Supplementation
Narrative Review
2014
Beta-hydroxy-beta-methylbutyrate (HMB) supplementation and resistance training
By Jacob M. Wilson and Ryan P. Lowery
Journal of the International Society of Sports Nutrition, 11(1), pp. 47
<h2>Abstract</h2>
<p>Beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of the essential amino acid <a href="/terms/leucine/" class="term-link" data-slug="leucine" title="leucine">leucine</a>, has been studied for its potential to reduce muscle protein breakdown and enhance resistance training adaptations. This review by Wilson and Lowery (2014) synthesized the available evidence on HMB supplementation in the context of resistance training, examining its effects on lean mass accretion, strength development, and muscle protein catabolism.</p>
<p>The review identified that HMB demonstrates its most robust effects in two specific populations: untrained individuals beginning resistance training, and trained individuals undergoing caloric restriction [1]. In untrained individuals, HMB supplementation consistently produced greater lean mass gains and strength improvements compared to placebo, likely by attenuating the elevated muscle protein breakdown that characterizes early-stage adaptation to novel training stimuli. In trained individuals under energy restriction, HMB's anti-catabolic properties appear to support lean mass preservation above what would be expected from protein intake alone [2].</p>
<p>The dose of 3g/day divided into three equal servings demonstrated the most consistent efficacy, with no significant additional benefit observed at higher doses. A free acid form (HMB-FA) showed superior bioavailability compared to the calcium salt form (HMB-Ca) in acute studies, though long-term outcome differences between the two forms were less clearly established [3].</p>
<p><strong>Keywords</strong>: HMB, beta-hydroxy-beta-methylbutyrate, leucine metabolite, muscle protein breakdown, anti-catabolic, resistance training, muscle mass</p>
<h2>Introduction</h2>
<p>Muscle protein turnover is a continuous and dynamic process in which muscle protein breakdown (MPB) and <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="muscle protein synthesis">muscle protein synthesis</a> (MPS) occur simultaneously. The net muscle protein balance — the difference between synthesis and breakdown — determines whether muscle mass is gained, maintained, or lost over time. While the extensive research focus on MPS stimulation through protein intake and resistance training is well established, the complementary role of reducing muscle protein breakdown has received comparatively less attention in sports nutrition [1].</p>
<p>Beta-hydroxy-beta-methylbutyrate (HMB) represents a biochemically interesting intervention point in this system. HMB is produced endogenously as a metabolite of <a href="/terms/leucine/" class="term-link" data-slug="leucine" title="leucine">leucine</a> transamination: following leucine deamination to alpha-ketoisocaproate (KIC), approximately 5% of KIC is converted to HMB in the mitochondria and cytoplasm. The remaining 95% undergoes alternative metabolic fates [2]. Given that only a small fraction of dietary leucine is converted to HMB, exogenous HMB supplementation provides levels of this metabolite that could not practically be achieved through dietary leucine alone.</p>
<p>The primary mechanisms by which HMB is proposed to reduce muscle protein catabolism include:
- <strong>Proteasome inhibition</strong>: HMB has been shown to inhibit the ubiquitin-proteasome pathway, the main intracellular protein degradation system, by reducing the expression of 26S proteasome components [3]
- <strong>Membrane integrity</strong>: HMB is a precursor for cholesterol synthesis and may enhance sarcolemmal membrane integrity, reducing exercise-induced membrane damage and the cellular stress response that activates catabolic pathways
- <strong><a href="/terms/mtor/" class="term-link" data-slug="mtor" title="mTOR">mTOR</a> activation</strong>: Some evidence suggests HMB activates mTORC1 signaling directly, potentially providing both anabolic and anti-catabolic effects</p>
<p>The research history of HMB is somewhat unusual in sports nutrition. Early studies published in the 1990s-2000s, largely by Steven Nissen's group at Iowa State University, reported dramatic effects — gains of several kilograms of lean mass and large strength improvements — that were substantially larger than those observed in subsequent independent replications [4]. This led to ongoing debates about the magnitude and robustness of HMB's effects that the review by Wilson and Lowery attempted to address through careful evidence synthesis.</p>
<h2>Evidence Review</h2>
<h3>Effects in Untrained Individuals</h3>
<p>The evidence for HMB supplementation is most consistent and impressive in individuals who are new to resistance training. Nissen et al.'s original trials in untrained men and women found that HMB supplementation (3g/day for 3-8 weeks) produced 1-1.5kg more lean mass gain than placebo over the training period, with corresponding improvements in <a href="/terms/one-repetition-maximum/" class="term-link" data-slug="one-repetition-maximum" title="1RM">1RM</a> strength [1].</p>
<p>Multiple independent replications confirmed the direction of this effect in untrained or lightly trained populations, though the magnitude was generally somewhat smaller than the original studies. The mechanistic rationale for greater HMB efficacy in untrained individuals is compelling: novel resistance training stimuli produce substantially greater muscle protein breakdown than equivalent training in adapted, experienced athletes. By specifically targeting MPB, HMB's anti-catabolic effects have greater absolute impact when MPB is elevated at baseline [2].</p>
<h3>Effects in Trained Individuals</h3>
<p>In experienced resistance-trained athletes, the evidence for HMB's effects on lean mass and strength is more mixed. Several well-controlled studies in trained athletes found no significant advantage of HMB over placebo for lean mass or strength when total protein intake was adequate, suggesting that the anti-catabolic benefit is smaller in magnitude when baseline muscle protein breakdown rates are more modest [3].</p>
<p>However, even trained athletes show clinically meaningful HMB effects in specific conditions:
- <strong>During <a href="/terms/overtraining/" class="term-link" data-slug="overtraining" title="overreaching">overreaching</a></strong>: When <a href="/terms/training-volume/" class="term-link" data-slug="training-volume" title="training volume">training volume</a> is deliberately high and recovery is incomplete, HMB may attenuate the excessive MPB that leads to non-functional overreaching and muscle mass loss
- <strong>During caloric restriction</strong>: Energy deficits independently elevate MPB; HMB's proteasome-inhibiting effects may partially counter this catabolic pressure even in trained athletes [4]
- <strong>Following periods of <a href="/terms/detraining/" class="term-link" data-slug="detraining" title="detraining">detraining</a></strong>: Returning to training after a break involves elevated <a href="/terms/muscle-damage/" class="term-link" data-slug="muscle-damage" title="muscle damage">muscle damage</a> and breakdown; HMB may accelerate the return to trained muscle protein balance</p>
<h3><a href="/terms/caloric-deficit/" class="term-link" data-slug="caloric-deficit" title="Caloric Deficit">Caloric Deficit</a> Applications</h3>
<p>Among the most robust and consistent evidence supporting HMB supplementation is its performance during hypocaloric conditions. Studies placing trained athletes in controlled caloric deficits found that HMB supplementation preserved more lean mass over the diet period compared to protein-matched placebo conditions [5].</p>
<p>The mechanism is straightforward: caloric restriction activates AMPK pathways that inhibit <a href="/terms/mtor/" class="term-link" data-slug="mtor" title="mTOR">mTOR</a> and activate FoxO transcription factors, increasing the expression of ubiquitin-proteasome components and promoting muscle atrophy. HMB's direct inhibition of the ubiquitin-proteasome pathway directly counteracts this caloric restriction-induced catabolism.</p>
<h3>HMB Forms: Calcium Salt vs. Free Acid</h3>
<p>HMB is available in two primary forms:</p>
<table>
<thead>
<tr>
<th>Form</th>
<th>Absorption Speed</th>
<th>Peak Plasma HMB</th>
<th>Practical Note</th>
</tr>
</thead>
<tbody>
<tr>
<td>HMB-Ca (calcium salt)</td>
<td>Slower (peak ~2h)</td>
<td>~100 μM</td>
<td>Most studied, powder/capsule</td>
</tr>
<tr>
<td>HMB-FA (free acid)</td>
<td>Rapid (peak ~30-60min)</td>
<td>~200-300 μM</td>
<td>Gel/liquid form, better for pre-workout</td>
</tr>
</tbody>
</table>
<p>Wilson et al.'s work specifically examining HMB-FA demonstrated more impressive acute performance effects compared to HMB-Ca, attributed to faster and higher plasma HMB concentrations. However, whether this pharmacokinetic advantage translates to meaningfully superior long-term outcomes remains an area of ongoing investigation [6].</p>
<h3>Dose Recommendations</h3>
<p>The 3g/day dose consistently demonstrates efficacy across studies. Mechanistic rationale: at approximately 3g/day, plasma HMB concentrations are sufficient to inhibit proteasome activity in muscle tissue. Higher doses (6g/day) have been studied but do not consistently provide additional benefit, suggesting a ceiling effect at or near the 3g threshold.</p>
<h2>Discussion</h2>
<h3>The Controversy: Reconciling Early and Later HMB Research</h3>
<p>HMB's research history is one of the more contentious in sports nutrition supplementation. Early studies by Nissen and colleagues reported effect sizes that, <a href="/terms/intermittent-fasting/" class="term-link" data-slug="intermittent-fasting" title="if">if</a> replicated, would make HMB one of the most powerful muscle-building supplements ever described — producing lean mass gains approaching those observed with anabolic steroids. Subsequent independent research typically found effects of considerably smaller magnitude, creating tension in the field [1].</p>
<p>Wilson and Lowery's review concluded that the truth likely lies between these extremes. The early studies had genuine methodological limitations (inadequate protein control in some cases, proprietary research funding), while some later studies used inadequate HMB doses, suboptimal forms, or insufficiently challenging training protocols that would not be expected to produce measurable anti-catabolic responses. The most carefully designed independent trials in appropriate populations (untrained subjects or trained subjects under caloric restriction) consistently show meaningful, if modest, HMB effects [2].</p>
<p>This reconciliation is important for appropriate expectation-setting: HMB is unlikely to produce the dramatic gains suggested by early research, but it is also not the ineffective supplement that some meta-analyses of poorly designed trials concluded. Its value is most apparent in conditions where muscle protein breakdown is elevated.</p>
<h3>HMB vs. <a href="/terms/leucine/" class="term-link" data-slug="leucine" title="Leucine">Leucine</a>: Complementary Mechanisms</h3>
<p>An important conceptual distinction separates HMB from leucine supplementation, even though HMB is derived from leucine. Leucine's primary ergogenic effect operates through <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="MPS">MPS</a> stimulation via <a href="/terms/mtor/" class="term-link" data-slug="mtor" title="mTORC1">mTORC1</a> activation. HMB's primary mechanism targets MPB inhibition through proteasome pathway suppression [3].</p>
<p>This means the two interventions are mechanistically complementary rather than redundant. Leucine maximally stimulates protein synthesis; HMB minimizes the simultaneous breakdown. In contexts where both synthesis is being optimized and breakdown is elevated (e.g., aggressive <a href="/terms/caloric-deficit/" class="term-link" data-slug="caloric-deficit" title="caloric deficit">caloric deficit</a> with resistance training), combining leucine-rich protein sources with HMB supplementation theoretically addresses both sides of the protein balance equation.</p>
<h3>Clinical Context: Muscle Wasting Conditions</h3>
<p>Perhaps the most compelling evidence for HMB efficacy comes from clinical populations experiencing pathological muscle wasting. Studies in elderly individuals with sarcopenia, cancer patients undergoing chemotherapy, and patients recovering from surgery or prolonged immobilization showed more consistent and impressive HMB effects than healthy athletic populations [4].</p>
<p>In these populations, protein breakdown rates are dramatically elevated due to disease-associated inflammation, cytokine activity, and metabolic derangements that HMB's proteasome-inhibiting effects can directly counteract. The magnitude of benefit in clinical muscle wasting is substantially larger than in healthy athletes, suggesting HMB's value scales with the degree of elevated protein breakdown [5].</p>
<h3>Cost-Effectiveness Consideration</h3>
<p>HMB is substantially more expensive per gram than leucine, despite being derived from leucine. When evaluating whether to include HMB in a supplementation stack, the cost-effectiveness calculation depends on which context applies:</p>
<ul>
<li>For untrained individuals or those in caloric deficits: HMB's specific anti-catabolic effect provides value that leucine supplementation or additional protein alone cannot fully replicate</li>
<li>For well-trained athletes in adequate caloric balance: the incremental benefit of HMB over optimizing total protein and leucine intake is likely small and may not justify the cost</li>
</ul>
<h2>Practical Recommendations</h2>
<h3>Who Should Consider HMB</h3>
<p>HMB supplementation is best justified in these specific circumstances:</p>
<table>
<thead>
<tr>
<th>Scenario</th>
<th>Expected Benefit</th>
<th>Priority</th>
</tr>
</thead>
<tbody>
<tr>
<td>First 6-12 months of resistance training</td>
<td>Moderate-large</td>
<td>High</td>
</tr>
<tr>
<td><a href="/terms/caloric-deficit/" class="term-link" data-slug="caloric-deficit" title="Caloric deficit">Caloric deficit</a> (cutting phase)</td>
<td>Moderate</td>
<td>High</td>
</tr>
<tr>
<td>Very high <a href="/terms/training-volume/" class="term-link" data-slug="training-volume" title="training volume">training volume</a> (<a href="/terms/overtraining/" class="term-link" data-slug="overtraining" title="overreaching">overreaching</a>)</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
<tr>
<td>Return to training after break</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
<tr>
<td>Well-trained athletes, adequate calories</td>
<td>Small</td>
<td>Low</td>
</tr>
<tr>
<td>Clinical muscle wasting conditions</td>
<td>Large</td>
<td>High (medical supervision)</td>
</tr>
</tbody>
</table>
<h3>Dosing Protocol</h3>
<ul>
<li><strong>Standard dose</strong>: 3g/day, divided into 3 equal doses of 1g each</li>
<li><strong>Timing</strong>: Distribute with meals or snacks — this maintains more stable plasma HMB levels throughout the day compared to single large doses</li>
<li><strong>Form considerations</strong>:</li>
<li>HMB-Ca (calcium salt powder/capsule): Standard form, slightly slower absorption; effective for regular daily use</li>
<li>HMB-FA (free acid gel): More expensive, faster absorption; may be preferable as a pre-exercise dose <a href="/terms/intermittent-fasting/" class="term-link" data-slug="intermittent-fasting" title="if">if</a> rapid peak plasma concentration is prioritized</li>
</ul>
<p><strong>Pre-exercise optimization</strong>:
- HMB-Ca: Take 2-3 hours before exercise
- HMB-FA: Take 30-60 minutes before exercise (faster absorption allows shorter pre-exercise window)</p>
<h3>Combining HMB with Other Supplements</h3>
<p>HMB's anti-catabolic mechanism is complementary to <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="muscle protein synthesis">muscle protein synthesis</a>-promoting interventions:</p>
<ul>
<li><strong><a href="/terms/creatine-monohydrate/" class="term-link" data-slug="creatine-monohydrate" title="Creatine">Creatine</a> + HMB</strong>: Some studies report synergistic effects on lean mass and strength in untrained individuals. Creatine supports phosphagen-based MPS stimulation; HMB reduces MPB. Combination may optimize both aspects of the muscle protein balance equation [1]</li>
<li><strong>High-quality protein</strong>: HMB works alongside, not instead of, optimal protein intake. Ensure <a href="/terms/leucine/" class="term-link" data-slug="leucine" title="leucine">leucine</a>-rich protein (1.6-2.2g/kg/day) remains the foundation, with HMB supplementing (not replacing) this base</li>
<li><strong><a href="/terms/vitamin-d/" class="term-link" data-slug="vitamin-d" title="Vitamin D">Vitamin D</a></strong>: HMB and vitamin D have complementary mechanisms for muscle protein metabolism in older adults, with some evidence of additive benefits</li>
</ul>
<h3>Practical Cutting Phase Protocol</h3>
<p>During a caloric deficit aiming to preserve lean mass:</p>
<ol>
<li><strong>Protein</strong>: 2.0-2.6g/kg/day distributed across 4-5 meals of 25-40g protein each</li>
<li><strong>HMB</strong>: 1g with each of 3 daily protein meals (morning, midday, evening)</li>
<li><strong>Training</strong>: Maintain or minimize reduction in resistance <a href="/terms/training-frequency/" class="term-link" data-slug="training-frequency" title="training frequency">training frequency</a> and volume</li>
<li><strong>Caloric deficit</strong>: Keep deficit at 300-500 kcal/day to avoid excessive catabolic stimulus</li>
</ol>
<h3>Realistic Expectations</h3>
<ul>
<li>HMB is not a "mass builder" in the way creatine is perceived to be</li>
<li>Its value is primarily anti-catabolic: reducing muscle mass loss rather than dramatically accelerating muscle mass gain</li>
<li>In a caloric deficit, HMB might help preserve an additional 0.5-1kg of lean mass over a 12-week cutting phase compared to protein intake alone — a meaningful but not dramatic effect</li>
<li>In untrained individuals beginning resistance training, HMB may accelerate initial lean mass development by approximately 1-2kg over 8-12 weeks compared to placebo</li>
</ul>
<h3>Safety and Tolerability</h3>
<p>HMB has an excellent safety profile with no significant adverse effects reported at 3g/day. Mild gastrointestinal symptoms have been reported in some individuals; dividing the dose into three equal servings minimizes this. No interactions with common supplements or medications have been identified [2].</p>