Yohimbine

Yohimbine {(16a, 17a)-17-Hydroxyyohimban-16-carboxylic acid methyl ester} is a naturally-occurring indole alkaloid with alpha2-adrenergic blocking activity. Yohimbine is found in the Coryanthe johimbe and related trees as well as in the herb Rauwolfia serpenta. Yohimbine, as a hydrochloride salt, has been used for years as a mydriatic and alpha2-adrenergic blocker. It has also been used as a prescription aphrodisiac (e.g. Yocon, Aphrodyne) with each tablet containing 5.4 mg of yohimbine HCl.

Yohimbe Bark Extract has been used for many years by bodybuilders—and rightly so—as there is mounting evidence that this compound (alone or stacked with others) acts as a fairly effective slimming agent, especially in women placed on calorie-restricted diets. In one study conducted at The Silesian School of Medicine in Poland, twenty obese female outpatients were subjected to a three-week low-energy diet and according to a double-blind protocol, randomized to receive one of two treatments of yohimbine. Ten subjects received 5 mg of oral yohimbine four times per day and ten subjects received a placebo. The study protocol provided that each subject "take their medication" and adhere to a 1,000 Kcal /diet for a total of three weeks. The oral yohimbine subject lost, on average, 107% more bodyweight that the placebo subject.8

Yohimbine has also demonstrated increased lipolysis as evidenced by increased plasma free fatty acids. In a study conducted as Laboratorie de Pharmacologie Medicale et Clinique in France, oral yohimbine at dosages of 0.25 mg/kg significantly increased non-esterified plasma fatty acids over a four-hour period, as well as increased oxygen consumption and carbon dioxide and heat production within 30 minutes after administration. This clearly illustrates an increase in metabolic rate. In addition, oral yohimbine increased sympathetic nervous system activity as indicated by increases in plasma norepinephrine.9

Another study at the same institution also yielded promising results. Oral yohimbine administration (0.2 mg/kg) induced lipid mobilization in fasting, non-obese women (body mass index = 20.2 +/- 0.5, age 35.5 years +/- 2.7 years) without significant action on plasma glucose, insulin levels, heart rate or blood pressure during the time-course experiment. Plasma norepinephrine levels increased by 100% after oral yohimbine administration. In obese women (body mass index = 36.4 +/- 2.1, age 37.0 years +/- 3.6 years), the effects were nearly identical with regards to lipolysis, plasma norepinephrine levels, etc. Oral administration of the beta-blocker propanolol dramatically reduced the lipid mobilizing effect of yohimbine.

This is exceptionally interesting because it was previously thought by many bodybuilding "gurus" that the fat mobilizing effects of yohimbine in women were probably due to an abundance of alpha2 adrenoreceptors around the fatty areas of the thighs and buttocks. We disagree. It appears that the lipid-mobilizing effects of oral yohimbine in women are mainly attributable to the increase in synaptic norepinephrine with a resultant increment in lipolysis by beta adrenergic agonism. The alpha2 adrenoreceptors seem to be a very minor component of the lipomobilizing effects of yohimbine.

Morever, when tested on non-obese women, the lipomobilizing effects of yohimbine is not enhanced when compared to obese women (those thought to have the abundance of alpha2 adrenoreceptors).10 This is something we would certainly expect to see if the alpha2 adrenoreceptors were involved to any great degree. We feel that yohimbine is relatively safe and certainly belongs in any thermogenic/lipolytic stack. A prescription drug in single doses above 3 mg, yohimbine can be sold without a prescription if the single dose amount is less than or equal to 2.9 mg.


L-Tyrosine

L-Tyrosine is a common, non-essential amino acid that can be synthesized in-vivo from the amino acid phenylalanine. In several studies conducted at The Massachusetts College of Pharmacy and Allied Health Sciences, L-Tyrosine potentiated the anorectic effect of various mixed-acting sympathomimetics (including ephedrine, amphetamine and phenylpropanolamine). Because these aformentioned mixed-acting sympathomimetics are known to increase blood pressure to varying degrees, these studies were conducted to examine the effects of L-Tyrosine's ability to influence the pressor response to these compounds. No potentiation was observed with the addition of L-Tyrosine. Thus, the anorectic potentiating effects that L-Tyrosine induces must be a centrally mediated response at a central locus.11,12 L-Tyrosine is an exceptionally safe compound found in many foodstuffs. We suggest the addition of L-Tyrosine to any thermogenic/lipolytic stack, especially when a calorie restricted diet it used.


Phenylpropanolamine

Phenylpropanolamine {dl-norephedrine} is a synthetic compound that has been used for several decades as an OTC decongestant, bronchodilator and anorectic. It is the active ingredient in most OTC weight loss products that you find in your local drug store (e.g. Dexatrim, Accutrim), Long overlooked by most of the bodybuilding community, phenylpropanolamine (dl-PPA) is actually superior to ephedrine in its thermogenic, lipolytic, and anorectic properties. In at least one study involvong various congeners and isomers of dl-PPA, it was shown to be significantly more thermogenic than ephedrine and not much less potent a thermogen than dl-amphetamine.13 (DL-amphetamine is a highly addictive medication that is a prescription only, Schedule C-II Controlled Substance in The Unites States while dl-PPA is an incredibly inexpensive substance with a cost factor similar to ephedrine.)

In one study, the effects of chronic treatment with dl-PPA on bodyweight (BW), food intake (FI), water intake (WI) and intercapsular brown adipose tissue (IBAT) thermogenesis in adult male Sprague-Dawley rats were evaluated. In the study, the rats were treated with either placebo or 5, 10, or 20 mg/kg of dl-PPA twice a day for 12 days. Rats in the 20 mg/kg treatment group exhibited significant decreases in FI and BW but not WI. Basal IBAT temperature was slightly increased in the chronic 20 mg/kg dl-PPA rats and there was no evidence of tolerance to the acute IBAT thermogenic effect of 20 mg/kg dl-PPA.14 Also, much like ephedrine, caffeine demonstrates a positive thermogenic and lipolytic synergy when co-admininstered with dl-PPA.

Another experiment using the same type of rats clearly demonstrated that the combination of caffeine and dl-PPA produced significantly greater thermogenesis than the use of dl-PPA alone.15 However, dl-PPA does not meet all of the inclusion criteria we originally set forth in above. Being a synthetic compound, dl-PPA is an OTC drug and NOT a food supplement. However, one of the isomers, the "levo" form, or l-PPA is naturally occurring and as luck would have it, the naturally occurring l-PPA possesses about twice the potency of the synthetic d-PPA with regards to thermogenesis, effect on bodyweight, and effect on decreasing food intake.11 Thus, l-PPA could easily be utilized and sold as a food supplement and not an OTC drug.

We feel that in addition to being a more potent thermogen and lipolytic when compared with ephedrine, l-PPA (or even dl-PPA) is a superior anorectic. This property may be of significant importance to individuals utilizing calorie-restrictive diets in addition to supplementation for weight reduction. The ability to stave off the pangs of hunger may have a dramatic and positive psychological effect in ANY weight reduction program. Phenylpropanolamine also has a better safety profile than ephedrine does and the potential side effects (e.g. increased nervousness, insomnia, tachycardia, hypertension, dry mouth, etc.) are typically more prevalent and exacerbated with ephedrine than with phenylpropanolamine. Thus, we suggest dl-PPA or the racemate, l-PPA if available, over ephedrine in any thermogenic/lipolytic stack.


Second Generation Thermogenic Stack

Based on a current review of literature and the various studies cited in this article, we feel that it is prudent to "reformulate ECA" to increase efficacy and improve safety. As previously stated, we feel that aspirin should be eliminated as an unnecessary potential hazard and L-Tyrosine and yohimbine should be added. We also feel that ephedrine should be eliminated and replaced with the vastly superior phenylpropanolamine (dl-PPA or preferentially, l-PPA). We offer the following suggested dosing schema which we call "The Schmitz and Kneller Formulation."

The Schmitz and Kneller Formulation (per serving/dose)

L-Tyrosine: 200 mg
Yohimbine: 2.9 mg
Caffeine: 100 mg
DL-Phenylpropanolamine: 25 mg*
L-Phenylpropanolamine: 18 mg*

*Either DL-Phenylpropanolamine or L-Phenylpropanolamine, not both.

