Bridging the Gap: Why Promising Lab Results for Alcohol Treatment Sometimes Fail in Humans

We are constantly searching for new ways to treat alcohol use disorder (AUD), a condition that affects millions of people and leads to significant health and economic costs. Recently, a type of drug called a PPAR-alpha agonist showed great promise in animal studies, significantly reducing alcohol consumption in mice and rats. In our latest research, we performed a "reverse translational" study to understand why these exciting results didn't carry over to humans in a clinical setting.

The Big Question

In collaboration with multiple labs, we wanted to know if fenofibrate, an FDA approved drug typically used to treat high cholesterol, could reduce alcohol craving and drinking in humans with AUD. When the human trial did not show the expected benefits, we asked a follow up question: Was the failure due to a lack of effectiveness in the drug itself, or was it because the dose humans can safely take is simply too low to reach the brain?

Exploring the "Dose Gap"

To find out, we conducted a study with two parts. First, we gave 50 volunteers with AUD either fenofibrate or a placebo for nine days. We then tested their craving levels by exposing them to alcohol related cues in the lab. Second, we went back to the lab to perform a "reverse translation". We tested rats and mice using the exact same doses that were given to the human volunteers, adjusted for their smaller body size.

What We Discovered

Our findings revealed a critical mismatch between laboratory models and human reality:

• No Effect in Humans: In our clinical trial, fenofibrate did not reduce alcohol craving or the amount of alcohol consumed compared to the placebo.

• The Problem with the Dose: When we tested the "human equivalent" dose in rodents, the drug also failed to work.

• A Matter of Brain Access: We realized that previous animal studies used doses more than five times higher than what is safely allowed in humans. Because fenofibrate has poor "brain penetrance"—meaning it is hard for the drug to get from the blood into the brain—the safe human dose was simply too weak to activate the necessary pathways.

  
  

Why This Matters

This research is a vital lesson in drug development. It proves that we cannot always assume a drug will work in humans just because it works in animals at very high doses.

We believe these results are actually a step forward. They show that PPAR-alpha agonists might still be a powerful tool for treating addiction, but we need to develop new, "brain penetrant" versions of these drugs that can reach the brain more effectively at safe doses. By closing this "dose gap," we can move closer to creating personalized, effective treatments that help people reclaim their lives from alcohol addiction.

Reference: Mason, B. J., Estey, D., Roberts, A., de Guglielmo, G., George, O., Light, J., Stoolmiller, M., Quello, S., Skinner, M., Shadan, F., Begovic, A., Kyle, M. C., & Harris, R. A. (2024). A reverse translational study of PPAR-α agonist efficacy in human and rodent models relevant to alcohol use disorder. Neurobiology of Stress, 29, 100604. https://doi.org/10.1016/j.ynstr.2023.100604