If you constructed a “Mount Rushmore” of dietary supplements, just about everybody would put creatine and caffeine on the side of that mountain. They are well-studied, effective, and safe when dosed appropriately. Naturally, it would make sense that the avid lifter would reap the rewards from both of them, and the majority of pre-workout supplements are formulated accordingly. But do they actually work when combined together?

Unfortunately, the answer to that question is a bit complicated. In 1996, Vandenberghe et al. [1] hypothesized that providing caffeine daily with creatine would make the creatine even more effective, by enhancing muscle uptake. To investigate this hypothesis, they carried out a study to evaluate the effects of daily caffeine supplementation on creatine uptake and leg extension performance. Contrary to their expectations, they found that caffeine had no effect on muscle creatine uptake. However, the far more interesting finding was that despite ample creatine uptake in both groups, the creatine only improved muscular endurance in the group receiving creatine without caffeine. The group receiving caffeine with their creatine had plenty of creatine in their muscles, but their performance was not improved by it.

This finding was quite unexpected, but the group followed up to determine how caffeine appeared to be blocking the performance benefits of creatine. They hypothesized that the answer related to calcium handling in the sarcoplasmic reticulum (SR). Without getting overly technical, calcium release from the SR is absolutely crucial for allowing muscles to contract and create force. For optimal muscle function, the SR must release sufficient calcium when the muscle is instructed to contract, and the SR must quickly regather the calcium so it can release it again as soon as possible. If something were to inhibit calcium release from the SR, or reduce the speed at which the SR regathers calcium, it would likely have negative effects on muscle function.

In their follow up study [2], this lab group found that creatine decreased muscle relaxation time, likely by enhancing calcium reuptake in the SR; this is a favorable adaptation that would theoretically contribute to improved exercise performance. In contrast, daily caffeine supplementation alone increased relaxation time, which is unfavorable, whereas the daily combination of creatine and caffeine had no effect on relaxation time. So, the researchers actually identified a viable mechanism by which frequent caffeine supplementation may counteract the performance effects of creatine.

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