Prototype Nutrition Ketoforce



DMAA: Not Dangerous After All?

By Patrick Arnold


DMAA, also known as methylhexanamine or “geranamine” is a controversial stimulant ingredient used in weight loss and energy supplements.  In April of this year the FDA made a strong statement regarding its health dangers and its lack of legal standing as a nutritional supplement.   Companies selling DMAA products for the most part stopped selling the stuff, and those who didn’t fully comply were subject to harsh enforcement actions by the FDA.

It took a long time for the FDA to act on DMAA, and that was in large part due to the fact that they really didn’t have clear cut evidence that the product was dangerous.  Outcries by certain people that claimed the product was responsible for various adverse medical events and deaths however became louder and louder.   These claims were not substantiated by any medical evidence though and so were not enough for the FDA to act upon.

The most publicized adverse health events regarding DMAA involved the US military.  The deaths of four servicemen were being blamed on DMAA.  As a consequence, the department of defense commissioned a safety study on the compound to determine whether it indeed was dangerous and to blame for the soldiers’ deaths (as well as other medical incidents involving soldiers).  This was to be the study that the FDA could rest its hat on and justify an emergency action against DMAA.

Things started getting strange though.  The study was supposed to be finished in February 2012.  That date came and went and no word on the study results were announced.  Then word came that the study was taking longer than expected and would be done in December 2012.  Well December 2012 came around and still no word.  Months passed and no one seemed to be talking about the huge DOD study that was supposed to prove once and for all that DMAA was deadly.

Then in April 2013 the FDA announced that it considered DMAA illegal to sell and warned of a whole variety of potential health risks.  No mention of the DOD study which was supposed to provide the scientific validation was made – the FDA announcement was based simply on theory.

What happened to the DOD study?   Well, in August the results were finally released (four months after the FDA’s arbitrary action).  They were released with such lack of fanfare and media coverage that even I was not aware of the results until just today (almost two months later).  Essentially they found that despite a high apparent usage of DMAA by soldiers (as much as 15 percent) the substance at doses recommended by manufacture poses a low risk of serious harm for most service members.  The study basically exonerated DMAA from being responsible for the deaths of the four soldiers.  They cautioned though that the “potential” of DMAA to cause harm still exists and ongoing studies would be needed to fully understand the health issues (I guess two years wasn’t enough).

Anyway, I have my own take on this situation.  I think it was clear quite a while ago that the DOD study was not going to provide the smoking gun that was expected and hoped for.   At that point the results were kept hush hush and the FDA decided to act anyway against DMAA.  Then they waited four months to quietly announce the study results – so quietly that it took me six weeks to even be aware of them.




Initial KetoForce (BHB mixed salts) Data

By Patrick Arnold

On my last blog I promised  I would show you some data on my KetoForce product (BHB mixed salts).  I have two sets of data – the first showing blood beta-hydroxybutyrate (BHB) responses and the second showing specific changes in physiological parameters during a controlled exercise experiment.

The blood data was done at a university on a set of subjects and the average changes in BHB levels are what this graph shows


bhb graph


These subjects drank a diluted version of the KetoForce product that was essentially equivalent to 36mL of KetoForce.*  The product was consumed on an empty stomach and as you can see blood BHB levels rose pretty quickly.  Levels appear to stay decently elevated until round the 180 minute (3 hour) mark.   30-60 minutes seems to be the sweet spot for maximum blood levels, so for pre-exercise use one should probably time the ingestion accordingly.

The exercise data I have was done using a 20% solution of the BHB salts which was equivalent to 40 mL of the  KetoForce product.  The data was done by an independent individual that does such research for a non-profit organization.  Out of respect for this fact – and the fact that the data is only preliminary (more research is going to be performed) – I won’t report the full data here.  I will give a glimpse into the most interesting thing he found though.

First of all this individual was ketoadapted.  Ketoadapated means he had been on a ketogenic diet for a period of time long enough so that he was in full ketosis and had developed a good ability to utilize ketones.  He did a bike exercise that was set up so the workload was maintained at a constant level roughly equal to 60% of his VO2 max.  During the first stage he did the exercise for twenty minutes without the salts, and during the second stage he consumed the salts 60 minutes prior to the exercise bout.

