There is controversy in the American horse racing industry after a handful of trainers face severe fines and suspensions after their horse(s) tested positive for metformin. The frequency of metformin positives has increased since HISA/HIWU has been acting as the governing body of drug testing and welfare in horse racing (https://www.hiwu.org/cases/pending) over the last year. All trainers claim they did not purposely administer metformin to their horses, affirming the positives must have been due to environmental contamination from the handlers of the horses. This article will cover what metformin is, how it may impact racehorse performance and recovery from exercise, and how it is metabolized in the horse which may result in a positive drug test.
What is Metformin?
Metformin is a human drug that is prescribed to treat Type II diabetes/metabolic disorder by helping control high blood sugar. Its mechanisms to reduce high blood sugar include reducing the absorption of sugars/carbohydrates in the intestines and reducing the creation of sugar/glucose in the liver. Metformin may help weight loss due to these mechanisms. Over 90 million people are prescribed metformin in the United States, as it is currently the primary treatment for type II diabetes. In horses, metformin has been used to treat metabolic syndrome and prevention of laminitis. This drug may not be as effective in horses as it is in humans because the absorption of metformin in the equine intestines is poor. There are mixed results as to how effective metformin is to increase insulin sensitivity in horses with metabolic dysregulation (Tinworth et al. 2012; Hustace et al. 2009; Durham et al. 2013; Colmer et al. 2024). Metformin is most commonly given orally to horses and humans. However, an injectable version of metformin may also be used.
Is Metformin actually performance enhancing?
There is some evidence to support that metformin can enhance acute athletic performance. In Learis et al. (2015), “fit” male subjects were given 500mg of Metformin (on the smaller side of a typical daily dosage of this medication for those with metabolic disorder) 1 hour before a supramaximal exercise test to exhaustion on a cycle ergometer (a stationary bike). “Supramaximal” means at exercise intensities above someone’s VO2max, or maximum oxygen consumption. In this case, the exercise intensity was 110% of the intensity that elicited each subject’s VO2max and the subjects had to maintain that intensity for as long as possible (a very painful exercise test). This intensity is actually pretty comparable to the intensities thoroughbred racehorses may elicit during 5-8 furlong races depending on the horse’s fitness. Every subject did this test- one with metformin and the other a placebo, in a blinded-randomized order. During the supramaximal test to exhaustion, every single one of the subjects were able to exercise 24 seconds longer on average after taking Metformin compared to a placebo for the exercise test to exhaustion. Statistically, this difference was very strong (p = 0.001), especially because all ten of the subjects in this study were able to exercise longer after taking Metformin vs the placebo (for my stats nerds out there, the Effect Size was 0.70, pretty high for a sample size of 10 subjects). Also keep in mind these trials were randomized, meaning some subjects did these tests with Metformin first, others did placebo first; this is to reduce the bias of the study, strengthening its results. Overall, this study means Metformin may in fact enhance performance in intense, short duration exercise– very similar to the exercise intensities and duration thoroughbred racehorses endure for racing. Researchers theorize this phenomenon is due to metformin’s potential to enhance the alactic (phosphocreatine) energy system. This study also found metformin had no effects on the aerobic system, contrary to other performance enhancing drugs like EPO (a blood builder).
Another study performed in rats found very similar results, finding that time to exhaustion significantly increased after the rats were given a very high dosage of metformin for 10 days compared to a placebo (Araujo et al. 2020).
Metformin and Fitness Gains
Whereas metformin has been shown to enhance short term performance in prolonged “sprint-like” exercise tests, repeated use of metformin in the long term may inhibit training adaptation or fitness gains. Prolonged metformin use (1,700mg/day) has been shown to blunt muscle growth and strength gains in older adults performing a strength training program due to its ability to reduce post exercise inflammation (Walton et al. 2019) (click here to read why post-exercise inflammation is important to stimulate fitness gains). This has been shown for cardiovascular fitness as well, with Moreno-Cabenas et al. (2022) finding that metformin reduced VO2max (aerobic capacity) gains by almost half compared to a placebo treatment following a 16 week long high-intensity interval training program (a common training program that has already strongly proven to significantly increase aerobic capacity in the exercise science field for all specimens). Those taking the placebo enhanced their aerobic capacity by 25.3% after 16 weeks, while those on metformin only increased their aerobic capacity by 12.7%. This effect metformin has on inhibiting training adaptation is similar, albeit not as severe, as Statins (a common medication to improve cholesterol).
