Sunday, December 30, 2012

Forskolin: Friend or Foe? Stories and Studies About Fat Loss, Lean Gains, Topical Cellulite Treatment, Testosterone, Cancer, Hepatotoxicity, Drug Interactions & More

There is a single human study that would suggest that forskolin would make you get closer to this classic physique w/out tons of salad (who said that's necessary anyway?).
Since Maxim asked in one of his more recent comments about the usefulness and/or downsides of forskolin, I dediced to dedicate this Sunday (finally again?) to answering a user question and am going to briefly sum up some older and the few novel findings on forskolin I am aware of.

For those of you who find that boring: Don't blame Maxim alone, another reason for this decision was that I have seen discussions on forskolin resurface elsewhere on the Internet. By the way, I write re-surfaced, because forskolin has once been hailed as a testbooster and fat loss adjuvant, but as the prices increased and people came out with faked or low-quality products that did not yield results, the market collapsed.

What is forskolin and where does it originate from?

As usually there is more than a single answer to this question. The most straight forward general ones are probably (a) it is a white to white with yellow cast powder, or (b) a labdane diterpenoid with antihypertensive, positive inotropic, platelet aggregation inhibitory and adenylate cyclase activating properties. Moreover, forskolin is able to activate the adenylate cyclase and thus increase the intracellular cyclic AMP levels in most tissues and cells. And hat  it's called forskolin, because it is derived from the Indiant plan Coleus forskohlii is probably something 99% of you knew already.

The reason I suppose that Maxim got interested in it, is that it is commonly used in cell studies to raise the levels of cyclic AMP (cAMP; cf. Alasbahi. 2012) and did a pretty impressive job in the recently discussed PGC-1a study. On the other hand, it did also increase the expression of the aromatase enzyme in the Yang study mentioned in the "Natural Sildenafil & Testosterone Alternative" post on which Maxim replied with the initially mentioned comment.

"Wait, wasn't it supposed to be a testbooster and now it also inhibits myostatin and increases estrogen? What does this stuff not do?" - Well, forskolin is, above all, a cAMP modulator

Forskolins chemical structure. Sometimes it's also referred to as Colforsin; 7-beta-acetoxy-8, 13-epoxy-1-alpha, 6-beta, 9-alpha-trihydroxylabd-14-en-11-one; or Coleonol (img. from Sigma-Aldrich's product database)
I know that sounds confusing, but in essence forskolin does nothing but increasing cAMP levels in almost all types of cells. cAMP a breakdown product of ATP (=> cAMP => AMP) in turn is one of those molecules which exert most their effects as intracellular signal transducer. In that, it is involved in the activation of protein kinases and regulates the effects of adrenaline and glucagon. It also modulates the calcium channels and contributes to growth hormone release; unfortunately, cAMP has also been implicated in the proliferation of not very beneficial cell growth aka cancer. The same ion-flux mediation has recently been implicated in the etiology of ADHD, as well (Arnsten. 2012).

Still, it's not all about c-AMP. Probably cAMP unrelated downsides of coleus forkohlii are for example:
  • forskolin induces hepatic CYP2C enzymes and coleus forskohlii extract and thus attenuates the anticoagulant action of warfarin. (Yokotan. 2012) 
  • even more than isolated forskolin, coleus forskohlii  messes with the hepatic enzyme cascade (P450) and has even been shown to be hepatoxic in a study published in the July issue of the Journal of Toxicology (Virgona. 2012)
On the other hand there are a handful of benefits, e.g.
  • Figure 1: Effects of 12 weeks on 2x250mg (10%) forskolin on testosterone (free and total) and lean & fat mass (Godard. 2005)
    In a 2005 study (Godard. 2005), which caused quite a stir in the health and fitness community back then, Godard et al. observed profound beneficial effects of testosterone and body composition (cf. figure 1) after the ingestion of 2x250mg of a 10% standardized forskolin (Forslean).

    Now, the unfortunate truth is that the15 subjects (average age, BMI, and body fat percent were 24.4 +/- 5.9 years, 32.5 +/- 4.1 kg/m2 , and 35.2 +/- 8.3%) who had been randomized to the active arm of the study, and the 15 participants in the placebo arm (28.7 +/- 8.6 years, 32.6 +/- 3.8 kg/m2 , and 35.0 +/- 7.3%) were non-active sedentary overweight/obese (BMI 26 kg/m2 or more) individuals. Add the funding by Sabinsa (Forslean producer) to the equation and decide for yourself how relevant you think the results are going to be for you...
  • In several in-vitro studies, forskolin has been used as a positive control to compare the effects of other compounds on the testosterone release in leydig cells. Lin et al. for example used it in 2001 as a comparison for lactate and found a ~3x increase in testosterone release in incubated leydig cells (Lin. 2001). A similar study by Yu et al. showed that the addition of green tea catechins lead to an additional stimulation of forskolin induced testosterone production in cell cultures (Yu. 2010).
  • Figure 2: Results of 12-week intervention w/ forskolin containing topical cream (Roure. 2011)
    As part of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, retinol and, obviously, forskolin it has shown some promise as a topical anti-cellulite and toning agent (Roure. 2011). The clinical study was however financed by Johnson & Johnson and I am not sure how much of the effects were actually brought about by forskolin (the placebo was a basic gel with the same texture containing mainly water, gelifying and preservative systems). So take the data in figure 2 with a grain of salt, ladies - I bet 12 weeks on this product are not going to be exactly inexpensive.
  • The administration of forskolin in conjunction with rutin (the glycoside between the flavonol quercetin and the disaccharide rutinose), vitamin B1 & B2 in a 2010 study by Pescosolido et. al. lead to a significant reduction in intra-ocular pressure in 15 glaucoma patients after 40 days (Pescosolido. 2010). Similar results were observed in a 2012 study for forskolin and rutin alone (Vetrugno. 2012)
  • An in-vitro study by Cristobal et al. provides first evidence for the ability of forskolin to restore PPA2 in acute myeloid leukemia. That would make it a potential candidate for the treatment of this type of cancer, but to my knowledge there is as of yet not even a rodent study that would support these in-vitro results. Moreover, previous studies have suggested that Forskolin may even favor the proliferation of other types of leukemia (Kobayashi. 1994)
Time to weigh the "established" benefits and downsides