One of the things that was measured was the amount of oxygen consumed during the exercise bouts.  Theoretically, ketones should reduce oxygen consumption because they are known to generate more cellular energy per unit  oxygen burned compared to glucose and other energy sources.  The data he got with the BHB salts strongly suggested that this theory was at work during the experiment.  Below is the difference in oxygen consumption reported as a percentage between a bout without the salts and a bout with the salts.

Last 5 minutes –  minus 8.8%

Last 10 minutes – minus 7.7%

Last 15 minutes – minus 6.6%

Apparently there was a substantial decrease in the amount of oxygen he needed to maintain the workload after taking the salts.  Very interestingly, this decrease in oxygen demand got more prominent as the session went on as well.

BHB salts are natural products that mimic the nutritional state of ketosis and have been studied in the past for medical applications as well.   KetoForce is  the first introduction of these salts to supplement and fitness industry so we are very early on in regards to figuring out how best to use them.  This preliminary data does give us some clues on how they may be used (timing wise) and what benefits they may offer.  We are very hopeful that our collaborations will enable us to generate a lot more research on the product (such as what performance benefits might be seen in non ketoadapted people)  in the very near future.


*  The KetoForce label suggests a serving size of 30mL instead of 36mL.  Since I don’t expect all my customers to own graduated cylinders many will  have to use the cap for measuring, and the cap holds 10mL .  For this reason I rounded the serving size off to 30mL.



Instant Ketosis?

By Patrick Arnold


In late 2010 a professor from a university in Florida approached me to see if I could synthesize a compound that he wanted to use in his research.  This compound was what is known as a “ketone ester”.  This ketone ester is a synthetic prodrug which, after ingestion, your body naturally breaks down into the ketone bodies beta-hydroxybutyrate (BHB) and acetoacetate (AcAc).

Ketone bodies are energy sources that your body naturally produce and burn under special metabolic conditions.  These conditions include starvation and a very high fat / low carbohydrate diet (known as the ketogenic diet).   Ketones are the end products of fatty acid metabolism, and compared to your body’s major source of caloric energy (glucose), they are pretty amazing.  Unlike glucose, ketones do not require insulin to enter cells and be incorporated into the metabolic cycles that generate the cellular fuel ATP.  They cannot be converted to body fat. Also, unlike most fats, ketones can freely enter the brain where they are an excellent fuel for brain cells.  On top of all that, ketones generate more ATP per unit oxygen consumed than any other energy source.  Ketones are essentially your body’s super fuel.

I ended up successfully synthesizing this ketone ester for the professor, and he ended up performing some pretty cool studies utilizing the product.  For instance in one study he made rats resistant to the toxic effects of high pressure oxygen upon the central nervous system (this has major implications for deep sea divers such as navy seals, as well as indirectly on folks suffering from epilepsy).  In another study he almost completely halted the growth of cancerous tumors in rats by giving them the ketone ester.  The professor also showed in a more informal study that rats taking the ketone ester could exercise quite a bit longer than control rats.

As a supplement manufacturer I found the potential health and performance implications for raising ketones through the administration of a “ketone supplement” very exciting.  Unfortunately the ketone ester I made for the professor is both  synthetic and extremely expensive, so it was wholly unsuitable for sale as a supplement.  My collaboration with the professor did get me thinking though, and I set out to see if I could develop a way to raise ketone levels by administering a natural product alternative.

My focus was on the ketones themselves.  As I mentioned previously, there are two major endogenous ketones: beta-hydroxybutyrate (BHB) and acetoacetate (AcAc).  AcAc I had to eliminate right off the bat because it is too unstable (it breaks down relatively quickly to acetone and carbon dioxide).  BHB on the other hand was a possibility – particularly in the form of one or more of its salts.  The problem was the only BHB salt which is commercially available is sodium BHB and it’s just too expensive.  So I had to embark on my own R&D project to figure out how to make BHB salts at a price that is not completely out of reach.

I ended up perfecting a proprietary manufacturing method for sodium and potassium mixed BHB salts.  Why mixed sodium and potassium salts?  The reason for that is because at the level of intake of BHB required for benefits you would have to ingest a substantial amount of cation (positively charged mineral such as sodium or potassium).  At such levels of cation ingestion it made sense that a balance of sodium and potassium salts would be the healthiest thing to do.

