plant, herbal preparations should be thought as acting through multiple pharmacologic mechanisms.
Animal data   Forskolin exhibits hypotensive properties through vasodilation, relaxing vascular smooth muscle. In small doses it demonstrated positive inotropic effects in the cat, rat, and the spontaneously hypertensive rat. 1 , 31 Radiolabeled forskolin was shown to bind to rat brain membranes in a saturable and specific manner. 32
Clinical data   In human heart tissues, forskolin activated adenylate cyclase and showed strong positive inotropic properties that were synergistic with isoproterenol. 33
Anithrombotic effect   Forskolin also has been shown to inhibit platelet aggregation through adenylate cyclase stimulation, augmenting the effects of prostaglandins. 34 , 35
Animal data   Its antithrombotic properties may be enhanced by cerebral vasodilation, which was observed in rabbits. This vasodilation was not potentiated by adenosine. 36 The use of crude C. forskohlii extract as a rational phytotherapeutic antithrombotic has been proposed. 2
Clinical data   Research reveals no clinical data regarding the use of forskolin for antithrombotic effects.
Asthma   The smooth muscle relaxant properties of forskolin also have led to investigation of its use in asthma.
Animal data   In guinea pigs, forskolin blocked bronchospasm caused by histamine, leukotriene-4, or antigen. 37
Clinical data   In human basophils and mast cells, forskolin blocked the release of histamine and leukotriene C-4, 38 while stimulating gastric acid and pepsinogen secretion by isolated rabbit gastric glands. 39 A small human study found that inhaled forskolin powder formulations were capable of causing bronchodilation in asthma patients. 40
Other uses   Forskolin had no lasting effect, however, on intraocular pressure in monkeys with glaucoma. 41 It also showed no effect on humans in reducing aqueous flow when applied topically to the eye. 42 A further study found that forskolin induced lipolysis in intact rat fat cells without increasing cAMP, but had no effect in homogenized cells. 43 A patent claiming promotion of lean body mass and antidepressant activity of a forskolin-containing extract was granted to the supplement company Sabinsa in 1998. 44 Forskolin showed antidepressant activity in a rat forced swimming model. 45 Due to its vasodilating properties, forskolin and analogs have been proposed for intercavernosal treatment of erectile dysfunction, however, only small clinical studies have been reported. 46 , 47
 
Administration & Dosage
Typical dosage is 100 to 300 mg/day of an extract containing 10% to 20% forskolin.
 
Pregnancy/Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.
 
Interactions
May have additive effects with anticoagulants, antihypertensives, and vasodilators.
 
Adverse Reactions
Avoid use with anticoagulants, antihypertensives, and vasodilators because of additive effects. Avoid use with ulcers because of stimulation of gastric acid and in diabetes due to stimulation of lipid release and gluconeogenesis. Avoid use with ulcers because of stimulation of gastric acid and in diabetes due to stimulation of lipid release and gluconeogenesis.
 
Toxicology
Research reveals little or no information regarding toxicology with the use of this product.
 
References
 

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2. de Souza NJ. Industrial development of traditional drugs: the forskolin example. A mini-review. J Ethnopharmacol . 1993;38:177-180.  PubMed

 

3. Bhat SV, et al. Structures and stereochemistry of new labdane diterpenoids from Coleus forskohlii Briq. Tetrahedron Lett . 1977;1669.

 

4. Paulus EF. Molecular and crystal structure of forskolin. Z Kristallogr . 1980;152:239.

 

5. Paulus EF. Molecular and crystal structure of 1-benzyl-7-desacetyl-7-bromoisobutyryl-forskolin. Absolute configuration of forskolin. Z Kristallogr . 1980;153:43.

 

6. Roy R, et al. Minor diterpenes from Coleus forskohlii . Phytochemistry . 1993;34:1577.

 

7. Khandelwal Y, et al. Isolation, structure elucidation, and synthesis of 1-deoxyforskolin. Tetrahedron . 1989;45:763.

 

8. Tandon JS, et al. Epi-deoxycoleonol, a new antihypertensive labdane diterpenoid from Coleus forskohlii. Bioorg Med Chem Lett . 1992;2:249.