Now lets interpret all of this from a racehorse training-performance perspective. Metformin may enhance exercise performance during short-high-intensity exercise, similar to what thoroughbred racing demands. However, metformin may also inhibit fitness gains if taken continually in the long term. This does not mean an older racehorse that has been racing and training for several months or years will suddenly become less fit after taking metformin. Metformin may not reduce fitness that is already obtained. But, metformin may make it a lot harder for a horse to gain fitness when coming back from a layup or during the early stages of their training/racing.
Metformin and Exercise Recovery
Inflammation
To add from the previous section, for racehorses that are older and have been racing/training for several months/years and are just trying to maintain their current fitness, metformin may be beneficial to help not only enhance acute racing performance, but also enhance recovery post exercise. As previously mentioned, the mechanism behind why metformin inhibits exercise gains is because it reduces the inflammatory response exercise causes (Khodadadi et al. 2022). Damage from exercise causes inflammation, and inflammation stimulates the body to recover and adapt to exercise to get stronger. However, if inflammation is artificially reduced (such as with metformin), exercise stimuli is reduced and so are the fitness gains. For horses that are already near their peak fitness and are simply trying to maintain that fitness, the anti-inflammatory effects of metformin may allow those horses to bounce back from races and workouts faster in order to train and race more frequently.
Glycogen Replenishment
Metformin may also enhance muscle recovery through its enhancement of GLUT-4 (Lee et al. 2012). GLUT-4 is a transport molecule in bodily tissues (particularly muscle) that helps take glucose/sugar from the blood and store it in the tissues as glycogen (the storage form of carbohydrates in tissues that serve as a primary energy source during high-intensity exercise). Exercise depletes muscle glycogen, and this depletion can inhibit exercise performance. Muscle glycogen replenishment post exercise is much slower in horses than it is humans, even when given high carbohydrate diets. Thus, glycogen replenishment post exercise is a significant factor in preventing training fatigue and reduced racing performance in racehorses (Lecombe 2003). Due to metformin’s ability to enhance GLUT-4, it may also speed up glycogen replenishment in racehorses following exercise, enhancing exercise recovery. This can allow horses to train harder more frequently. This effect is similar to Thyroxine, now a banned substance under HISA/HIWU. In humans, metformin has been shown to significantly accelerate glycogen replenishment after prolonged exercise compared to a placebo (Scalzo et al. 2017).
Grain is essential for horses undergoing daily high intensity exercise in order to maximize muscle repair and glycogen storage replenishment. However, not all horses are able to metabolically handle high amounts of grain in one sitting and are at higher risk for laminitis. Metformin may be effective in increasing insulin sensitivity, allowing horses to eat higher quantities of grain more safely.
Weight Loss
In humans, it has been reported that metformin can induce a 2-3% body weight in the first year of taking the drug. Although the reasoning for this is not fully understood, research has found metformin can reduce appetite which may be associated with this weight loss (Stanford Medicine). As any trainer will tell you, reducing appetite is not exactly beneficial for racehorses, unless they are in a paddock 24/7 on a layup with pastures rich in carbohydrates. Metformin’s effect to increase insulin sensitivity can also reduce fat storage after eating a high carbohydrate meal, possibly further contributing to weight loss. There is little research on metformin’s effects of weight loss in horses. The loss of fat mass in overweight horses can be advantageous in enhancing racehorse performance to reduce energy cost while racing to some extent. Although, this effect may not be as potent as Thyroxine- which was once a commonly prescribed oral medication given to racehorses before it was banned by HISA/HIWU. Thyroxine is also much more easily absorbed by the horse and is likely much easier to evade drug tests after administration compared to metformin.
Why Metformin is a Banned Substance
Under The Horseracing Integrity and Safety Act/The Horse Racing Integrity and Welfare Unit (HISA/HIWU), any drug/substance that does not have FDA approved use in horses is considered a banned substance (with a few exceptions). Metformin is not FDA approved for horses, thus is a banned substance. Furthermore, the only legitimate reason to give metformin to a horse is to treat insulin dysregulation and metabolic syndrome (proven with a glucose tolerance test, fasted blood sugar/insulin levels, etc) if diet change alone and other FDA approved medications are ineffective. That being said, metabolic dysregulation is extremely unlikely, if not unheard of, in young, fit thoroughbreds undergoing racehorse training. Therefore, there should be little reasoning to give metformin to a racehorse.
Lisa Laurzus, the media spokesperson for HISA, has gone on to say “We have intelligence that suggests that some trainers believe it is performance-enhancing, whether it is or it isn’t,” in a 2024 Paulick Report article after being questioned why metformin is a banned substance.
Despite the findings that metformin has the capacity to enhance athletic performance in prolonged sprints and improve muscle recovery, the World Anti-Doping Agency does not ban metformin for professional athletes. The reasoning for this is not clear.
