EM PharmD

The exhilarating high of crossing the finish line first in a race shares a fascinating similarity to the euphoria from heroin: both are reversed by naloxone. When we think of the lengths at which some individuals go to seek the next high from heroin, is it really any surprise that some may go to the same lengths to win an Olympic gold medal? What about breaking a world record?

The current state of the world of distance running is best described by the old ABC’s Wide World of Sports opener: The thrill of victory and agony of defeat.  Euclid Kipchoge, a Keynan Olympic marathon chapion has just broken the world record for the marathon. His time of 1:59:40 marks the first human to run 26.2 miles in under 2 hours. Let’s take a moment to put that number into perspective: his time roughly equates to an average of 4:33 minutes per mile. My best time for the 1-mile race as a Division 1 NCAA athlete was 4:16. His world record time was once thought to be physically impossible for a human, exactly what was said about Sir Rodger Bannister’s sub-4 minute mile.

While the world of athletics celebrates this champion, the American distance running team, Nike Oregon Project, is facing the agony of defeat. And possibly worse. Their coach, Roberto Salazar, has been at the center of a doping scandal that has rocked the American distance running world. For a team that was instrumental at bringing Americans back to the top of the podium on the world running stage, their legacy is at stake because of alleged nefarious dietary supplemental practices. 

While the whole report is necessary to read to understand the accusations, evidence, and testimony, I want to focus on the drugs at the center of the scandal.  For anyone who has followed doping in endurance athletics (Tour De France for example) the doping one would think I’m referring to has to do with erythropoietin/blood transfusions. But the accusations of what was actually administered to some NOP athletes was L-carnitine. Specifically, not even the route of administration (intravenous). The alleged infraction related to the volume of IV diluent used in the administration of L-carnitine, specifically that it exceeded the USADA volume of 50 mL in a 6 hour period (new 2020 regulation increased to 100mL but over a 12 hour period).[1,2]

The rationale for the IV volume restriction is thought to prevent athletes from rapidly rehydrating between competition events, or as a means to prevent masking of a blood or urine sample by dilution. The L-carnitine, however, is a little more interesting. Taking L-carnitine as a dietary supplement, or via valid prescription pursuant to a physician-athlete relationship for a legitimate diagnosis (medical exemption), is permitted by the USADA. So what was the issue related to the NOPs use of L-carnitine in some athletes? To understand the rationale for L-carnitine use by an athlete, we need to understand it’s actions a little better.

Why would a runner want to take L-carnitine?[3-6]

Anyone that runs greater than about 70-80 minutes is familiar with a sensation of “bonking” or “hitting the wall.” For well-trained runners or professional runners, they may not hit the wall until about 20-23 miles into the race. Physiologically, this is the depletion of glycogen stores and the initiation of a shift of metabolic production of ATP from fatty acids. While fat supplies more energy than carbohydrates (9 vs 4 kcal/g), and we have vastly larger stores of fat versus carbohydrates, the process to produce ATP is more complex. If you recall, while glucose is relatively easily converted to pyruvate and then to acetyl-CoA, fatty acids require several additional steps. 

On the surface of the mitochondrial outer membrane, long-chain fatty acids are converted to acyl-CoA after being catalyzed by long-chain acyl-CoA synthetase (LACS). This newly formed acyl-CoA, along with carnitine (forming acylcarnitine), is shuttled into the intermembrane space by carnitine palmitoyltransferase I (CPT1). From there, acylcarnitine is brought through the inner mitochondrial membrane by CPT2 and also by acylcarnitine translocase. Acylcarnitine translocase has a dual function of shuttling carnitine back out of the mitochondrial cytoplasm to be recycled (see valproic acid toxicity). CPT2 similarly has a dual function by converting acylcarnitine back into acyl-CoA which can then enter beta-oxidation to produce NADH, FADH2 required for ATP synthesis. 

The oxidation one 16 carbon fatty acid chain yields approximately 107 ATP compared to 32 molecules of ATP from one molecule of glucose. Not to mention, the total body stores of fatty acids greatly exceed the total body store of glycogen. So any method to enhance fatty acid oxidation could hypothetically lead to greater endurance and performance by simply not running out of fuel. Supplementing L-carnitine, as a potential rate-limiting factor in this process could do the trick.

