Wednesday, January 22, 2014

Yohimbine HCl: A Fat Loss Aid?

There's been one burning question on the lips and minds of dieters around the world: can yohimbine HCl help me lose stubborn fat? 

In my usual fashion, I've crafted a painstakingly thorough and long-winded answer to that question, full of sciency crap no one but me and like five other people care about.  Even so, this article should provide you with everything you ever wanted to know about yohimbine HCl supplementation. 


Note: If you've Googled yohimbine, there's a 99% chance you've read what Lyle McDonald has to say on it - if not, you'll probably want to take a look at his website, bodyrecomposition.com, and/or his book The Stubborn Fat Solution, where speaks to greater depths on the supplement.

What is Yohimbine?

Yohimbine hydrochloride (HCl) is the standardized extract of the active ingredient found in yohimbe bark, which grows natively in western Africa. Yohimbe bark has been used for generations as a holistic aphrodisiac, but supplement companies have recently begun to tout yohimbine HCl as both an ergogenic and fat loss aid. Right now, there's a relatively healthy body of research involving Yohimbine HCl as treatment for erectile dysfunctions and certain neurological conditions, but very little data on it's efficacy as a fat loss agent.

So, from a body composition perspective, what's this stuff actually supposed to do? Depending on who you ask, the supposed benefits of yohimbine HCl supplementation include heightened metabolic rate, appetite suppression, and preferential lipolysis (targetted fat loss) in “stubborn” adipose sites. 

Is there any merit to these claims? Let's dive right in and find out. 


*please note, yohimbine HCl is NOT the same supplement as yohimbe. Yohimbe supplements are generally uncontrolled, unstandardized, ground up tree bark. The dosage of active ingredient, yohimbine HCl, can vary wildly. If you're considering supplementation, get a quality yohimbine HCl extract.

A Very Condensed Endocrine Primer
To understand yohimbine, you must have at least a rough understanding of adrenergic receptors and catecholamines.  The endrocrine system can get a bit messy, so we'll try to keep this fairly simple.   

Catecholamines

The word "catecholamine" is used to describe a number of plasma bound hormones, but it usually just refers to adrenaline (epinephrine) and noradrenaline (norepinephrine).  These hormones play a number of roles in the body, but it's common knowledge that adrenaline is a potent stimulant which increases heart rate, vasoconstrictor (closes blood vessels -> increases blood pressure), bronchodilator (opens airways -> increases airflow).  Most importantly for us, it also suppresses hunger, and increases blood sugar via inhibiting insulin (which normally mediates sugar from the blood, into cells) and signaling sugar release from the liver.  The net result is an increase in metabolic rate.  (Barth et al, 2007).  From an exercise physiology standpoint, some of these effects are not unlike what occurs as a result of aerobic training.  

Catecholamines are responsible for jacking up the sympathetic nervous system, and in fact you have a basal flow of these hormones at all times.  A large release of catecholamines occurs during the well documented fight-or-flight response, triggering a very noticeable manifestation of these effects.  You already know this though - think about what happened the last time you were in a fight-or-flight situation; your heart rate and blood pressure went up, you lost your appetite, and you got warm.  


A large release or infusion of catecholamines would be undesirable, as you'd basically be "on 11", and the effects would wear off shortly - so don't go sticking yourself with an epi-pen to try and lose weight.  That being said, it is well documented that an increase in plasma concentrations of these hormones does increase metabolic rate. 


Lastly, there is an important effect of catecholamines that, for some reason, always seems to fly under the radar: catecholamines increase tissue lactic acid and reduce muscle tissue's ability to use it as a gluconeogenic precursor (how we get sugar from non-sugars when more is needed for exercise, a very important factor in anaerobic endurance) (Hamann, et al. 2001).  Not only does this effect reduce time until fatigue under heavy anaerobic work, it also means that that blood will acidify more rapidly because there's less lactic acid being shunted into muscle tissue.  I won't get any further into lactic acid because it's a whole other can of worms, but these are potentially serious implications for exercise performance.


Adrenergic Receptors

Adrenergic receptors are the the body's way of monitoring and making use of catecholamines.  They come in two main flavors - alpha, α, and beta, β.  There's a number of subgroups with a huge host of varying hormonal implications between them, but we're only going to examine a few of the effects and keep it specific to fat loss and exercise performance:

Effects of Agonizing (Activating) Each Receptor:

