Pharmacokinetic Modelling Article Review

Shannon Wilkens

Chemist specializing in Cannabis

Abstract

 

In August 2023, a study by Eichler et al. that examined the amount of time cannabidiol (CBD) and its metabolites remained detectable in horses’ systems after consumption was published in Frontiers in Veterinary Science.1 The study was broken into two parts. The first part determined how long it took for CBD and metabolite levels to taper off and reach equilibrium after horses were given a single fixed dose of CBD; this was performed with three different dosages. The results showed that CBD levels reached their peak within the first hour after administration, and CBD and its metabolites were still detectable after 12 hours. The second part of the study looked at retention times for CBD and its metabolites in serum and urine when horses were given the maximum dose of CBD twice a day for 15 days. CBD and its metabolites reached a pseudo-equilibrium between 2.5 and 15 days following the last CBD administration, and they remained detectable at low levels in serum and urine 30 days following the last CBD administration. CBD and similar compounds are highly soluble in fat and are retained in fatty tissues for an extended amount of time, which can be highly beneficial for therapeutic effects. The results of this study indicated retention of CBD in fatty tissues and an extended CBD metabolism. This important study was done under veterinarian supervision and showed that, regardless of the dose of CBD administered, all horses had kidney and liver biomarkers and complete blood counts within normal reference ranges throughout the study. 

Currently, limited information exists regarding the amount of time cannabidiol (CBD) and its metabolites remain in a horse’s system after consumption. Studies using rodent, canine, and human models have emerged, and these studies have been useful for providing some preliminary insight.2-7 However, they do not give information specific to horse metabolism. Horse owners are notorious for their diligence when it comes to their horses’ health and nutrition. With rigorous testing standards for horses in competition circuits, owners must be extremely careful about what compounds their horses ingest and how long those compounds remain detectable. In August 2023, a well-designed and insightful study about the pharmacokinetics of CBD specifically in horses was published by Eichler et al. in Frontiers in Veterinary Science and included collaborators from renowned research institutions in Germany and Poland.1 This research not only provides a guide for horse owners looking to understand CBD metabolism time and retention in tissues but also gives regulatory bodies and testing labs guidance on best practices and methodology for determining presence and amount of CBD and its metabolites in serum and urine. 

This study monitored the concentration and distribution of CBD in horses after it was administered and then looked at how long CBD and its metabolites remained detectable in their systems. While it did not give a definitive answer to the question of how much time exactly it takes for CBD and its metabolites to clear the system, it provided valuable insight for figuring out dosing and for determining when to stop administering CBD for those competing.

 

Experiments: 

There were 6 horses involved in this study – three mares and three stallions. They ranged in age from 3 to 16 years (median=11 years), and the mean body weight was 488 ± 55 kg. The maximum amount of CBD administered in the study was 3 mg/kg. For an 1100 lb. horse, that translates to a dose of approximately 1500 mg.

 

The study was broken into two parts. Both parts used standardized formulations of a CBD paste that was given orally. The first part looked tracked the CBD and metabolite levels in serum and urine at fixed intervals after a single administration of a fixed dose. This experiment was performed three times with three different dosages, allowing a week in between each administration to ensure proper baseline levels. The second part examined the retention times for CBD and its metabolites when horses were given the maximum dose of CBD paste twice a day for 15 days. 

 

Results:

The first part of this study showed that, regardless of dose, CBD and its metabolites were still detectable in both serum and urine 12 hours after administration. There was an initial spike in concentrations in serum within the first hour of administration, and then the concentrations leveled off after approximately 4 hours after administration.

 

The second part of the study showed that the terminal half-life of for CBD was approximately between 5 and 8.5 days, and terminal half-life for its major metabolite was approximately between 2.5 and 4 days. “Terminal half-life” is a term used in pharmacology to show how much time it takes for the amount of a certain substance in serum (blood testing) to be divided in half once the levels in the blood reach a type of steady state called pseudo-equilibrium. It is NOT the amount of time for the body to eliminate half of the substance administered. Further, the terminal half-life cannot be multiplied by two to determine the total amount of time it takes for the body to eliminate all of a substance (i.e. we cannot say for sure that all of the CBD ingested will be eliminated from the body between 10 and 17 days). Hopefully we will see further studies done to determine how long CBD and its metabolites remain in horses’ bodies before they become undetectable.

 

Discussion:

The first part of the study was valuable for determining how long after administration horses’ bodies reach peak levels of CBD. People often ask about when the best time is to administer CBD to their horse prior to going into a potentially stressful situation, e.g., performances or travel. This model showed that administering CBD approximately one hour before a horse goes into stressful situation is ideal to ensure maximum calming effects. This part of the study also showed that, while the levels of CBD and its metabolites spike and then taper off, the compounds stay in the horses’ system at an equilibrium level for at least 12 hours after administration.

The second part of the study was insightful for narrowing in on about how long horses’ bodies retain CBD in their systems when they are given regular doses over an extended period of time. The data shows that CBD and its metabolites take a moderate amount of time to diminish from both serum and urine. CBD and compounds like it are highly fat-soluble. These types of compounds take longer to clear the body system than water-soluble compounds. This study suggests that CBD and its metabolites get stored in fat and fatty tissues and are slowly metabolized over time, which is highly beneficial for maintaining therapeutic effects.

While the weights of the horses was considered in this study, it showed no statistically significant impact on the results.

Important to note is that the CBD used in this study was administered orally as a paste to ensure a standardized method of administration and to eliminate variability in digestion, absorption, and metabolism resulting from different formulations. Alternate forms of administration (e.g. oromucosally as an oil) would likely impact the amount of time it takes for CBD levels to reach their peak and could also affect the retention times of CBD and its metabolites in horses’ tissues. 

In both parts of the study, all horses were closely monitored by veterinarians, and complete blood count as well as kidney and liver biomarkers were analyzed for each horse throughout both parts of the study. This testing was in addition to the monitoring of CBD and its metabolites in serum and urine. An important finding was that these biomarker levels generally remained within a typical range for all horses regardless of the dose administered. There were also no negative side effects or abnormalities observed for any of the horses.

The Fédération Équestre Internationale (FEI) lists CBD as a Specified Substance on its list of 2023 Prohibited Substances.8 This means that it is considered to be a compound that is likely to have been ingested for purposes other than enhancement of sport performance. While the World Anti-Doping Agency (WADA) lists cannabinoids as prohibited substances in competition, it excludes CBD from this list.9 FEI lists detection times and quantifiable limits for many banned substances, but this list does not contain information for CBD or other cannabinoids.10 More research like the study by Eichler et al. will hopefully help provide methods for determining these values in the future.

 

References:
  1. Eichler, F.; Błażej Poźniak; Machnik, M.; Schenk, I.; Wingender, A.; Baudisch, N.; Thevis, M.; Wolfgang Bäumer; Lischer, C.; Ehrle, A. Pharmacokinetic Modelling of Orally Administered Cannabidiol and Implications for Medication Control in Horses. Frontiers in Veterinary Science 202310. https://doi.org/10.3389/fvets.2023.1234551.
  2. Abbotts, K.S.S.; Ewell, T.R.; Butterklee, H.M.; Bomar, M.C.; Akagi, N.; Dooley, G.P.; Bell, C. Cannabidiol and Cannabidiol Metabolites: Pharmacokinetics, Interaction with Food, and Influence on Liver Function. Nutrients 202214, 2152. https://doi.org/10.3390/nu14102152
  3. Bartner, LR , McGrath, S , Rao, S , Hyatt, LK , and Wittenburg, LA . Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. Can J Vet Res. (2018) 82:178–83.
  4. Gamble, L-J , Boesch, JM , Frye, CW , Schwark, WS , Mann, S , Wolfe, L, et al. Pharmacokinetics, safety, and clinical efficacy of cannabidiol treatment in osteoarthritic dogs. Front Vet Sci. (2018) 5:165. doi: 10.3389/fvets.2018.00165
  5. Millar, S. A.; Stone, N. L.; Yates, A. S.; O’Sullivan, S. E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Frontiers in Pharmacology 20189. https://doi.org/10.3389/fphar.2018.01365.
  6. Vaughn, DM , Paulionis, LJ , and Kulpa, JE . Randomized, placebo-controlled, 28-day safety and pharmacokinetics evaluation of repeated oral cannabidiol administration in healthy dogs. Am J Vet Res. (2021) 82:405–16. doi: 10.2460/ajvr.82.5.405
  7. Xu, C.; Chang, T.; Du, Y.; Yu, C.; Tan, X.; Li, X. Pharmacokinetics of Oral and Intravenous Cannabidiol and Its Antidepressant-like Effects in Chronic Mild Stress Mouse Model. Environmental Toxicology and Pharmacology 201970, 103202. https://doi.org/10.1016/j.etap.2019.103202.
  8. 2023 Equine Prohibited Substances List. https://inside.fei.org/sites/default/files/2023%20Prohibited%20Substances%20List.pdf.
  9. WADA. The Prohibited List. World Anti-Doping Agency. https://www.wada-ama.org/en/prohibited-list
  10. FEI LIST of DETECTION TIMES. https://inside.fei.org/system/files/FEI%20Detection%20Times%202022.pdf.

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About the author

 

Shannon holds a B.S. in Chemistry from Loyola University Chicago and began her journey in cannabis chemistry in 2018. Passionate about cannabis science, she developed protocols for in-house testing, established cannabis testing and research labs across the USA, and trained future chemists.

At Brave Horse, Shannon serves as a chemist, ensuring product quality and championing the benefits of cannabis through chemistry education. Outside of work, she cherishes moments with her family and her playful boxer, Chance.

If you have any burning questions, she loves to answer anything chemistry-related!

 

Shannon Wilkens

Chemist specializing in Cannabis

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