Actovegin: an unfortunately legal Performance Enhancing Drug

Have you ever wondered what Usain Bolt, Ronaldo, Michael Jordan, Paula Radcliffe, etc. all have in common? Obviously athletic super-stardom and its many physiological underpinnings and financial perks.  However, there’s an underlying thread that connects all of them, and it’s likely been a significant facilitator of their super-human sporting prowesses.  That underlying connection is the drug Actovegin and its primary peddler, Dr. Hans-Wilhelm Müller-Wohlfahrt.  Below, we will examine this magic and its magician.

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Lately, the state of global athletics has had the gears in my mind spinning full bore about athletes, namely runners, at the extreme ends of the performance spectrum and the potential doping-related activities that may be knowingly or unknowingly supporting them.  A recent piece in the New York Times (link) discussed the sub-2-hour marathon project, and in it, it chronicled the struggles of world record holder Kenensia Bekele in his attempt to return to racing form.  The article mentioned a German doctor, Hans-Wilhelm Müller-Wohlfahrt, and a distant bell was rung in my brain, as I had heard this name associated with other big athletes (the article even mentions Usain Bolt) and his unconventional treatment methods.

After digging a bit deeper into this guy his main treatment go-to, Actovegin, a lot of pieces across a lot of sports unfortunately connected.  Many previous reports have tossed around mention of this drug, and usually just leave it at ‘ambiguous’, ‘questionable’, or ‘gray’, and move on.  It actually gained prominent media attention in 2000, when Lance Armstrong and the US Postal Team was caught trying to get loads of the stuff across the French border.  Since then, most people in the sporting world have acknowledged its use, but shrugged it off as homeopathic voodoo.  However, after reviewing some recent scientific literature on the drug (most notably a crazy study published just a few months ago, which will be discussed below), it’s benefits should absolutely not be ignored.  Given that this doctor has penetrated literally all of global athletics (Michael Jordan, Usain Bolt, Ronaldo, innumerable soccer stars, etc. etc.), it appears that the effects of Actovegin might just underlie most major world-record and Olympic performances in running, as well as many many other sports.

What is Actovegin?

The common phrase to describe it is “calf’s blood”.  I think this rhetoric is why most people simply dismiss it and leave it at that.  However, it’s not as if it’s just an injection of calf’s blood yanked straight from the cow (which would then be a really dangerous and kinda gross form of blood doping).  It’s much more complicated than that: the blood goes through many rounds of ultrafiltration processing, including vacuum distillations, titrations, and electrophoresis verifications.  The result is a substance that’s had all the protein removed, and leaves a soup of molecules that have been pretty tricky to pin-down.  Some studies have attempted to ID all the different compounds within it, yet there is no identified ‘active ingredient’ of any sort.  It seems to be a mess of protein fragments, intermediaries of steroid hormones, amino acids, sugars, electrolytes, and other organic compounds.  It’s an approved pharmaceutical overseas, but hasn’t been approved for use by the FDA.

What does it do?

Put simply, it enhances cellular metabolism and respiration.  That is, it helps get glucose (fuel) into the muscle cells faster and helps the mitochondria (energy producers) in the muscle cells burn that glucose more efficiently.  It’s marketed as a drug overseas for diabetic treatments (as it has an insulin-like effect of getting sugar into muscle cells) and is also used to treat patients who suffered from hemorrhages, strokes, or muscle injuries.  One pilot study of soccer players who suffered hamstring tears found that those receiving conventional treatments took 20 days to return to play, whereas those receving Actovegin injections returned after only 12 days.  It’s role in enhancing energy production in the cells is well documented in rat models, but until recently, purely anecdotal for humans.

Legality of Actovegin

Currently, it’s not on the World Anti-doping Agency’s (WADA) prohibitied substance list.  However, WADA does ban injections of any substance, including Actovegin, exceeding 50 ml every six hours.  Prior to the formation of WADA, the International Olympic Commitee (IOC) banned the use of Actovegin in December of 2000.  They had noticed that a multitude of countries had brought it to the Sydney Games, and it appeared to be a mainstay acorss many teams in that year’s Tour de France.  They proceeded to ban it in December as a performance-enhacing substance.  However, they curiously lifted the ban 2 months later in February of 2001 pending further research.  WADA’s current stance on it: legal, but illegal to inject more than 50 mL (which is 25 times higher than the amount that’s been reported for muscle tear rehabilitation).  It should be noted that this is completely arbitrary, as if someone were to want to use it along these guidelines, they could concentrate it to any dose they’d like and inject multiple times per day.