Additionally, I discovered that the product had to be delivered as a concentrated liquid because potassium BHB is simply too hygroscopic to isolate as a powder (it picks up water from the atmosphere and turns into mush at an astonishing rate, whether by itself or mixed with sodium BHB).

So, just to make things clear, is I have developed a supplement product that raises blood ketone levels.  This product does not require a ketogenic diet to raise ketone levels as it is essentially providing an external source of ketones.  As such, it will raise ketones even if you eat a plate of spaghetti before taking it (still, its benefits are maximized when combined with either a ketogenic or other sort of low carb diet).

This kind of thing is a lot of work.  For instance it involved developing novel analytical testing methodologies (which as an organic synthesis guy isn’t second nature by any means!)  But after about a year of work  this weekend I am proud to announce the introduction my sodium and potassium mixed  BHB salts on my website.

I hope to continue this topic next week and introduce you to some blood data and exercise performance data on my BHB salts that I think you will find very exciting.  Also I will give some tips on how to possibly best uitilize this product for whatever health or fitness goals you may have.

So stay tuned!



Progesterone Derivative Sold as Prohormone

By Patrick Arnold


I was recently asked a question about a very strange new prohormone product.  What makes it strange is that is actually based on a female hormone – specifically it is based upon a hormone called 17alpha-hydroxyprogesterone.

17a-hydroxyprogesterone (or 17-HP) is a hormone intermediate in the steroidogenic pathway between progesterone and androstenedione.  17-HP is present in the blood of women in varying amounts during their monthly cycle and is present in particularly high amounts during pregnancy.  It has similar actions to progesterone  (albeit somewhat weaker), and is thought to serve a complimentary role to progesterone as an endogenous progestogen.

The prohormone in question here is not actually 17-HP however, but a close structural derivative to 17-HP that I will call Dehydro 17-HP.  For all intents and purposes however, the metabolism of the derivative should be analogous to 17-HP.  Specifically, here are the potential pathways of the two

17-HP ——– Androstenedione  —– Testosterone

Dehydro 17-HP ——— Boldione ——–  Boldenone


So it is definite that the potential for 17-HP and Dehydro 17-HP to convert to active anabolic/androgenic hormones is there.  There are two questions though.  How much do they convert and is there any HPTA suppression from the progestational action of the parent compounds?

Perusing the research on 17-HP I did find a little bit of information on the first question.  Apparently at least one study found that given to humans and to rats the compound results in a substantial increase in urinary 17-ketosteroids (androgenic metabolites).  This indicates that it does convert to a significant extent to androstenedione at least.  Furthermore, a study where 17-HP was given orally to cockerels (immature roosters) showed it to have one half the androgenic activity of methyltestosterone.  It is important however to note that androgenic activity in a cockerel is measured by the size of that red comb on their heads, which is not necessarily easily translatable to anything in a human.

The answer to the second question –  involving whether the compound is HPTA suppressive – is harder to answer.  Data on women show varying effects on 17-HP at different times throughout the cycle, but this data is irrelevant to men.  I couldn’t find anything on men and LH/FSH levels.  So that part of the equation remains unanswered.

I guess I don’t really know what to say about this stuff.  If it works at all I would expect one to have to take many hundreds of milligrams before an effect is seen (due to it being a two step conversion via an intermediary dione).  Whatever the case, it is sort of amusing how creative companies will get in an attempt to fulfill customers’ demands while trying to minimize legal exposure.



More Craziness over Craze

By Patrick Arnold

As I said in my last piece, things are moving fast in this Craze scandal.  Word just came out today that the product was tested in Sweden and confirmed to contain the same meth analog that the Australian federal police said they identified

“In this material we found substances chemically similar to amphetamine and that probably would have similar effects to amphetamine has been says Anna Stenfeldt Henning, Head, Drug Analysis Unit, SKL.”

SKL is the Swedish National Lab for Forensic Science. The Swedes refer to the chemical as N-ethyl-1-phenyl-2-butylamine, but it also goes by the names N,alpha-diethylbenzeneethanamine and N,alpha-diethylphenethylamine.  As I mentioned in my last installment it is considered a structural isomer of methamphetamine.  Why is it considered a structural isomer to methamphetamine while some other phenethylamine derivatives are not?  If you want to get technical it is because it contains an alkyl (hydrocarbon chain) alpha to the nitrogen atom.  The presence of the alkyl group blocks the enzyme monoamine oxidase, which normally inactivates such neurotransmitter type compounds.  In other words it makes it potent so you get the classic “speed” high.