We would suggest this combination be taken 1-3 times per day, preferably every four hours and immediately after meals. People who are currently taking Monoamine Oxidase Inhibitor medications, have hypertension, cardiovascular disease, thyroid problems, prostate problems, or who are pregnant or about to become pregnant or are currently nursing should not utilize this stack nor any of it's components. We feel that our stack, much like ECA, will work best if undertaken with a healthy diet and proper exercise. Always consult your healthcare provider before undertaking any new diet, exercise or supplement regimen.

EDITOR'S NOTE: This formulation is not available in stores or anywhere else, for that matter. However, given that the individual ingredients are readily available, it would be possible for someone to "blend" the mixture on his own.


About the Authors

Stephen Schmitz, MD, MPH is a pharmacoepidemiologist and Associate Medical Director for Drug Safety and Medical Information for a biopharmaceutical company in Cambridge, MA. Stephen is board certified in both Family Medicine and Occupational Medicine and has completed an approved fellowship in Preventive Medicine. He has been a health care practitioner for over 15 years.

Bruce Kneller, BSN, RN is a Clinical Data Manager researching the effectiveness of small molecule drugs in the treatment of Congestive Heart Failure and Resistant Cirrhotic Ascites for a biopharmaceutical company located in Cambridge, MA. Bruce has authored over three dozen article published in various bodybuilding magazines and has over 10 years experience in supplement research as well as over 4 years experience in drug development.

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References

1) Goodman and Gillman, The Pharmacological Basis of Therapeutics, Ninth Edition, p.221.
2) FDA New Final Rule Regarding Serious Adverse Events (effective 04/06/98).
3) Office of Special Nutritionals: Market Review of Dietary Supplements Containing Ephedrine Alkaloids, August 27, 1996.
4) Lak CR, Rosenberg DB, Gallant S, et al. Phenylpropanolamine Increases Plasma Caffeine Levels. Clinical Pharmacology and Therapeutics, 1990;47:675-684.
5) Federal Register, Vol. 62(107). 21 CFR Part 111, Dietary Supplements Containing Ephedrine Alkaloids, Proposed Rule.
6) Horton TJ, Geissler CA. Post-prandial Thermogenesis with Ephedrine, Caffeine and Aspirin in Lean, Predisposed Obese and Non-obese women. Int J Obes Relat Metab Disorder, 1996 Feb;20(2):91-95.
7) Horton TJ, Geissler CA. Aspirin Potentiates the Effect of Ephedrine on the Thermogenic Response to a Meal in Obese but not Lean Women. Int J Obes, 1991 May;15(5):359-366.
8) Kucio C, Jonderko K, Piskorska D. Does Yohimbine Act as a Slimming Drug? Isr J Med Sci 1991 Oct:27(10):550-556.9) Galitzky J, Vermorel M, Lafontan M, Montastruc P. Thermogenic and Lipolytic Effect of Yohimbine in the Dog. Br J Pharmacol 1991 Oct;104(2):514-518.
10) Berlan M, Galitzky J, et al. Plasma Catecholamine Levels and Lipid Mobilization Induced by Yohimbine in Obese and Non-obese Women. Int J Obes 1991 May;15(5):305-315.
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12) Kull KM, Maher TJ. L-tyrosine Fails to Potentiate Several Peripheral Actions of the Sympathomimetics. 1991 Jul;39(3):755-759.
13) Wellman PJ, Marmon MM. Comparison on Brown Adipose Tissue Thermogenesis Induced by Congeners and Isomers of Phenylpropanolamine. Life Sci 1985 Sep 16;37(11):1023-1028.
14) Wellman PJ, Sellers TL. weight loss Induced by Chronic Phenylpropanolamine: Anorexia and Brown Adipose Tissue Thermogenesis. Pharmacol Biochem Behav 1986 Mar;24(3):605-611.
15) Welman, PJ, Marmon MM. Synergism Between Caffeine and DL-Phenylpropanolamine on Brown Adipose Tissue in the Adult Rat. Pharmacol Biochem Behav 1985 May;22(5):781-78.