To further complicate things, WADA’s code now bans “any growth factor(s) affecting muscle, tendon or ligament protein synthesis/degradation, vascularisation, energy utilisation, regenerative capacity or fibre type switching” as well as the nebulous “spirit of the sport” legality, prohibiting “… the potentially unhealthy abuse of certain substances without therapeutic justification based on the mistaken belief they enhance performance is certainly contrary to the spirit of sport regardless of whether the expectation of performance enhancement is realistic…”.  The use of Actovegin certainly seems to violate even these somewhat foggy guidelines.

Unfortunately, because there are no identified “active ingredients” (which has been one of the reasons the FDA hasn’t approved it), it would be pretty difficult to develop a test for it, even if WADA wanted to.  There’s no scientific consensus on what’s in it, let alone how to identify it in an athlete.

Does it Enhance Performance?

“It’s a powerful performance-enhancing drug” – Victor Conte (BALCO infamy)

As stated above, it’s effects for athletes are two-fold: it helps get fuel into the muscles faster and helps them burn that fuel more efficiently.  Why would you want to be able to get glucose (fuel) into the muscles faster and more efficiently (hint: insulin helps with this, and is in fact a banned substance)?  Think recovery: restock the muscles’ energy supply so you can give another maximal effort, or so you can really “carbo-load” to the maximum.  Preparing for a marathon, riding a stage race, back-to-back tennis matches, repeated soccer games, rounds in track championships, and just day-to-day training recovery.  Moreover, because it has an insulin-like effect of enhancing glucose uptake into muscle cells but doesn’t seem to have the downside of increasing glucose storage as fat in fat cells (the other job of insulin), it seems like quite the gem for the athlete.

The other benefit, which was until recently, more anecdotal, was the effect that the drug had on energy production within the cells.  A study published just last January showed, for the first time (link), a clear enhancement of cellular respiration and energy production in human muscle cells.  The efficiency of the mitochondria in the cell were enhanced in a concentration-dependent manner (i.e. the more you take, the greater the benefit), meaning, essentially, that the muscle cells could burn more oxygen faster after being exposed to Actovegin.

Maximal rates of in vitro energy production in human skeletal muscle (Sondergard et. al.)

So for comparison, the infamous performance-enhancer for endurance sports (and likely many other sports) is EPO.  As we all know, EPO increases the number of red blood cells in your body, thereby delivering more oxygen to the muscle cells.  Actovegin essentially helps the muscle cells use that oxygen more efficiently.  This ability to enhance O2 flux and glucose-derived energy-utilization on the mitochondrial level may be ringing bells for the scientific minds out there.  Indeed, this mechanism is similar to the drug that most recently dominated headlines: Meldonium.  Maybe Maria Sharapova has a ‘legal’ alternative (though one can’t help but suspect it may have already been in the medicine cabinet…)!

So, it seems like it’s benefit is two-fold:

1.) it increases the energy-production capacity of the muscle cells, meaning more bang for your energetic buck.  It does this by getting fuel into the cell (like insulin, which is banned, but doesn’t have the potential downfall of fat storage or metabolic disruption associated with too much insulin) and then using that fuel more efficiently by enhancing the mitochondria (like Meldonium, also banned).

2.) It seems to be a powerful injury recovery aid (anecdotally and in rodent models), maybe through these metabolic enhancements, or maybe through other growth-factor related pathways that haven’t been explored.  Again, the stuff is a tricky, not-completely-understood chemical soup!

Who uses it?

Track and Field Current/Former World Record Holders:
Paula Radcliffe (for over two decades)
Usain Bolt (since he was 16)
Kenensia Bekele
Meseret Defar
Patrick Makau
Maurice Greene

That’s just from a quick Google search – by the sounds of it, many of the overseas agents/physios direct their major stars towards this before and after injuries

Other prominent persons:
Michael Jordan
Christiano Ronaldo
Ronaldo
Andy Murray
Vladimir Klitschko
Luciano Pavoratti
Bono

Again, those are just people mentioned by major articles from news outlets.  From reading about Dr. Mueller-Wolfharft aka Healing Hans (more below), it seems like just about every soccer player in Europe goes to see him for Actovegin treatments (among other injectable enhancements), and many prominent athletic figures around the globe go seek his services.

Natural vs. Unnatural

Some supporters of the drug’s legality may make the claim that because it’s a ‘natural’ compound from calf’s blood, that it’s somehow distinct from a drug like EPO or testosterone.  Flawed argument.  One, it’s no more ‘natural’ or ‘unnatural’ than something like recombinant EPO, which is made via bacterial cell culturing (which one could say is more ‘natural’ given that that comes from human DNA, rather than a foreign species).  Two, it’s not like they’re just injecting cow-blood into their veins; the blood goes through many rounds of industrial pharmaceutical processing steps to get the final drug.  Third, the fact that it relies on the method of injection should raise eyebrows for it’s claims of being ‘natural’ and within the spirit of the sport.

The Doctor: ‘Healing Hans’

The doctor at the center of all this is Hans-Wilhelm Müller-Wohlfahrt.  ESPN’s Outside the Lines did an incredible profile on him a few years ago (link), so I won’t go into the depths of his backstory (highly recommended read).  The cliff notes are this: He’s a German doctor who relies primarily on injectable treatments outside of the mainstream, regulated pharmaceutical and medical industry.  He has been in practice for many decades, and has been using Actovegin and other methods for 40+ years on a clientele of almost exclusively elite athletes.  However, though he claims his methods are completely legitimate and in fact, superior to most traditional medical treatments, he has not offered any of his findings or methods to the scientific community.  Despite having a global impact, he has no publications in medical journals or any other peer-reviewed outlet.  Most of this magic occurs behind closed doors in his Munich office.  He was the team doctor for the Bayern Munich soccer club and German national team for many years, and seems to be basically an institution across European soccer.  Through his career, he has worked his magic on global sports stars from all over the world.  Track fans have probably often heard about Usain Bolt repeatedly flying to Germany for treatments from Healing Hans, and Paula Radcliffe regularly got his magic for the better part of two decades.  I wouldn’t be surprised if many NFL and NBA stars make the trans-Atlantic flight to consult with this ‘wunderheiler’.

The Actovegin must be keeping that 72-year-old Flow ripe (source: Getty)

Final Thoughts

World Record holders (Paula Radcliffe, Usain Bolt, etc.) and other sporting megastars openly admitting to regularly using a drug that seems to be definitively performance-enhancing.  It really bums me out that this is legal, as it seems to be no different than any other injectable PED in terms of its unnatural enhancements.  Obviously, there’s no way to test for it, which further bums me out.  I guess my takeaway is that it’s at least informative to identify a cornerstone piece of the frustrating puzzle of what makes seemingly super-human performances indeed super-human.

Links:

Søndergård, S. D., Dela, F., Helge, J. W., & Larsen, S. (2016). Actovegin, a non-prohibited drug increases oxidative capacity in human skeletal muscle.European journal of sport science, 1-7. http://www.tandfonline.com/doi/abs/10.1080/17461391.2015.1130750

Buchmayer, F., Pleiner, J., Elmlinger, M. W., Lauer, G., Nell, G., & Sitte, H. H. (2011). Actovegin®: a biological drug for more than 5 decades. Wiener Medizinische Wochenschrift, 161(3-4), 80-88. http://link.springer.com/article/10.1007/s10354-011-0865-y

Lee, P., Rattenberry, A., Connelly, S., & Nokes, L. (2011). Our experience on Actovegin, is it cutting edge?. International journal of sports medicine, 32(4), 237-241. http://europepmc.org/abstract/med/21271496

Lee, Paul, L. Nokes, and P. M. Smith. “No Effect of Intravenous Actovegin® on Peak Aerobic Capacity.” International journal of sports medicine 33.4 (2012): 305. http://www.pilarmartinescudero.com/nov13/actovegin_picomaxoxigeno.pdf

Incredible pieces from 2011 by ESPN OTL on Muller-Wohlfart:
The Doctor They Call ‘Healing Hans’
Making the Rounds with ‘Healing Hans’