Is Licorice Illegal?

Summary:

• Neither licorice, glycyrrhizin nor eugenol is currently listed as a banned substance by FEI or USEF.
• The eugenol content in most licorice-containing supplements, including SynAir is negligible; for physiologic effect, and also for drug testing.
• SynAir is formulated to help promote lower airway health in equine athletes, positively contributing to their health and quality of life.

Discussion:

The USEF published an article written by Glenye Oakford on December 26, 2017 entitled, Know Your Treats: Some Natural Ingredients Can Cause Accidental Drug Positives.  While I believe the general concept of the article is benevolent, it appears some of the information is a bit misguided.

For example, eugenol is listed as a compound contained in numerous plant-based ingredients, including licorice.  This is factually true.  However, at the time of this writing, it is not on the banned substance list.  Now, as a natural analgesic, eugenol certainly has the potential for misuse.  This fact is not in question.  The question is: Does licorice contain enough eugenol to elicit a physiologic response and/or result in a “positive test” at normal serving sizes? The short answer is not likely.

Offered here is some clarification when it comes to the use of licorice in dietary supplements and treats for horses.  Licorice has numerous potential health benefits due to its primary bioactive compound, glycyrrhizin.  The amount of eugenol in dried ground licorice root is approximately 1 part per million (1ppm or 1mg/Kg).

SynAir contains 1.5 g of licorice per serving.  This translates to approximately 1.5 micrograms of eugenol per serving, an insignificant amount. Animal studies have used from 2-100 mg/Kg, which translates to 900-45,00 mg or 600,000-30,000,000 times the amount in one serving of SynAir.

Furthermore, studies involving detectable eugenol in animals involve at least 10 mg/Kg, over 3 million times the amount in one serving of SynAir.  The actual amount of eugenol in a horse’s urine sample 2-6 hours after a serving of SynAir can be estimated at 10 ng/L2.  That’s 10 parts per TRILLION; likely well below any diagnostic laboratory threshold.

With all that stated, let’s get to the real issue.  SynAir is formulated to promote lower airway health in horses stressed by intense exercise, a serious health concern for equine athletes and their owners.  SynNutra Equine believes SynAir helps support lower airway health.

Let’s not get to the point in this industry where the health benefits of quality supplements and medications are outweighed by insignificant and virtually non-existent effects of questionable compounds that if present at all, are certainly at levels too low to matter.

1. Raja et al., Pharm Anal Acta 2015, 6:5  DOI: 10.4172/2153-2435.1000367)

2. For those interested: Calculation of Urinary Concentration of Eugenol

Parameters and Assumptions

1. Volume of Distribution (Vd):
Eugenol has an estimated Vd of 2–3 L/kg in mammals. For a 454 kg horse: Vd=2 L/kg×454 kg=908 LVd = 2 \, \text{L/kg} \times 454 \, \text{kg} = 908 \, \text{L}Vd=2L/kg×454kg=908L
2.  Initial Plasma Concentration (C₀):
The initial plasma concentration can be estimated as: C0=DoseVdC₀ = \frac{\text{Dose}}{\text{Vd}}C0​=VdDose​ C0=1.5 μg908 L=0.00165 μg/LC₀ = \frac{1.5 \, \mu g}{908 \, \text{L}} = 0.00165 \, \mu g/\text{L}C0​=908L1.5μg​=0.00165μg/L
3.  Liver Metabolism (Clearance):
Eugenol is rapidly metabolized, with a half-life in mammals of approximately 2–3 hours. Assuming first-order kinetics: Ct=C0×e−ktC_t = C₀ \times e^ {-kt} Ct​=C0​×e−kt Where k=ln⁡2t1/2k = \frac{\ln 2} {t_ {1/2}} k=t1/2​ln2. For t1/2=2.5 hours_{1/2} = 2.5 \, \text{hours}t1/2​=2.5hours: k=ln⁡22.5 hours=0.277 hr−1k = \frac{\ln 2}{2.5 \, \text{hours}} = 0.277 \, \text{hr.}^{-1}k=2.5hoursln2​=0.277hr−1
4.  Urinary Excretion:
Approximately 5–10% of the eugenol dose is excreted unchanged in the urine, with the remainder excreted as metabolites.
Urine production in horses is about 3–5 ml/kg/hour. For a 454 kg horse: Urine Flow Rate=454 kg×4 ml/kg/hour=1.82 L/hour\text{Urine Flow Rate} = 454 \, \text{kg} \times 4 \, \text{ml/kg/hour} = 1.82 \, \text{L/hour}Urine Flow Rate=454kg×4ml/kg/hour=1.82L/hour

Eugenol Plasma Concentration Over Time

Using the equation Ct=C0×e−ktC_t = C₀ \times e^ {-kt} Ct​=C0​×e−kt, calculate plasma concentrations at 2, 4, and 6 hours post-consumption:

Ct(2 hours)=0.00165 μg/L×e−0.277×2=0.00111 μg/LC_t (2 \, \text{hours}) = 0.00165 \, \mu g/\text{L} \times e^{-0.277 \times 2} = 0.00111 \, \mu g/\text{L}Ct​(2hours)=0.00165μg/L×e−0.277×2=0.00111μg/L Ct(4 hours)=0.00165 μg/L×e−0.277×4=0.00075 μg/LC_t (4 \, \text{hours}) = 0.00165 \, \mu g/\text{L} \times e^{-0.277 \times 4} = 0.00075 \, \mu g/\text{L}Ct​(4hours)=0.00165μg/L×e−0.277×4=0.00075μg/L Ct(6 hours)=0.00165 μg/L×e−0.277×6=0.00050 μg/LC_t (6 \, \text{hours}) = 0.00165 \, \mu g/\text{L} \times e^{-0.277 \times 6} = 0.00050 \, \mu g/\text{L}Ct​(6hours)=0.00165μg/L×e−0.277×6=0.00050μg/L

Eugenol Urinary Excretion

Assume 7.5% of the dose is excreted unchanged. The excreted eugenol over 6 hours is:

Excreted Dose=1.5 μg×0.075=0.1125 μg\text{Excreted Dose} = 1.5 \, \mu g \times 0.075 = 0.1125 \, \mu gExcreted Dose=1.5μg×0.075=0.1125μg

The urine volume over 6 hours:

Urine Volume=1.82 L/hour×6 hours=10.92 L\text {Urine Volume} = 1.82 \, \text{L/hour} \times 6 \, \text{hours} = 10.92 \, \text{L}Urine Volume=1.82L/hour×6hours=10.92L

The average urine concentration of eugenol:

Urine Concentration=Excreted DoseUrine Volume=0.1125 μg10.92 L=0.0103 μg/L\text {Urine Concentration} = \frac{\text{Excreted Dose}} {\text{Urine Volume}} = \frac{0.1125 \, \mu g}{10.92 \, \text{L}} = 0.0103 \, \mu g/\text{L}Urine Concentration=Urine VolumeExcreted Dose​=10.92L0.1125μg​=0.0103μg/L