This testing by the Swedes comes on the heels of a consumer who took Craze for two weeks and ended up in the hospital.  This case led the magazine SVT Nyheter to contact the SKL who then took it upon themselves to test the product.

The makers of Craze have responded to SVY Nyheter by claiming that their product does not contain the meth analog and that it must be one of the counterfeit Craze jars that allegedly have been floating around europe.  However, SVT Nyheter contacted the retailer that they bought the Craze from and they claimed to have bought it directly from Driven Sports.

I have yet to hear of any action regarding this product here in the states.  Online retailers continue to sell the product.  I don’t know if that is going to continue for long.   The liability of selling a product with the knowledge that it may contain an illegal and potentially dangerous substance might be too risky for large distributors and retailers.  Usually in situations such as this the product is put on temporary hold until more information is available and the situation clarified, because not to do so puts a company at potentially greater legal risk in the future should the fears be confirmed and a criminal investigation launched.

So if you love your Craze, and you don’t care about any of the scary stuff coming to light lately, you might want to stock up.



Craziness over Craze

By Patrick Arnold

Driven Sports (formerly Designer Supplements) is a somewhat popular company in the sports nutrition arena. They have a dedicated cult following due to their history of introducing controversial and intriguing products such as the now infamous designer steroid “superdrol” to the market place. Their latest hit product is a “pre-workout” product called Craze. This product gained insane popularity over the last couple of years and users who have taken it have reported amazing energy and euphoria. Since the ingredients on the label did not seem to list anything that could explain such remarkable effects, much suspicion arose over whether the product might be “spiked” with some sort of undisclosed stimulant compound.

Well, in early February that suspicion reached a fever pitch when supplement retailers disclosed that federal police in Australia told them that Craze (which has been a popular import there) was found to contain a methamphetamine analog. It appears from various sources that the analog they were referring to was N-alpha-diethyl-benzeneethanamine.

As a consequence, Craze has been banned from Australia and all imports are now being confiscated. Curiously, this comes right on the heels of an announcement of the ban of a Rugby player by the Australian Sports Ant-Doping Authority (ASADA) for the same chemical analog plus another analog called 1-phenylbutan-2-amine (which interestingly would be an expected metabolite of the analog allegedly found in Craze). No mention however is made that this positive is the result of the athlete ingesting Craze.

I am following this story closely and right now there is nothing completely confirmed by any official documentation. One thing is curious though, and that is the fact that craze does contain a compound on the label with the exact same molecular formula – differing only by the placement of one of the ethyl groups.

Very curious. What could this mean? Could the aussies have mistaken this listed ingredient for the meth analog? Very doubtful, as they must have been fully aware of the difference. Also, from my research the actual mass spectrum for the analog appears to be recorded in the literature, and so could be matched up. Conspiracy theorists might imagine that a company who wanted to slip such an analog into a product could try to throw testers off by listing an extremely close structural isomer on their label. Hmmm…

Right now it is not clear what is going on but things are unraveling and I will keep everyone updated soon. As far as what the ramifications for Driven Sports would be in the United States should this all prove to be true….well…. that can vary from minor to major. Perhaps a warning from the FDA or worse a criminal charge of adulteration / misbranding etc. Worse still would be a felony charge of distribution of a controlled substances, since analogs of CII substances like methamphetamine can be considered also controlled under US law.

Stay tuned



mass spec



Stem cell breakthrough for muscle repair and growth??

By Patrick Arnold

What if they could liposuction fat out of you, put it in some machine, and then get super cells out the other end that you could have injected into your muscles to repair injury and possibly cause local growth? It sounds pretty cool doesn’t it? Apparently this is what some new research suggests is possible, and thanks to some recent technological breakthroughs it appears that it might not be too difficult or expensive to do.

You probably have heard of stem cells. Stem cells are a special kind of cell that exist in a sort of “unprogrammed” state. There are many different kinds of stem cells that can be derived from many different tissues, but the fundamental property they all have is a varying ability to differentiate from their primordial state into cell types of all sorts such as blood cells, heart muscle cells, bone cells, organ cells, brain cells etc.

The most useful stem cells are those derived from embryos and they are known as “pluripotent” stem cells. That basically means they have the ability to differentiate into any cell type in the body. Due to ethical concerns, and the obvious raw material limitations of harvesting embryos, this sort of stem cell does not enjoy practical exploitation in medicine. There are also stem cells that can be harvested from adult tissues. Although adult bodies primarily consist of fully differentiated cells that serve our various needs, there also are stem cells present. Adult stem cells are known as multipotent stem cells. They don’t quite have the flexibility to easily morph into anything like embryonic stem cells do, but they can be coaxed to differentiate into lots of useful cell types. And of course they don’t share the controversy and limitations associated with embryonic stem cells.

Blood marrow has been one such important source of multipotent adult stem cells for medical research and application in the recent past. As useful as bone marrow is however, the process of drilling into your bone to suck out the marrow is invasive and distasteful. Thankfully, in recent years it has become apparent that fat stores harbor an impressive variety of adult stem cells as well (reportedly containing 100-300 times as many useful cells as blood marrow).

Fat stores are easily accessible. Cosmetic surgeons suck out pounds of the stuff every day from women’s hips and men’s bellies and then proceed to chuck it all in the medical waste bin. Adipose tissue derived regenerative cells (ADRCs) as they are called can be isolated from all this waste fat, however until recently the process has been less than rapid and practical because it involves a prolonged culturing period. Luckily, a new filtering system has been developed which rapidly separates out the ADRC fragments of the fat and dumps out all the needless junk. [ADRCs by the way consist partly of adipose tissue derived stem cells as well as other progenitor cells of value to injury repair such as vascular related endothelial cells, fibroblasts, and preadipocytes.]

In recent years there have been some interesting studies performed using ADRCs in muscle tissue. In one study, the cells were injected into mice with muscular dystrophy and the muscle strength and resistance to fatigue improved In another, the cells were injected into normal mice and new muscle tissue was observed to be formed at the injection site Just recently though a study was released looking at the effect of ADRCs on muscle tissue injury in mice, and the mechanisms of the actions were examined in more detail then in the previous studies

In this study rats had their tibialis anterior muscles lacerated with a scalpel. One group had a simple phosophate saline solution injected at the site, a second group had human bone marrow stem cells injected, while a third were injected with human ADRCs. The rats injected with ADRCs showed greatest improvement in healing out of the three groups. The formation of new blood vessels (angiogenesis) and new muscle cells (myogenesis) was observed, and fibrosis was suppressed.

The researchers looked to see exactly what was going on. Since the rats were injected with human progenitor cells they could examine certain markers to see if these cells were differentiating into muscle and vascular cells in the rats. Although that was observed to a small degree, it appeared that what was mostly going on was that these injected cells were secreting lots of cytokines and growth factors such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), and these were stimulating the rapid repair and regrowth of the native tissue in the injection area.

Whatever the mechanism, the technique seems to have potential due to its ease of preparation and also due to the low risk of immune rejection (since one’s own cells are being reinjected into their body). Also, we don’t know whether if when human ADRCs are injected into human tissues there may be more actual differentiation into new tissue going on, and not just mostly paracrine stimulation of growth of existing tissue from secreted growth factors.

I expect to see this technique to soon gain popularity in elite sports injury repair along with current new fangled techniques such PRP injections.



The Bulimia Machine

By Patrick Arnold

You may have heard of the new personal stomach pump invention by the guy that brought us the Segway personal transport thingy. The contraption is called the AspireAssist Device. In Europe the device has been clinically tested on several overweight people and found to be very effective over the long term. 24 obese people lost an average of 49 percent of excess weight (which comes to around 45 pounds) after using it as directed for a year. The makers of the AspireAssist device hope to gain FDA approval sometime in the near future.

This story has caused a lot of controversy. First of all, the product itself works in a rather disgusting manner. Basically it works like this – you get an operation where a tube is installed the goes from the inside of your stomach out through the front of your body. There is an opening on your belly skin where you can stick some sort of pump device. The idea is, after you eat a meal and wait 20 minutes (to let your food digest and get liquified and evenly dispersed) you then use the pump to remove 30 percent of your stomach contents. [I have no idea how it is able to gauge what 30 percent of your stomach contents are, but then again I don’t know how a Segway works either.] You then spray these contents into a suitable disposal apparatus such as your toilet, or if you are an animal lover, a baby birds mouth.