Figure 3: Effect of different doses of forskolin with and w/out epinephrine on FFA release from rat adipocytes - watch out this is from yet another in-vitro study with rodent cells (Litosch. 1982)
 In view of the fact that the aforementioned study by Godard is the only human study is only backed up by in-vitro data from rodent studies (Litosch. 1982, cf. figure 3), the fat loss benefits are as  Jeukendrup et al. point out in their 2011 review of purported fat burners...
"[...] promising, there is [yet] only one study at the present time and more work is required before forskolin can be recommended as a fat metabolism-enhancing substance." (Jeukendrup. 2011)
If you add to this the host of wanted and unwanted, known and unknown side effects that occur in response to the coleus foskohlii induced cytochrome P450 modulation (e.g. the mice in the aforementioned study by Virgona lost some visceral fat, but the costs were increased fat deposition in the liver and elevated transaminase levels).

With the questionable "fat loss" benefits (remember stress is also a powerful lypolitic and the problem is not to get the fat out of the cell, but rather to burn it), and the almost non-existant human data on the purported testosterone boosting effects, this should be reason enough not to buy more than one bottle for a test-run. After which I highly suggest to do some lab work to see if whatever good or bad you believe you are feeling is an actual boost in T (check T-levels) or hepatic side effects (check ALT, AST & ALP).

Note (update in response to comments): As far as the hepatoxicity is concerned the suggested dosage of 2x 250mg coleus forskholii most supplements come with may be higher than the medium dose in the study by Virgona, but is still probably "liver save" if you double dose on that, you are however landing in the no-man's land (=not tested for) gray zone between the medium dosage and the "danger zone" of  ~49mg/kg per day (human dose equivalent) that was tested in the study. Don't freak out, if you did that in the past, the levels return to normal afterwards and temporarily elevated ALT + AST or ALP levels do not necessarily mean that your liver is whacked forever ;-)

References:
  • Alasbahi RH, Melzig MF. Forskolin and derivatives as tools for studying the role of cAMP. Pharmazie. 2012 Jan;67(1):5-13.
  • Arnsten AF, Jin LE. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 2012 Mar;85(1):45-58. Epub 2012 Mar 29.
  • Godard MP, Johnson BA, Richmond SR. Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. Obes Res. 2005 Aug;13(8):1335-43. 
  • Jeukendrup AE, Randell R. Fat burners: nutrition supplements that increase fat metabolism. Obes Rev. 2011 Oct;12(10):841-51. 
  • Kobayashi K, Nishikawa M, Omay SB, Toyoda H, Deguchi K, Shirakawa S. Forskolin potentiates G-CSF-induced proliferation of a murine myeloblastic leukemia cell line. Leuk Res. 1994 Feb;18(2):111-7.
  • Lin H, Wang SW, Wang RY, Wang PS. Stimulatory effect of lactate on testosterone production by rat Leydig cells. J Cell Biochem. 2001 Jun 26-Jul 25;83(1):147-54.
  • Pescosolido N, Librando A. Oral administration of an association of forskolin, rutin and vitamins B1 and B2 potentiates the hypotonising effects of pharmacological treatments in POAG patients. Clin Ter. 2010;161(3):e81-5. 
  • Roure R, Oddos T, Rossi A, Vial F, Bertin C. Evaluation of the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol, In vitro, ex vivo and in vivo studies. Int J Cosmet Sci. 2011 Dec;33(6):519-26.
  • Vetrugno M, Uva MG, Russo V, Iester M, Ciancaglini M, Brusini P, Centofanti M, Rossetti LM. Oral administration of forskolin and rutin contributes to intraocular pressure control in primary open angle glaucoma patients under maximum tolerated medical therapy. J Ocul Pharmacol Ther. 2012 Oct;28(5):536-41.
  • Virgona N, Taki Y, Yamada S, Umegaki K. Dietary Coleus forskohlii extract generates dose-related hepatotoxicity in mice. J Appl Toxicol. 2012 Jun 22.
  • Yokotani K, Chiba T, Sato Y, Taki Y, Yamada S, Shinozuka K, Murata M, Umegaki K. Hepatic cytochrome P450 mediates interaction between warfarin and Coleus forskohlii extract in vivo and in vitro. J Pharm Pharmacol. 2012 Dec;64(12):1793-801.
  • Yu PL, Pu HF, Chen SY, Wang SW, Wang PS. Effects of catechin, epicatechin and epigallocatechin gallate on testosterone production in rat leydig cells. J Cell Biochem. 2010 May 15;110(2):333-42.