Do muscle-building supplements beyond protein and creatine actually work? The HMB test case

Protein and creatine have the deepest, most consistent evidence base of any muscle-building supplements — which is exactly why the rest of the supplement aisle works so hard to convince you that you need something more. β-hydroxy-β-methylbutyrate, or HMB, is one of the most heavily marketed examples: a metabolite of leucine (one of the amino acids most responsible for triggering muscle protein synthesis) sold on the promise that it adds muscle and strength beyond what training and protein alone deliver. A 2020 systematic review and meta-analysis in Nutrients, led by muscle-protein researcher Stuart Phillips, tested that promise directly.

What the meta-analysis actually found

Pooling 11 studies and 302 participants aged 18–45 doing structured resistance-exercise training, the researchers found a significant effect of HMB supplementation on one outcome only: total body mass. Critically, that small increase in total body mass did not translate into significantly greater gains in fat-free (lean) mass, strength, or reductions in fat mass — the actual outcomes anyone buying the supplement cares about.

HMB produces a small effect on total body mass gain, but this effect does not translate into significantly greater increases in fat-free mass, strength or decreases in fat mass during periods of resistance exercise training. Our findings do not support the use of HMB aiming at improvement of body composition or strength with resistance exercise training.

Why a supplement can gain traction despite weak evidence

HMB is a useful case study precisely because its mechanism sounds plausible — it genuinely is a byproduct of leucine, which genuinely is involved in triggering muscle-building signalling — and early, smaller studies did show some promising individual results, which is often enough to build a marketing narrative around. What changes the picture is pooling all the higher-quality data together: the apparent early signal did not hold up as a genuine driver of fat-free mass or strength once a larger, better-controlled dataset was analyzed. This pattern — a plausible mechanism, some early positive individual studies, and a null result once properly meta-analyzed — recurs across much of the non-essential supplement market.

What this means for your supplement stack

This isn’t an argument that every supplement beyond protein and creatine is worthless — it’s a case study in why claims deserve scrutiny before they earn a spot in your routine and your budget. The honest hierarchy the current evidence supports: hitting your protein target and total training volume are the foundational levers; creatine monohydrate has the next-strongest, most consistent evidence for a genuine (if modest) strength and power benefit; and most of what fills the rest of the supplement aisle, HMB included, has either weak, mixed, or null evidence once rigorously tested.

The practical takeaway

Before adding a new supplement, ask whether it has actually been tested against a real, well-controlled comparison group — not just whether the mechanism sounds convincing. Money and attention spent chasing a marginal or non-existent supplement effect is money and attention not spent on the levers with real evidence behind them: protein intake, training volume, sleep and consistency.

This is why Misi’s nutrition targets prioritise your protein floor and total training volume as the levers the app actively tracks and coaches, rather than recommending an ever-growing supplement stack — and why our supplement guidance defaults to the small list (protein, creatine, vitamin D where relevant) with genuinely consistent evidence behind it.

Misi is a coaching and wellness platform, not a medical service, and this article is educational and not a substitute for personalised medical or nutritional advice. Always check new supplements against your medications and health conditions with a doctor or pharmacist.