So why is this controversial you ask? Well, where do I start? First of all, the idea grosses people out and reminds them of bulimia (bulimia is generally considered a very bad thing). It also is offensive to those people who believe one should approach dieting from a healthy direction – with lifestyle changes that involve healthy food choices and eating habits and all that stuff. To them the idea of a quick fix approach sounds abhorrent, especially one that just seems so creepy. Some folks also express fear that this device may lead to health issues associated with classic bulimia, such as nutritional deficiencies and metabolic dysfunctions.

I think everyone should just chill out. First of all, if this device is approved it surely will be only for morbidly obese folks, and then only after classic diet and behavior counseling has proven ineffective. Mobidly obese folk are very sick and they almost always have severe diabetes and accompanying health issues that I can’t even begin to list. Right now the options for these folks are not good and usually involve some sort of bariatric surgery. Bariatric surgery is a horrible procedure and carries a frightening fatality risk. Plus, it can be absolute torture to prepare for, and even worse to recover from. This AspireAssist device on the other hand requires a relatively simple surgical procedure to install, and if needed the device can be removed quite easily and rapidly as well. And what about the risk of nutritional deficiencies and associated bulimia type issues? I don’t see the possibility of that, since you are removing stomach contents which should be homogenously distributed (if you wait the required 20 minutes after eating), and you are only removing 30 percent of the contents. It’s not really different then if you just ate 30 percent less to begin with.

So once you get over the yuck factor and think about it, AspireAssist may actually prove to be a pretty nifty and valuable medical breakthrough. Technological advancements are often met with alarm and disdain, especially if they encroach on sensitive subjects such as personal appearance and fitness. In the end though, they can come to be accepted if they fulfill their promise.



Homemade Steroids Making Users Sick?

By Patrick Arnold

In Panama City Florida a steroid bust was made at what appeared to be some “garage lab”. The amount of steroids seized allegedly had a street value of one million dollars (I have no idea how that is calculated but I suspect it is warped on the high side.) What made this story a bit unusual was that the steroids apparently were making people ill.

I read this story on the internet and it originated from a newspaper called The News Herald which is out of the panhandle area of florida. What is described sounds like injectable steroids, in other words, steroids dissolved in oil. Authorities claim that some of these steroids had residue stuck to the side of the vials and some had “debris” floating in them.

Residue and debris in injectable steroids sounds unclean and potentially harmful and that very well could be the case. It also could be the case that this residue and debris was precipitated steroid crystals due to the product being loaded into the oil at too high of a concentration. That may not necessarily be unclean or harmful (other than potential harm from steroids themselves), but is indicative that whoever was making the product didn’t know what they were doing. Oddly, the cops commented on the fact that the “cook plate”, which I assume means hot plate, was anything but sterile. I am not sure why a hot plate would have to be sterile for product that is put into a vial to be sterile. I bet the house the hot plate was in wasn’t sterile either.

What made this story interesting to me though was the fact that these products were producing troubling physical symptoms in many of the users. These were acute symptoms of coughing and chest pain. Authorities weren’t sure if it was the steroid in the product or something else in the product. Since I am familiar with this area I can say with relative confidence that it was likely one of two things. First of all, the steroids could have contained trenbolone acetate, which is a steroid commonly known to cause an anaphylactic type reaction in users upon injection. An anaphylactic reaction is an allergic response that comes on very quickly (seconds or minutes) after exposure to an allergen and involves symptoms such as coughing due to shortness of breath, chest pain, sweating etc. Also known to cause anaphylactic reactions are the chemicals benzyl alcohol and benzyl benzoate. These chemicals are often added to injectable preparations in small amounts, but when added in larger amounts they have been known to cause anaphylactic like reactions in people (sometimes quite severe).

It’s a very bad idea to use an oil based injectable steroid or anything that is not made under proper pharmaceutical conditions. And although the risk of infection due to sterility problems is much less than that of water based preparations, there still can be a host of other problems that can cause you some serious problems. Unfortunately the desire to use performance enhancement drugs is widespread and the current laws forbid the use of steroids and other PEDs for things other than disease. As a result, people are buying stuff from idiots that mix up Chinese steroid powder in oil in their basement.