  • α-1
    •  Blood vessel constriction, notably in the gastrointenstinal tract. Sphincter contraction in the gastrointenstinal tract
  • α-2
    •  Can increase or decrease blood vessel diameter based on agonist type and dosage. Reduced force of heart contraction. Inhibition of lipolysis. Inhibition of noradrenaline secretion
  • β-1
    •  Heart rate/force of heart beat increase.  Lipolysis (fat loss).  Dilate skeletal muscle vessels.  Increased sugar production and metabolism in liver and muscle tissue.
  • β-2
    •  Bronchodilation (opening of the airways)
  • β-3 
    •  Lipolysis
Again, this is a very limited list of what these receptors do, and I encourage you to look more into them if you plan on taking any sort of receptor agonist or antagonist (which yohimbine HCl is).
File:Adrenoceptor-Signal transduktion.PNG
Ripped straight off of Wikipedia
These receptors are found all over the body, and though their downstream effects vary, they all share one common trait -they are the targets of catecholamines.  Greatly simplified, upstream structures produce catecholamines, some event(s) happen, the catecholamines are released, and they make their way to the adrenergic receptors.  At this point the catecholamines either agonize (boost the effects of) or antagonize (diminish the effects of) whatever the function(s) of that receptor may be - again, this varies greatly depending on the type and concentration of receptors, the tissue they're located in, the type and amount of catecholamines, and a lot of other variables.  

Yohimbine: A Strong α-2 and Weak α-1 Antagonist

Yohimbine HCl is a non-selective alpha antagonist, but has a much higher affinity for alpha-2 receptors compared to alpha-1 receptors, meaning that it antagonizes α-2 receptors to a much greater extent. It's a little tricky to understand the noradrenaline inhibiting function of the α-2 receptor, so pay attention to the following: as catecholamines diffuse across the synaptic cleft, they bind to pre and postsynaptic terminals. When catecholamines pass the presynaptic terminal of an α-2 receptor, a negative feedback loop activates, which inhibits release of additional catecholamines.   In this regard, α-2 receptors essentially act as a “flow check” for upstream catecholamine secretion (Philipp et al. 2002).  

It's a lot like how the heating system in your house works; you have a set point controlled on your thermostat, the furnace (those upstream functions which release the catecholamines) fires up, heat is applied to the water in the pipes (catecholamines enter the blood stream), the hot water reaches the space you want heated and sensors determine that no more hot water is required (receptors determine that the tissue doesn't need any more catecholamines, and the negative feedback loop is activated, stopping further release upstream).


Antagonizing this receptor reduces this function, which is to say that it reduces the receptor's effect on reducing the upstream flow of catecholamine secretion. In other words, it's like tricking those sensors in your heating system to not work as well, making your furnace release more hot water than it needs. Heat goes up in the room, more catecholamines are delivered to tissues (actually a decent analogy since heat increases in both examples).


Take another look at this graphic:



File:Adrenoceptor-Signal transduktion.PNG
Ripped straight off of Wikipedia
You'll see that agonizing (the regular line) the α-2 receptor inhibits (the checked line) transmitter (norepinephrine) release. The important thing for us to keep in mind is that yohimbine HCl essentially inhibits the inhibitor, which actually increases transmitter release. Through this mechanism, Yohimbine HCl should ultimately increase noradrenaline release. 
 
To summarize, yohimbine HCl acts as a non-selective α receptor antagonist, having a high affinity for α-2 receptors and a moderate affinity for α-1 receptors (Millan, 1999).   The potent α-2 blocking effect of yohimbine HCL downregulates the catecholamine-inhibiting action of the α-2 receptor. This, in turn, causes upregulation of norepinephrine secretion (Okamoto et al, 2012, Shibao et al. 2010).

It is extremely important to understand that this increase occurs upstream, meaning that noradrenaline secretion is increased at the sites of production. This means that plasma concentrations will increase and all downstream receptors will experience an increased flow of noradrenaline, not just the α-2 sites.


This noradrenaline will then go on to agonize all α and β receptors to a varying extent based on affinity, and that's where this situation gets interesting.  Noradrenaline is a strong agonist of α-1, α-2, and β-3 receptors, but a weak agonist of β-1 and β-2 receptors.  What happens when these receptors are agonized all at once, to different extents?  The answer is obviously dose-dependent - in theory, more yohimbine hcl taken, the more upstream norepinephrine secretion occursIt stands to reason, then, that supplementing with yohimbine HCl essentially causes all of the effects of increased noradrenaline discussed in the catecholamine section. 


In reality, this begs more questions than it answers.  How does this increase in noradrenaline effect each receptor in each tissue? How would each receptor respond to having noradrenaline flow increased relative to adrenaline flow? Does the answer to that question change depending on the dosage, or perhaps some other variable we aren't aware of? And so on and so forth. The answers to these questions matter, because each receptor has different affinities for and responses to each type, ratio, and quantity of catecholamine - and when you're dealing with mechanisms that control functions like cardiac output and airway tone, it's kind of important to know these things. 


