Fact Check: The Pharmacology Of Betamethasone In Horses

It's clear that the battle over the outcome of the 2021 Kentucky Derby is likely to wage on for years to come. The Kentucky Horse Racing Commission (KHRC) has yet to make a ruling, but preliminary and split sample tests on winner Medina Spirit both came back positive for betamethasone in violation of Kentucky rules. Attorneys for Medina Spirit trainer Bob Baffert and owner Zedan Stables have been vocal about their feelings that the finding in the horse shouldn't matter for a variety of reasons — they say the administration of the drug to the horse came from a topical and not an injectable, they claim that post-race drug testing is designed to find therapeutic drugs at an unreasonably small concentrations, and they claim that the concentration found in Medina Spirit had no appreciable impact on the outcome of the race.Further, Baffert attorney Craig Robertson said in a CNN interview June 3, a small amount of betamethasone detected in blood couldn't even be having an appreciable impact on the horse's body.
“Just because that's the rule doesn't mean that it's a proper rule,” Robertson said to anchors John Berman and Brianna Keilar on New Day. “And the reason why it's not a proper rule is that at that level, there would be zero pharmacology in a horse – zero – and it would have had no effect on this race. And one thing that you haven't heard, and you will not ever hear, is an equine pharmacologist to come out and say that 21 picograms, 25 picograms would have any pharmacology in a horse. They're not going to say that, because they can't say that.”
But the research – what little peer-reviewed research exists on betamethasone in horses — doesn't support that.
It's difficult to know what concentration of a drug in a horse does or doesn't influence a race; that's a separate question altogether, but there have been two peer-reviewed studies published in recent years which suggest that even small amounts of betamethasone in the blood may indeed reflect some effect on a horse's body.
A study published in the Journal of Veterinary Pharmacology and Therapeutics in 2015 sought to learn more about the pharmacology of intra-articular betamethasone injections in horses. Researchers administered two intra-articular betamethasone to eight 4-year-old Thoroughbreds and exercised them, then took blood and urine samples to check on levels of betamethasone and hydrocortisone for six weeks.
They found that the administration of betamethasone coincided with a reduced production by the horses' bodies of hydrocortisone. Hydrocortisone is naturally produced by the horse's body and acts similarly to its fellow corticosteroid betamethasone. There are synthetic versions of hydrocortisone out there in therapeutic medications, too.
It's thought that circulating levels of a closely-related, administered drug are read by the horse's brain similarly to the endogenously-produced substance, and the brain will halt production of its own corticosteroid until the synthetic corticosteroid wanes. The study found that the suppression of hydrocortisone was present for 96 to 120 hours after the administration of betamethasone.
The study found the last detectable level of betamethasone in plasma at an average of 64 hours post-injection and 69 hours in urine, although those measurements were using .05 nanograms per milliliter (or 50 picograms per mL) of plasma and .25 nanograms per milliliter (or 250 picograms per mL) of urine as their limit of detection – much larger concentrations than what was detected in the Medina Spirit case.
More interestingly though, in 2017 the journal Drug Testing and Analysis published a study which examined the concentrations of betamethasone in blood, urine, and joint fluid in Thoroughbreds. That study found that when betamethasone was injected in a horse's joint, concentrations of the drug in fell below detectable levels much sooner in plasma (96 hours) and urine (seven days) than it did in joint fluid. It took between 14 and 21 days for the drug to disappear from joint fluid in the joint that received the treatment.
“One of the basic tenants of pharmacokinetic/pharmacodynamic analysis is that blood levels reflect drug concentrations at the site of pharmacologic effect, thereby allowing the extent and duration of effect to be estimated based on blood concentrations,” wrote the study authors, led by Dr. Heather Kynch. “However, this does not appear to be the case for intra-articular corticosteroids.”
The study's findings were not wholly surprising, given that corticosteroids generally are known to be a little fickle in their withdrawal times. One previous study found triamcinolone in joint fluid for 35 days after a joint injection, and another found methylprednisolone 77 days after a single intra-articular dose.
Knych's study also noted that the diffusion of drugs from joints may vary from one joint to another.
“Although more comprehensive pharmacodynamic studies are necessary, these findings suggest that the anti-inflammatory effects may continue even though drug is no longer detected in blood,” wrote the Knych team. “A major concern with this finding is that horses may be able to return to racing before they are completely healed following an injury. Even though blood concentrations would be below the recommended threshold, allowing the horse to race, therapeutic drug concentrations in the joint may mask the clinical signs of an injury that is not completely healed. This could ultimately increase the risk of additional damage to the joint.”
At the time Knych and her team performed that study, the Racing Medication and Testing Consortium (RMTC) recommended a seven-day withdrawal of corticosteroids to clear a regulatory threshold of 10 picograms per mL. In the intervening years, jurisdictions like California and Kentucky backed up their corticosteroid administration timeframes to coincide with additional layers of pre-race veterinary checks performed to improve safety after the Santa Anita fatalities. In Kentucky, any level of corticosteroids like betamethasone in a post-race sample is a violation, based on the belief that the drug now can't be found farther out than 14 days post-administration.
Perhaps incredibly, those two studies seem to be the bulk of the peer-reviewed, published research that has been done on the behavior of betamethasone in a horse's body. It's not uncommon for research into equine medications to be limited, even for commonly-used therapeutic drugs like betamethasone.
Baffert's view on the Medina Spirit case would likely dismiss both studies as irrelevant. He asserts he gave the drug via a topical cream to treat a skin condition, not a joint injection, as was done in both studies. Further testing of the blood and urine from Medina Spirit will seek to clarify whether the betamethasone found in the horse came from an injection or an ointment, and it seems that will be an ongoing point of debate for his legal team. But with the limited peer-reviewed research available, the suggestion that the drug doesn't have any pharmacological effect at low levels of detection in blood is going to be an uphill battle.