Hypertension and anabolic steroids. A new pathway?

By Patrick Arnold

People familiar with the use of anabolic steroids know that water retention and hypertension (high blood pressure) are potential side effects. This is due to the fact that all androgenic hormones have the capacity to cause some sodium retention (and hence water retention) through direct action via androgen receptors in the kidneys. Furthermore, anabolic steroids that are estrogenic or can convert to estrogens can cause even more sodium retention via additional interaction with renal (kidney) estrogen receptors. So it’s often thought that an anabolic steroids propensity for water retention is related to its potency both as an androgen and as an estrogen (manifested via aromatization to estrogenic metabolites).

Confusion has often arisen however when people have noticed that some steroids – which traditional thinking tells us should not result in extraordinary water retention – end up doing just that. Steroids that should not aromatize to estrogens such as oxymetholone (anadrol) and methyl-1-testosterone are known to result in extreme water retention in some individuals. A recent paper* suggests a heretofore unmentioned explanation for this.

There is an enzyme that is localized primarily in the kidneys whose function is to protect the kidneys from circulating cortisol. The kidneys have receptors called mineralcorticoid receptors (MR’s) which are meant to bind to specific adrenal hormones (called mineralcorticoids) in the body such as aldosterone. The result of this binding is a signal to increase sodium and water retention in the body, while stimulating the excretion of potassium. This is an important mechanism to maintain fluid and electrolyte balance in the body.

A problem exists though in that cortisol can also bind activate these receptors. Cortisol is a widely circulating hormone and serves a multitude of functions throughout the body. However its intended biological functions do not include mineralcorticoid action in the kidneys, so to prevent this from happening the kidneys are rich in the enzyme 11b-hydroxysteroid dehydrogenase 2 (11b-HSD2). This enzyme deactivates cortisol by converting it into cortisone before it can bind to the renal MRs.

Certain substances can block 11b-HSD2, and that can lead to problems. One example is a constituent of black licorice known as glycyrrhetinic acid. This enzyme inhibition potential is precisely why people that consume a lot of black licorice are known to retain water and experience high blood pressure and electrolyte disturbances. Interestingly, legend has it that Genghis Khan had his armies ingest licorice while on the march to prevent thirst and dehydration. Of course Genghis Khan had no idea that 11b-HSD2 inhibition was responsible for these effects, and today many have been similarly unaware that this property might be responsible for some of the salt/water effects of anabolic steroids.

The study I referred to earlier found that many anabolic steroids indeed do share the ability to block this enzyme, and some of them are as powerful as glycyrrhetinic acid. Fluoxymesterone (halotestin) in particular was shown to be about as potent as glycyrrhetinic acid in this regard. This makes sense, since fluoxymesterone shares the same 11b-OH group as cortisol and can be oxidatively metabolized by 11b-HSD2 in an analogous manner.

The fact that fluoxymesterone serves as a substrate for 11b-HSD2 in this manner makes it a competitive inhibitor of the enzyme. Other anabolic steroids were also found to be potent inhibitors of the enzyme as well, although the mechanisms for these are not clear as they do not share the 11b-OH group.

In addition to fluoxymesterone other 11b-HSD2 inhibitor steroids of interest are oxymetholone (anadrol), oxymesterone, and testosterone. The question arises as to how relevant this enzyme inhibiton is in the real world. Fluoxymesterone is generally not associated excess water retention, but then again doses used are relatively low (20mg or less per day). In contrast, oxymetholone is well associated with excess water retention and the doses used of that are often high (50-150mg per day). So this may be a dose related phenomenon. Another question that I have is what sort of inhibition might methyl-1-testosterone have, since it seems to be the worst water retaining and hypertensive steroid ever made. Few have had decent explanations for this and perhaps 11b-HSD2 inhibition is a culprit (the study did not test this steroid).

A final point of interest to mention here is the intriguing fact that 11-ketofluoxymesterone (the metabolite formed in the kidneys as mentioned previously) is actually a stronger anabolic steroid than fluoxymesterone according to animal tests. I find that interesting because one would also expect it to generally lack the troublesome enzyme inhibition that can lead to mineralcorticoid related disturbances. Maybe if the inventors of fluoxymesterone had decided to just simply oxidize the 11b-OH group they would have ended up with a more healthy and effective steroid to sell.