 

9. Shah VC, D'Sa AS, de Souza NJ. Chonemorphine, stigmasterol, and ecdysterone: steroids isolated through bioassay-directed plant screening programs. Steroids . 1989;53:559-565.  PubMed

 

10. Inamdar PK, Dornauer H, de Souza NJ. GLC method for assay of forskolin, a novel positive inotropic and blood pressure-lowering agent. J Pharm Sci . 1980;69:1449-1451.  PubMed

 

11. Inamdar PK, et al. Quantitative determination of forskolin by TLC and HPLC. Planta Med . 1984;50:30.  PubMed

 

12. Vishwakarma RA, et al. Variation in forskolin content in the roots of Coleus forskohlii . Planta Med . 1988;54:471.  PubMed

 

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14. Yanagihara H, Sakata R, Shoyama Y, Murakami H. Rapid analysis of small samples containing forskolin using monoclonal antibodies. Planta Med . 1996;62:169-172.  PubMed

 

15. Prakash O, et al. Carbon-13 and proton two-dimensional NMR study of diterpenoids of Coleus forskohlii. Magn Reson Chem . 1988;26:117.

 

16. Demetzos C, Kolocouris A, Anastasaki T. A simple and rapid method for the differentiation of C-13 manoyl oxide epimers in biologically important samples using GC-MS analysis supported with NMR spectroscopy and computational chemistry results. Bioorg Med Chem Lett . 2002;12:3605-3609.  PubMed

 

17. Mersinger R, Dornauer H, Reinhard E. Formation of forskolin by suspension cultures of Coleus forskohlii . Planta Med . 1988;54:200-204.  PubMed

 

18. Mukherjee S, Ghosh B, Jha S. Establishment of forskolin yielding transformed cell suspension cultures of Coleus forskohlii as controlled by different factors. J Biotechnol . 2000;76:73-81.  PubMed

 

19. Seamon KB, Padgett W, Daly JW. Forskolin: unique diterpene activator of adenylate cyclase in membranes and in intact cells. Proc Natl Acad Sci U S A . 1981;78:3363-3367.  PubMed

 

20. Iwatsubo K, Tsunematsu T, Ishikawa Y. Isoform-specific regulation of adenylyl cyclase: a potential target in future pharmacotherapy. Expert Opin Ther Targets . 2003;7:441-451.  PubMed

 

21. Sutkowski EM, Robbin JD, Tang WJ, Seamon KB. Irreversible inhibition of forskolin interactions with type I adenylyl cyclase by a 6-isothiocyanate derivative of forskolin. Mol Pharmacol . 1996;50:299-305.  PubMed

 

22. Zhang G, Liu Y, Ruoho AE, Hurley JH. Structure of the adenylyl cyclase catalytic core. Nature . 1997;386:247-253.  PubMed

 

23. Onda T, Hashimoto Y, Nagai M, et al. Type-specific regulation of adenylyl cyclase. J Biol Chem . 2001;276:47785-47793.  PubMed

 

24. Toya Y, Schwencke C, Ishikawa Y. Forskolin derivatives with increased selectivity for cardiac adenylyl cyclase. J Mol Cell Cardiol . 1998;30:97-108.  PubMed

 

25. Kashiwagi A, Huecksteadt TP, Foley JE. The regulation of glucose transport by cAMP stimulators via three different mechanisms in rat and human adipocytes. J Biol Chem . 1983;258:13685-13692.  PubMed

 

26. Morris DI, Speicher LA, Ruoho AE, Tew KD, Seamon KB. Interaction of forskolin with the P-glycoprotein multidrug transporter. Biochemistry . 1991;30:8371-8379.  PubMed

 

27. Hoshi T, Garber SS, Aldrich RW. Effect of forskolin on voltage-gated K+ channels is independent of adenylate cyclase activation. Science . 1988;240:1652-1655.  PubMed

 

28. Heuschneider G, Schwartz RD. cAMP and forskolin decrease gamma-aminobutyric acid-gated chloride flux in rat brain synaptoneurosomes. Proc Natl Acad Sci U S A . 1989;86:2938-2942.  PubMed

 

29. Albuquerque EX, Deshpande SS, Aracava Y, Alkondon M, Daly JW. A possible involvement of cyclic AMP in the expression of desensitization of the nicotinic acetylcholine receptor. A study with forskolin and its analogs. FEBS Lett . 1986;199:113-120.  PubMed

 

30. Wagoner PK, Pallotta BS. Modulation of acetylcholine receptor desensitization by forskolin is independent of cAMP. Science . 1988;240:1655-1657.  PubMed

 

31. Dubey MP, Srimal RC, Nityanand S, Dhawan BN. Pharmacological studies on coleonol, a hypotensive diterpene from Coleus forskohlii . J Ethnopharmacol . 1981;3:1-13.  PubMed

 

32. Seamon KB, Vaillancourt R, Edwards M, Daly JW. Binding of [3 H]-forskolin to rat brain membranes. Proc Natl Acad Sci U S A . 1984;81:5081-5085.  PubMed

 

33. Bristow MR, Ginsburg R, Strosberg A, Montgomery W, Minobe W. Pharmacology and inotropic potential of forskolin in the human heart. J Clin Invest . 1984;74:212-223.  PubMed

 

34. Siegl AM, Daly JW, Smith JB. Inhibition of aggregation and stimulation of cyclic AMP generation in intact human platelets by the diterpene forskolin. Mol Pharmacol . 1982;21:680-687.  PubMed

 

35. Adnot S, Desmier M, Ferry N, Hanoune J, Sevenet T. Forskolin (a powerful inhibitor of human platelet aggregation). Biochem Pharmacol . 1982;31:4071-4074.  PubMed

 

36. Wysham DG, Brotherton AF, Heistad DD. Effects of forskolin on cerebral blood flow: implications for a role of adenylate cyclase. Stroke . 1986;17:1299-1303.  PubMed

 

37. Kreutner W, Chapman RW, Gulbenkian A, Tozzi S. Bronchodilator and antiallergy activity of forskolin. Eur J Pharmacol . 1985;111:1-8.  PubMed

 

38. Marone G, Columbo M, Triggiani M, Cirillo R, Genovese A, Formisano S. Inhibition of IgE-mediated release of histamine and peptide leukotriene from human basophils and mast cells by forskolin. Biochem Pharmacol . 1987;36:13-20.  PubMed

 

39. Hersey SJ, Owirodu A, Miller M. Forskolin stimulation of acid and pepsinogen secretion by gastric glands. Biochim Biophys Acta . 1983;755:293-299.  PubMed

 

40. Bauer K, Dietersdorder F, Sertl K, Kaik B, Kaik G. Pharmacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma. Clin Pharmacol Ther . 1993;53:76-83.  PubMed

 

41. Lee PY, Podos SM, Serle JB, Camras CB, Severin CH. Intraocular pressure effects of multiple doses of drugs applied to glaucomatous monkey eyes. Arch Ophthalmol . 1987;105:249-252.  PubMed

 

42. Brubaker RF, Carlson KH, Kullerstrand LJ, McLaren JW. Topical forskolin (colforsin) and aqueous flow in humans. Arch Ophthalmol . 1987;105:637-641.  PubMed

 

43. Okuda H, Morimoto C, Tsujita T. Relationship between cyclic AMP production and lipolysis induced by forskolin in rat fat cells. J Lipid Res . 1992;33:225-231.  PubMed

 

44. Majeed M, et al. Method of preparing a forskolin composition from forskolin extract and use of forskolin for promoting lean body mass and treating mood disorders. US patent 5804596. 1997.

 

45. Maeda H, Ozawa H, Saito T, Irie T, Takahata N. Potential antidepressant properties of forskolin and a novel water-soluble forskolin (NKH477) in the forced swimming test. Life Sci . 1997;61:2435-2442.  PubMed

 

46. Drewes SE, George J, Khan F. Recent findings on natural products with erectile-dysfunction activity. Phytochemistry . 2003;62:1019-1025.  PubMed

 

47. Mulhall JP, Duller M, Traish AM, et al. Intracavernosal forskolin: role in management of vasculogenic impotence resistant to standard 3-agent pharmacotherapy. J Urol . 1997;158:1752-1758.  PubMed