When examined in highly trained athletes, a systematic review and one additional recent study demonstrated a modest effect on VO2max but no actual change in endurance athlete performance.  While many of these studies used single oral doses of L-carnitine, the studies with the most observed benefit used longer regimens of up to 3 grams daily for 15 days. Ultimately, oral L-carnitine proved to be not the magical performance elixir.

NOP and their physician’s regimen

So if it doesn’t work orally, why not try parenterally? While this question is often the bane of pharmacists’ existence (talking about you, acetaminophen), in the case of L-carnitine this is a reasonable question. As we know, oral absorption of L-carnitine isn’t terrific – on the order of 15% bioavailability. Thus administration of it intravenously could overcome this. From unpublished evidence cited in the arbitration tribunal document, this method of one time(?) L-carnitine infusion improved athletic performance.

An astute member of the NOP brought up a concern that the original plan to administer roughly 9.6 grams of L-carnitine in 1 L of dextrose over a few hours. For context, a 60 kg professional runner, their dose for treating valproic-acid hyperammonemia would be approximately 6 g bolus followed by 3 g IV q8h. The issue, in this case, was not the dose, but the volume over the given time period. In order for the 1L to be compliant with USADA regulation at the time, it would have taken 120 hours to infuse. So the pharmacist compounding the L-carnitine reformulated the solution to a total volume of 45 mL (to account for some overfill and ensure volumes under the regulations). Good pharmacist. L-carnitine can also be given as an IV bolus. This option was not addressed.

From my read of the arbitration document, there was no further evidence that any NOP athlete received a volume larger than permitted under regulation. The only case which was the focus of the investigation was one member of the team (it’s unclear if he was an athlete, coach, or consultant at the time) may have received the 1L bag. Additionally, there is speculation as to whether there was some obstruction to the investigation and alleged inappropriate handling of athletes’ concern of whether this was a permitted substance. 

Got low-T?

The other allegation against Salazar was his own personal use of Androgel. While the USADA does not specifically prevent coaches from using banned substances, of which Androgel is one, it is banned for athlete use. The allegation surrounds the NOPs investigation into whether one could tamper with an athlete to “spike” them with testosterone. 

In the document, after an evening race in Oregon, Galen Rupp (NOP athlete) was patted on the back by an individual named in the document. As pats on the back go, this one was felt to be suspicious given that Rupp felt like the person had applied something to his back during the encounter and this individual had been accused of doing so in the past.

After this incident, which was reported to the USADA, the NOP undertook a series of tests on a nonathlete member of the team to determine the minimum required dose/application of Androgel required to yield a positive drug screen. Analogous to owls testing licks of a tootsie pop, the magical number was 3 pumps of Androgel.

However, from another perspective, the NOP could have been conducting these tests to determine the MAXIMUM amount of Androgel athletes could use without being caught. The arbitrating committee felt this was the case given other athlete testimony.

Banned, but not forgotten

As a result of the evidence put forth in the arbitration, Salazar was handed a 4-year ban from coaching. In the fallout, the NOP was disbanded by Nike and the athletes were left coachless days before a major event. This ban was handed down without a single positive athlete drug screen and involved one banned substance and one large volume parenteral infusion. Four years.

Perhaps my bias leans in defense of NOP. Perhaps there was an activity that was in the gray area of USADA regulation. The jury, in this case, is already out.

1. USADA vs Alberto Salazar. Available at: https://www.usada.org/wp-content/uploads/Salazar-AAA-Decision.pdf
2. USADA and WADA Prohibited List 2020. Available at: https://www.usada.org/wp-content/uploads/wada_2020_english_prohibited_list.pdf
3. Howland M. L-Carnitine. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank’s Toxicologic Emergencies, 11e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.ezproxy.uttyler.edu:2048/content.aspx?bookid=2569&sectionid=210262359. Accessed October 12, 2019.
4. Rapoport BI. Metabolic Factors Limiting Performance in Marathon Runners. PLoS Comput Biol. 2010 Oct; 6(10): e1000960. PMID: 20975938.
5. Fielding R, Riede L, Lugo JP, Bellamine A. l-Carnitine Supplementation in Recovery after Exercise. Nutrients. 2018 Mar; 10(3): 349. PMID: 29534031
6. Burrus BM, Moscicki BM, Matthews TD, Paolone VJ. The Effect of Acute L-carnitine and Carbohydrate Intake on Cycling Performance. Int J Exerc Sci. 2018; 11(2): 404–416. PMID: 29541331