Metformin Absorption in Horses
Hustace et al. (2009) has shown metformin is poorly absorbed in horses, meaning in order for there to be significantly high concentrations of metformin in the blood, the horse must be given high amounts of metformin in order to get the desired effects. In this study, horses were given 6,000mg of metformin orally with feed or without feed. The half-life of the drug is fairly fast, reducing its concentration in the blood in half about every 25 minutes. As estimated, only 7.1% of the 6,000mg of metformin given without feed was actually absorbed by the horse. When horses were given the drug orally with feed, only 3.9% was absorbed (this is extremely low. To compare, Flunixin, a common non-steroidal anti-inflammatory given to horses, when fed orally has an absorption rate of 86%, Equine Emergencies 2014). The peak concentration of metformin in the blood found was 0.4 ug/mL at almost an hour after the 6,000mg was administered, thereafter the concentration reduced by half about every 25 minutes (per its ‘half-life’). For those that are not familiar with pharmacology kinetics, that is an extremely low peak concentration after having given a horse 6,000mg of metformin.
Under HISA/HIWU, there is no threshold for metformin, for it is a banned substance. This means that metformin, unlike ‘controlled substances’, cannot be given to racehorses at any time and that if they test positive for any amount of metformin, it is a positive test and the trainer may be fined and/or suspended based on those findings.
This is where the controversy of environmental contamination comes into play. 1 in 12 people in the U.S. are prescribed metformin. Thus, it is very plausible a groom, trainer, or hotwalker is prescribed the medication. Conversely, metformin is very poorly absorbed by the horse with a very short half-life (meaning it is metabolized quickly). Furthermore, we have not seen as frequent positive drug tests in racehorses from other more commonly prescribed medications in the U.S. that are also ‘Banned Substances’ under HISA/HIWU. These substances include Lisinopril (88 million prescriptions between 2004-2021), Amlodipine (70 million), Losartan (55 million), and Hydrocodone (70 million). Lisinopril has a much higher bioavailability (absorption capacity) in horses compared to metformin (60-86% vs ~7.0%; Afonso et al. 2013). Amlodipine bioavailability has not been studied in horses, but in humans, dogs, cats, and rats, absorption rates range from 63-100% (Stopher et al. 1988). Losartan also has not been studied in horses, but in pigs and humans, absorption rates are about 33% (Rudy & Kostis 2005). Keep in mind that the equine digestive tract is not comparable to other species, but these substances may have the potential to have higher bioavailability to equines than metformin.
More research warranted
It is unknown what incriminating details HISA knows about these metformin cases that the general public does not know. Furthermore, more research on the contamination risks of metformin and other substances in racehorse stables is needed. In a study by Fenger et al. (2017), Metformin was found to contaminate two out of twenty one "ship in" horse stalls at Charles Town Racetrack that were swabbed for potential environmental contamination risks for racehorses. Brewer et al. (2024) further concludeds that the amount of Metformin contaminated in these stalls are "fully consistent with its occational identification at trace levels in racehorse blood and urine samples." This article, Brewer et al. (2024), performed an expert analysis on Metformin's risk of environmentally contaminating racehorses. The researchers reccomend a 'Screening Limit of Detection' of 5ng/ml in blood. Keep in mind, the racehorses that have tested positive for Metformin in the past year have been testing for levels ranging from 162-630 pg/ml in blood. A nanogram (ng) is equal to 1000 picograms (pg). The article goes on to mention reasonable possibilities for Metformin to be environmentally exposed to racehorses through human contact of those taking Metfomrin and possibly through tap water.
However, it is clear metformin may have acute performance enhancing effects for racehorses and may improve recovery post exercise. Although it may actually inhibit long term training gains in fitness if given frequently. Albeit, the study mentioned prior, Learis et al. (2015), found that when 500mg was administerd 1 hour before a high intensity exercise test to fatigue, time to fatigue was significnatly increased compared to a placebo. These male subjects were likely around 60kg (the study does not state), meaning the dose was likely around 8.3mg/kg of body weight. If we were to apply this to a 450kg thoroughbred, the equivalent dose would be 3,735mg. If we add in the factor of the very low bioavailability of about 7% on averags as listed by Hustace et al. (2009), to get the effects from that dosage (if the performance enhancing effects were similar in horses as it is humans as shown in Learis et al.), you would need to administer 53,357mg of metformin to said horse roughly 1 hour before post time. With that, the horse would most definitely test well over 5ng/ml (the recomended screening limit from Brewer et al. 2024) in post blood samples. This is where the side of a trainer delibrately giving metformin to a racehorse for acute performance enhancement becomes questionable.
