The Chemist

Q. Patrick, I’m an endurance athlete, and I was wondering if there’s any supplements out there that can work like EPO?

A. I studied this area quite a bit in the past because I knew there was a market for a natural blood booster. A “natural EPO” would definitely be a good seller, but on the other hand, it would probably garner me a lot of negative attention from the drug-testing folk and their political and media lackeys. Because of this, I knew I had to be careful and not sell something that had too many potential downsides (e.g., toxicity), but at the same time, I wanted to make sure that the stuff actually had a measurable effect on athletes. There were two ideas in particular I studied with interest. The first involved a category of testosterone metabolites called 5beta-androstanes. 5beta-androstanes are lesser known than the “DHT” class of testosterone metabolites, which are of course known as 5alpha-androstanes. The major difference between 5alpha-androstanes and 5beta-androstanes is that all of the latter are hormonally inactive while the 5alpha-androstanes are often very active. Now, while it’s known that androgens can increase red blood cell production via increases in erythropoietin (EPO) production, this isn’t how the 5beta-androstanes metabolites work. 5beta-androstanes appear to stimulate the production of erythrocytes (red blood cells) by a post-EPO pathway—perhaps by stimulating the synthesis and incorporation of hemoglobin into differentiated erythrocyte progenitor cells. Medical researchers Frank Gardner and Harinder Juneja had success using the 5beta-androstane alpha-etiocholanolone in aplastic anemia patients. They had to administer prednisone along with the alpha-etiocholanolone, however, because this steroid metabolite is highly pyrogenic—that is, it produces fever and pain at the injection site. Later, researchers working for a company called Supergen found that the pyrogenesis problem associated with a-etiocholanolone administration can be avoided by the use of its direct precursor, etiocholandione. Etiocholandione is an interesting compound that also has been studied for anti-obesity properties. Supergen holds the patents on the use of etiocholandione for both anti-obesity and for usage as an erythropoietic agent. I was familiar with the chemistry of etiocholandione, and I knew I could probably synthesize it efficiently and economically. So around nine or ten years ago, I visited with the Supergen people in California to discuss licensing the compound for one of these uses. However, what they had to tell me was a big letdown, as they informed me that the clinical trials on the compound were very disappointing and they’d pretty much given up on the stuff. So I gave up on it too. I don’t wanna sell something that sucks, even if you can tell a great marketing story using some published literature.

Before EPO
Before recombinant EPO was available, there weren’t a lot of effective treatments available for anemic patients. If your anemia wasn’t respondent to nutritional interventions such as iron, vitamin B12, or folic acid supplementation, there wasn’t much left other than perhaps anabolic steroids (which can have unwanted side effects, especially for women and children). So scientists took notice when they discovered that excessive exposure to the common metallic element cobalt was responsible for a disorder called polycythemia, which is nothing more than excessive production of red blood cells. Cobalt is a common element that is in the same periodic table group as iron and nickel. We consume very small amounts of cobalt every day, mostly in the form of vitamin B12, which is a complex molecule called a coordination compound that has an atom of cobalt in the center. In larger amounts, cobalt ingestion has been associated with conditions such as asthma and pneumonia. After studying cobalt administration (as cobaltous chloride) in animals and then humans, medical researchers discovered that doses can be given that result in marked increases in hematocrit (percentage of red blood cells in blood) in patients with anemic diseases (usually patients on dialysis). Doses as low as 30 milligrams a day given for several weeks were sufficient. Since cobalt is rapidly eliminated, there was minimal buildup in the system, so blood levels weren’t too hard to control. The mechanism by which cobalt stimulates erythropoeisis is by creating in the body what is essentially a “false hypoxic state,” which basically means it tricks your body into thinking it isn’t getting enough oxygen. Your body responds to hypoxic conditions by increasing the efficiency of energy production through anaerobic glycolysis, production of new blood vessels (angiogenesis), and of course, the production of more red blood cells (erythropoeisis). These events are mediated by a group of biochemical messengers known as hypoxia inducible factors (HIFs).

The Problems With Cobaltous Chloride

Okay, so it all sounds great. Cobaltous chloride is dirt-cheap and works remarkably well. So why didn’t I market it as a supplement? Well even though the toxicity of cobalt at the dosages used for this purpose isn’t unreasonable, the potential for problems is still there. Stomach issues including nausea aren’t uncommon, and cardiomyopathy (damage to the heart muscle) has been reported with its usage. Hypothyroidism is also a potential concern, as is interference with the absorption and utilization of dietary iron. But even with toxicity put aside, just the nature of its intended effect is troublesome to me. Raising your hematocrit for performance benefits isn’t something that is a game. If you misjudge and raise it too high (hematocrit over 54 or so), you run the risk of all kinds of cardiovascular dangers such as stroke and congestive heart failure. It’s just not worth the risk.