Yohimbine HCl and Stubborn Fat
As mentioned, catecholamines have a well documented effect on lipolysis (fat loss).  The efficacy of catecholamines’ ability to induce lipolysis varies between adipose sites, primarily because of differences in blood flow and the ratio/number of  α and β receptors (Arner, 1999).  Historically “stubborn” fat sites, particularly those around the hip and butt, have a higher concentration and ratio of α-receptors, where fat in the abdomen tends to have a higher concentration of β-receptors. Sites with high α-receptors also tend to have less blood flow compared to abdominal fat (Millet et al., 1998). 

Does yohimbine HCl target "stubborn" fat? There's a few studies done on supplementation and overall fat loss, but there's no clinical data or research that I'm aware of which tested for fat loss in specific areas - so for now, its a guessing game. That being said, since one of the primary functions of α-2 receptor agonism is the inhibition of lipolysis, then anything which antagonizes α-2 receptors should in turn promote lipolysis. This is especially true of areas where there is a high concentration of α-2 receptors and a low concentration of β receptors (again, typical of "stubborn" fat sites). Though unsubstantiated, yohimbine HCl should indeed help bust stubborn fat. 


Performance Enhancement and Hunger Suppression

Yohimbine HCl has not shown any capacity for improving physical performance measurements whatsoever.  It might be logical to assume that anything which triggers what is essentially a very low grade fight-or-flight response would improve performance. Alas, this is not the case. Ostojic, 2002, and McCarty, 2002, both found that yohimbine failed to improve exercise performance, and there's more studies out there with similar results. The lack of performance enhancement coupled with it's catabolic properties makes yohimbine HCL entirely unsuitable as a pre strength training supplement.


The hunger suppression question is an interesting one.  One of the functions of α-2 receptors is to block hunger and decrease stomach motility. It stands to reason that anything which antagonizes α-2 receptors should actually increase hunger. 


There's no studies I'm aware of which polled for hunger suppression, but many users anecdotally report that it does reduce appetite.  Perhaps the overall increase in noradrenaline agonizes receptors which elicit hunger suppression potent enough to override the hunger boosting effect of directly antagonizing α-2 receptors. Or maybe not, and it's all in people's heads. In either case, the reported hunger suppression effect is mild at best, so we can deem yohimbine HCl ineffective as an appetite blocker. 


A Look At Some Existing Research
A study by Bharucha et al., 2008, administered an acute dose of 0.125 mg/kg body weight followed by an infusion of 0.006 mg/kg body weight in 55 healthy human adults.  Blood pressure, heart rate, and plasma catecholamine levels were measured both before and after a 300 kcal liquid feeding.  The study found that the yohimbine HCL dose increased serum catecholamine levels by 2-3 fold.  Heart rate remained unchanged, but blood pressure increased significantly.

Similarly, a study by Galitzky et al, 2001, administered a 0.4 mg/kg acute dose to 13 healthy adult male dogs following an 18-20 hour fast.  All 13 showed significant increases in catecholamine levels, as well as blood pressure. Resting metabolic rate was also increased by an average of 16%.  It must also be noted that restlessness and anxiety were all significantly increased as well, though no change to alertness was found.
Another study by Kucio et al, 1991, placed 20 obese females on a 3 week, 1,000 kcal/day diet.  They were kept on the same diet for another 3 weeks, but half were given 5 mg of yohimbine HCL 4 times a day, while the other half were given placebo.  The yohimbine HCL group lost an average of 3.55 kg, while the placebo group lost an average of 2.21 kg.  

A study by Sax, 1991, had half of a 47 health adult male cohort take up to 43 mg yohimbine HCL per day for six months, while the other half took placebo.  No differences in BMI, body weight, and body fat change were measured between the two groups.  It must be noted that caloric intake was not addressed or monitored during this study.   


Similar studies by Ostojic, 2002, and McCarty, 2002, both found that a moderate pre-exercise dose of yohimbine HCL increased serum FFA concentrations both during and after exercise, and that fat loss was significantly higher amongst the yohimbine HCL group compared to placebo.  Blood pressure was increased, but not heart rate.  Both studies noted no increase in exercise performance markers between the groups.  


...and so on. Most of the studies corroborate the same results; when used with a hypocaloric diet, yohimbine HCl increased the secretion of catecholamines and thus increased lipolysis.



Safety 
Multiple studies have shown that yohimbine HCL increases blood pressure, though seems to have little, if any, effect on heart rate.  This is likely just how the change in catecholamine levels pans out in regards to vascular tone.  Yohimbine HCL supplementation is contraindicated for anyone with conditions, diseases, or risk factors impacted by an increase in blood pressure. In a similar vein, yohimbine HCL can reverse the vasodilative/blood pressure lowering properties of certain medications, most notably clonidine (Smet and Smeets, 1994). Yohimbine HCL is contraindicated for those on antihypertensive medications.

In studies which polled for it, an increase in anxiety was reported with high frequency after yohimbine HCL dosage (Galitzky et al, 2001). The reports are almost always more severe for those with preexisting symptoms of depression or anxiety. This is a well-documented effect with a large body of evidence from studies testing yohimbine HCL on mood and anxiety disorders. While not necessarily a contraindication, users may expect some minor to moderate mood alteration and increase in anxiety.  

Lastly, there appears to be a synergistic, cascading effect from taking yohimbine HCl with other stimulants such as caffeine (McCarty, 2002). Considering the well-documented increase in smooth muscle tone and thus blood pressure caused by yohimbine HCL supplementation, it is logical that any substance which further increases either smooth muscle tone or heart rate would potentially lead to tachycardia or hypertensive crisis.  Many other supplement, especially those used as thermogenics/performance enhancers, also affect adrenergic receptors. The moderate dosage of caffeine most users usually coingest with yohimbine HCl is fairly benign, but you wouldn't catch me taking it with ephedrine HCl or any other more potent stimulants. If you chose to take an ECY (ephedrine, caffeine, yohimbine) stack or any other combination of yohimbine HCl and other substances shown to increase cardiac output/vascular tone, you're taking a significant risk. If you wind up in the ER with hemorrhaging eyes and a pulse so high you're getting friction burns on your heart, don't tell the ER doc I didn't warn you.


Dosage 

Dosage has always been done in the 0.2 mg/kg body weight range; some study started this (I forget which) and the trend has just sort of continued. This dosage has proven effective and relatively safe for eliciting lipolysis. Up to 20 mg a day, split into two 10 mg doses, has improved lipolysis in healthy adult males. I wouldn't go any higher than that in any circumstance, and it's probably best to just stick to the 0.2mg/kg body weight range. Within a normal range, it really comes down to stimulant sensitivity and your own personal mental stability - as mentioned, for many with existing depression/anxiety, yohimbine HCl has exacerbated these conditions. Pushing the dosages higher than this will likely result in some nasty and potentially serious side effects of the cardiac and psychological nature. 

While we're on the subject, an effective dose requires keeping insulin to a minimum. A function of pancreatic α-2 receptors is to block insulin release, so antagonizing them will increase the effect of anything which triggers an insulin spike. The effects of yohimbine HCl don't dissapear in the presence of insulin; it actually boosts the release of insulin thereby negating any lipolytic effects it may otherwise have provided. Many will tell you that yohimbine HCl has to be taken while fasting - that's a sure way to avoid an insulin spike, but it can also just be taken with a non-insulinogenic meal (basically a keto style, medium-low protein, high fat meal with little to no carbs).

Odds and Ends 
A study by Keller et al., 1989, indicates that norepinephrine boosts th effects of ketosis - but the study didn't use yohimbine HCl, rather a direct infusion. Glucagon and insulin levels were also regulated via infusion. Yohimbine HCl may increase norepinephrine which may intensify ketosis, but that is not what this study tested for directly. Food for thought. 

I'm going to go out on a limb and say that it wouldn't surprise me if supplementing with yohimbine HCl would A) lead to some measure of blunted catecholamine response once you come off , and B) lead to acutely reduced catecholamine secretion once you come off. I have absolutely no evidence for this. It's a phenomenon seen with other supplements/medications which alter the natural production or secretion of something the body produces. The body often grows accustomed to an exogenous substance doing some of the work it usually does, and when that substance goes away, there's usually lag time until the body adapts to not having that substance anymore. Again, no evidence, just something to consider.


Conclusion and the Cliff Notes
So, what can we ultimately say about yohimbine HCl as a fat loss agent?  Based on mechanism of action alone, the supplement should increase norepinephrine levels, which should enhance lipolysis.  Likewise, it should also antagonize α-2 and α-1 receptors, increasing lipolysis specifically in classically stubborn fat sites. It is probably not particularly effective as an appetite suppressant at nominal dosages.

In regards to the research, its pretty clear that in studies where yohimbine HCl was used in conjunction with a hypocaloric diet, the supplement appeared to be an effective fat loss aid. In studies where calories were unaccounted for, yohimbine HCl itself did not cause fat loss. This should be a no-brainer to anyone with a basic understanding of how fat loss works. 


We can say with a fair degree of confidence that yohimbine HCl:

  • Antagonizes α-2 receptors
  • Increases upstream secretion of noradrenaline
  • Increases amount of noradrenaline received by all adrenergic receptors
  • Improves overall lipolysis
    • Improve lipolysis specifically in stubborn fat sites
  • Increases vascular tone, blood pressure
  • Likely exacerbates preexisting psychological conditions
  • Is not an effective performance enhancer or appetite suppressor
  • Is effective at a dosage of 0.2 mg/kg body weight 
  • Should be taken fasted or with non-insulinogenic, keto-style meals 
  • Is a suitable pre aerobics supplement, but not a suitable pre strength training supplement

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