Once again, more research is clearly needed before major regulatory decisions are made. Especially in regards to the absorption/metabolism of metformin in equines and whether or not it has the potential to be performance enhancing to young fit racehorses. Additionally, future research should entail what the post blood sample concentration level of metformin would test for if the minimum performance enhancing dose (if any) was given before exercise in young thorougbreds. However, this complex research may require much time and funding to perform.
Final Thoughts
I personally cannot conclude whether these horses that have tested positive for metformin were deliberately treated with the substance or were truly from environmental contamination. Both are plausible events. I am simply here to provide the facts from an exercise physiologist’s point of view that also has experience working within the horse racing industry.
References:
“Metformin improves performance in high-intensity exercise, but not anaerobic capacity in healthy male subjects” (Learsi et al. 2015)
https://pubmed.ncbi.nlm.nih.gov/26250859/#:~:text=Metformin%20improved%20performance%20and%20anaerobic,anaerobic%20capacity%20in%20healthy%20subjects.
“Chronic metformin intake improves anaerobic but not aerobic capacity in healthy rats” (Araujo et al. 2020)
“Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blinded, placebo-controlled, multicenter trial: The MASTERS Trial” (Walton et al. 2019)
“Effects of chronic metformin treatment on training adaptations in men and women with hyperglycemia: A prospective study” (Moreno-Cabenas et al. 2022)
“An update on mode of action of metformin in modulation of meta-inflammation and inflammaging” (Khodadadi et al. 2022)
“Metformin Regulates Glucose Transporter 4 (GLUT4) Translocation through AMP-activated Protein Kinase (AMPK)-mediated Cbl/CAP Signaling in 3T3-L1 Preadipocyte Cells*” (Lee et al. 2012)
https://www.jbc.org/article/S0021-9258(20)41650-3/pdf#:~:text=Metformin%20also%20ameliorates%20insulin%20resistance,role%20in%20cellular%20energy%20homeostasis.
“Muscle Glycogen Metabolism in Horses: Interactions between substrate availability, exercise performance, and carbohydrate administration” (Lecombe 2003)
“Pharmacokinetics and bioavailability of metformin in horses” (Hustace et al. 2009)
“Disposition and excretion of flunixin meglumine in horses” (Soma et al. 1988)
https://pubmed.ncbi.nlm.nih.gov/3247913/#:~:text=Flunixin%20meglumine%20was%20rapidly%20excreted,bound%20to%20protein%20in%20plasma.
“The effect of oral metformin on insulin sensitivity in insulin resistant ponies” (Tinworth et al. 2012)
“Effects of metformin hydrochloride on blood glucose and insulin responses to oral dextrose in horses” (Durham et al. 2013)
https://pubmed.ncbi.nlm.nih.gov/23600690/#:~:text=Reasons%20for%20performing%20study%3A%20Metformin,responses%20to%20oral%20carbohydrate%20ingestion.
“The effect of pre-dosing with metformin on the insulin response to oral sugar in insulin-dysregulated horses” (Colmer et al. 2023)
“Ergogenic properties of metformin in simulated high altitude” (Scalzo et al. 2017)
https://pubmed.ncbi.nlm.nih.gov/28394459/#:~:text=Metformin%20augments%20glucose%2Fglycogen%20regulation,glucose%2Fglycogen%20dependence%20is%20increased.
“Weight loss caused by common diabetes drug tied to ‘anti-hunger’ molecule in study” (Stanford Medicine)
“Keeping Pace: ‘More Drugs’ is never the right answer in Horse Racing” (Paulick Report 2024)
“Pharmacodynamic evaluation of 4 angiotensin-converting enzyme inhibitors in healthy adult horses” (Alfonso et al. 2013)
“The metabolism and pharmacokinetics of amlodipine in humans and animals” (Stopher et al. 1988)
“Losartan Potassium - an overview: Angiotensin II Receptor Antagonist” (Rudy & Kostis 2005)
Flunixin Overview - Bioavailability and Half-life: Equine Emergencies 2014
https://www.sciencedirect.com/topics/veterinary-science-and-veterinary-medicine/flunixin#:~:text=Flunixin%20is%20rapidly%20absorbed%20after,serum%20levels%20within%2030%20minutes.&text=Absorption%20is%20delayed%20by%20feeding.&text=The%20Vd%20is%200.1%20to,is%201%20to%202%20hours.
"Metformin as an environmental substance transfering to horses -- a case report and analysis" (Brewer et al. 2024)
"An In-Depth Look at Stall Contamination" (Fenger et al. 2017)
HIWU Controlled Substance List and Substance Thresholds in Blood and Urine:
HIWU Banned Substance List:
ARCI Banned Substance List: