Rhodiola rosea and caffeine may provide synergistic benefits for resistance training Original paper

In this randomized controlled trial, cosupplementation with caffeine and Rhodiola rosea improved muscle strength and endurance more than either supplement alone in men with no resistance exercise training experience. In men with resistance exercise experience, the combination only improved lower body strength, compared to placebo.

The effect of supplementation with caffeine (CAF), Rhodiola rosea (RHO), and their combination (CAF+RHO) on muscle strength (bench press, deep squat, and maximal voluntary contraction) and muscle endurance (maximal repetitions at 60% of 1 repetition maximum).

A total of 72 men; 48 untrained in resistance exercise (average age of 20) and 24 trained in resistance exercise (average age of 24, >5 years of training experience).

All participants completed a resistance training program (bench press and deep squat) 30 days before the physical performance assessment.

Participants with no resistance exercise training were randomized to one of four groups:

• CAF+RHO consumed 2.4 g/day of RHO (containing 12 mg of salidrosides, the primary bioactive compound of RHO) for 30 days leading up to the physical performance assessments and 3 mg/kg of CAF on the day of physical performance assessments.
• CAF consumed an active CAF capsule and placebo RHO capsules.
• RHO consumed active RHO capsules and a placebo CAF capsule.
• Placebo consumed two different capsules with no bioactive ingredients (i.e., sugar pills).

Participants with resistance exercise experience were randomized to the placebo and CAF+RHO interventions.

In men with no resistance exercise experience, supplementation with CAF, RHO, and CAF+RHO improved all measures of muscular strength and endurance when compared to placebo. Although the proper statistics for comparing supplements to each other were not reported, CAF and RHO appear to have improved muscle strength and endurance to the same degree, whereas CAF+RHO improved muscle strength and endurance more than either supplement alone.

Muscle strength and endurance outcomes in resistance exercise-untrained men

*Estimated statistically significant difference from CAF and RHO alone.

In men with resistance exercise experience, supplementation with CAF+RHO improved lower body strength (i.e., deep squat and maximal voluntary contraction), but not upper body strength or endurance (i.e., maximal repetitions and bench press), when compared to placebo.

Muscle strength and endurance outcomes in resistance exercise-untrained men

*Estimated statistically significant difference from CAF and RHO alone.

All participants were instructed to maintain their dietary habits and record the types and portions of foods consumed. The researchers calculated macronutrient and calorie intakes. The participants were also provided with “several packages” of food that “met the appropriate national food safety requirements”.

Caffeine is one of the most commonly used supplements for enhancement of physical performance. Although it has the strongest evidence for providing moderate to large improvements in aerobic endurance exercise, caffeine has also been shown to have small to moderate benefits for muscular strength and endurance in both untrained and trained people when consumed in doses of 3–6 mg per kilogram of body weight, 30–60 minutes prior to exercise.^[1] Caffeine concentration in blood has been reported to peak at 30 to 120 minutes after consumption.^[2]

The bioavailability of caffeine is almost 100%, meaning that most, if not all, of consumed caffeine is absorbed ^[3], so interindividual differences in benefits are attributed to genetic and environmental (e.g., habitual caffeine intake, smoking, hormonal contraceptives) factors related to caffeine metabolism.^[4][5][1] In fact, the average half life of caffeine is 4–6 hours but can vary between individuals by up to 1.5–10 hours.^[3] This makes a difference because performance benefits likely involve caffeine metabolites.^[4] Studies have reported that approximately 40% of the variability in the gene for the main caffeine metabolizing enzyme (CYP1A2) could be explained by genetic and nongenetic factors like diet and lifestyle.^[6][7] Interestingly, a 2020 systematic review reported that only 4 of 17 included studies demonstrated different responses between genotypes of CYP1A2 on exercise performance.^[8] Other genes have also been implicated, including the adenosine A2a receptor gene, or ADORA2A, but studies report conflicting results.^[4] There are always differences regarding dose and duration of treatment, ingestion time, time of day and intensity of training, and more that may also influence results. Although some studies suggest that habitual caffeine intake may reduce its exercise performance enhancing effects,^[9] a 2022 meta-analysis of 60 randomized controlled trials (covered in this study summary) reported that habitual caffeine intake does not influence its short-term benefits on physical performance.^[10]

Although the underlying mechanism for performance benefits from caffeine is not completely clear, there are three main purported mechanisms:

• Antagonism (i.e., binding) of adenosine receptors
• Calcium release within muscle (i.e., sarcoplasmic reticulum)
• Preservation of muscle glycogen

The last two mechanisms seem to occur with doses of more than 6 mg per kilogram of body weight.^[4] Adenosine is a central nervous system neuromodulator that slows down activity (e.g., creates the feeling of sleepiness) when bound to its receptor. Caffeine binds to adenosine receptors, preventing adenosine from binding to its receptor and the body from slowing down, thus keeping fatigue at bay. Antagonism of adenosine receptors is also associated with increased activity of various neurotransmitters like dopamine and acetylcholine, and hormone systems like adrenaline.^[11][12] Central nervous system stimulation improves alertness and reaction time and reduces perceived exertion and is the “generally accepted” mechanism for caffeine’s effects, with the other two being more hypothetical. A small part of the performance benefits may also be due to a placebo effect.^[13][14] Caffeine may also influence thermoregulation.^[15][16]

Rhodiola rosea or RHO is a perennial herb with adaptogenic properties that is known to reduce fatigue. Adaptogenic compounds help the body respond to stress. A 2022 systematic review of 10 human trials using this herb (covered in a previous study summary) reported improvements in markers of exercise performance and recovery, such as pain and muscle damage (e.g., creatinine), antioxidant capacity, and power output, but differences in dose and duration of treatment, as well as study design, complicate the interpretation of the reported benefits.^[17] For example, a 2021 randomized controlled trial reported increases in upper body strength, but decreases in endurance, after short-term (3 days prior to testing) supplementation with RHO (1,500 mg/day and 500 mg prior to testing), compared to placebo. That study also reported higher norepinephrine levels in the RHO group before testing.^[18] However, a 2013 randomized controlled trial reported improved endurance exercise performance, seemingly via decreased perception of effort, during a 6-mile time trial on a bicycle ergometer after an acute oral dose of 3 mg per kilogram of body weight.^[19]

Despite the use of RHO in traditional medicine across various regions in Asia and Europe for high-altitude sickness, anoxia, stress, fatigue, and overall health and longevity, the underlying mechanisms are not clear. RHO has been suggested to stimulate neurotransmitter systems (e.g., dopamine, serotonin, acetylcholine, noradrenalin) by preventing neurotransmitter degradation (i.e., monoamine oxidase inhibition) and enhancing blood-brain barrier permeability to neurotransmitter precursors.^[20] RHO also may improve blood supply, tissue oxygenation, hypoxia, cell survival, mitochondrial health, oxidative stress, and inflammation.^{[21][20][22][23]} Although RHO has a lot of potential, most of the research regarding its benefits has been conducted in animals and is yet to be confirmed in human studies.

Overall, the evidence suggests that CAF and RHO can benefit muscle strength and endurance. The underlying mechanisms of CAF and RHO appear to overlap to some degree (e.g., neurotransmitter systems and fatigue) and branch from each other in complementary ways (e.g., stimulation and blood supply), supporting the concept of a synergistic effect from supplementation with both, but further higher quality mechanistic research and human trials are needed to fill out this area of research.

These results should be interpreted with caution because there was no objective measure of compliance with the directions to refrain from caffeine, alcohol, or nutritional supplement intake during or 3 months before the study. The RHO group could have developed an advantage throughout their 30-day supplementation period compared to the acute CAF intake group, so the results are not generalizable to daily CAF intake. In addition, the confidence intervals that drove the estimated statistical analysis for between-supplement differences in the outcomes were not reported by the authors but were extrapolated using WebPlotDigitizer.

The authors of the study under review also conducted an animal trial with the same sample size (n=48) and treatments (placebo vs. CAF vs. RHO vs. CAF+RHO) as the trial that involved men with no resistance exercise experience. This trial reported improvements in the following outcomes when compared to placebo: grip strength from CAF, RHO, and CAF+RHO (+18%);\, dopamine levels from CAF and CAF+RHO (+13%), and maximal mitochondrial respiration and erythropoietin levels (stimulated red blood cell production) in kidney and serum from RHO and CAF+RHO.