Many investigations have employed short-term (10 days or less) as well as long-term (greater than 10 days) supplement interventions both with and without a concurrent training intervention. Studies including a training intervention are termed ‘training studies,’ while those that employed a single testing bout of exercise are termed ‘supplement loading studies.’ Additionally, some studies used protocols which incorporated MIPS ingestion on the day of post-testing. These studies and their relevant supplementation protocols are outlined in Tables 2 and 3.

Table 2 Performance outcomes and training adaptations in short-term (7–10 days) MIPS studies Full size table

Table 3 Performance outcomes and training adaptations in long-term (> 10 day) MIPS studies Full size table

Short-term supplementation (< 10 days)

Force production

At best, short-term MIPS consumption might preserve 1-RM performance after several bouts of fatiguing exercise but does not appear to favorably impact maximal strength. For example, Collins et al. [23] performed a 6-day supplement loading study. During baseline testing, participants completed 1RM and muscular endurance (3 sets of 10 repetitions, last set to fatigue) testing of the bench and leg press before and after an acute dose of MIPS or placebo. All participants were instructed to consume MIPS for an additional 5 days, and on the sixth day, participants performed identical post-testing. The authors claim that placebo consumption resulted in significantly lower leg press 1-RM after exhaustive exercise, while those who had consumed MIPS for 5 days retained greater force production and thus had significantly greater 1RM performance (d = 0.18, p = 0.3, very weak). However, the combination of the large reported p-value and small effect size suggest that there was no difference between placebo and MIPS. Similarly, Outlaw et al. [48] found no influence of MIPS on bench press or leg press 1RM relative to placebo following an 8 day supplementation protocol coupled with four resistance training bouts. Given the minimal amount of research, it is difficult to conclude that any marked benefit of short-term MIPS supplement loading on force production is present.

Muscular endurance and total volume completed

Several studies have evaluated muscular endurance following a short-term supplement loading protocol, with somewhat promising results. Collins et al. [23] claimed that short term supplementation (5 days) with a MIPS tended to significantly increase repetitions to failure on the leg press compared to placebo (d = 0.455, p = 0.116, moderate) and improve leg press lifting volume after exhaustive exercise (d = 0.24, p = 0.157, weak). Again, however, the large p-values suggest that these claims are not evidenced by the results of this investigation. Similarly, Kraemer et al. [49] found that 7 days of MIPS supplementation significantly improved Smith machine squat repetitions to fatigue during 6 sets at 80% 1RM (d = 0.41–1.08, p < 0.05, moderate - strong). However, Martin and colleagues [50] found no effect of short-term MIPS supplementation on total repetitions or volume load completed during four sets of bilateral leg extensions to fatigue at both 30% and 80% 1RM. Again, given the minimal volume of research in this area, no solid conclusions can be made at this point in time.

Power production

A paucity of evidence exists regarding the effect of short-term MIPS supplementation on power production. Additionally, broad differences in study design make comparisons between the conclusions of relevant studies difficult. Kraemer and associates [49] found that individuals who had consumed MIPS for 7 days exhibited higher vertical jump power output than individuals consuming placebo (NA). These results may suggest that brief supplement loading may enhance performance during a single exercise bout. However, these findings contrast with those of Outlaw et al. [48], who found no difference in peak anaerobic power production during a 30-s Wingate Anaerobic Cycle test between subjects who consumed MIPS or placebo for 8 days. Collins et al. [23] similarly found no difference in anaerobic power output during a 4 km time trial in participants who had consumed MIPS for 5 days compared to placebo consumers. The difference in testing paradigms may potentially explain some of the discrepancy in findings, as the vertical jump depends largely on the ATP/PCr energy system, while a Wingate test draws upon both anaerobic energy systems. Clearly, more research is needed to investigate the effect of short-term MIPS supplementation on power production.

Serum hormones and markers of muscle damage

Limited evidence exists regarding the effect of short-term MIPS consumption on hormones or markers of muscle damage caused by acute exercise. Kraemer et al. [49] found no difference in lactate, glucose or insulin between MIPS or placebo users after 7 days of supplementation. However, serum levels of creatine kinase were significantly lower midway through squat exercise (d = − 0.85, p < 0.05, strong), immediately after exercise(d = − 0.76, p < 0.05, moderate), and during 15 min of recovery (d = − 0.61, p < 0.05, moderate), while myoglobin was reduced immediately following exercise (d = − 0.82, p < 0.05, strong) in MIPS users relative to placebo, potentially suggesting that the supplement may have affected muscle damage. Kraemer and colleagues [49] also found that MIPS consumption resulted in greater increases in GH (NA) and free testosterone (NA) midway during six sets of squats performed to fatigue at 80% 1RM and during 15 min of recovery (NA). Likewise, IGF-1 was elevated in the treatment group immediately before exercise (i.e. about 30 min after acute supplement ingestion) (NA), though insulin was no different between MIPS and placebo.

Gender

The only study included in this review which studied a female population consuming a MIPS for a short period of time is the investigation by Collins and colleagues [23]. Roughly half of their total sample size was female and gender was used as a covariate in their analysis. Though expected differences in variables such as height, body composition, absolute upper and lower body strength, and relative upper body strength were noted, researchers did not find the MIPS to exert a different effect on females than males over time. However, more research utilizing hormonal control is needed to fully understand the effects of gender on MIPS.

Long-term supplementation (> 10 days)

A significantly greater volume of research exists that has investigated the benefits of MIPS supplementation lasting more than 10 days, typically in conjunction with some form of an exercise program. However, it is vital to note that not all of these investigations are placebo-controlled, as several studies opted to provide a comparator product lacking a proprietary blend of ingredients withheld by the supplement manufacturers as a control condition. However, these studies do not circumvent the central issue of differing proprietary blends and formulations in the various MIPS that were investigated, making it difficult to compare between products or identify primary active ingredients.

Force production

A substantial body of evidence suggests that long-term consumption of MIPS positively influences force production. It appears that long-term MIPS ingestion paired with resistance training results in increased 1-RM bench press strength compared to training alone in both trained (RE = 104.1–106.5, p < 0.02) [51, 52] and untrained [53, 54] males (d = 0.23–0.63, p < 0.05, weak - moderate). It is worth noting that both of the studies that found improvements in untrained males examined the same pre-workout supplement (containing a proprietary blend of caffeine, whey, BCAAs, creatine, β-alanine, and L-arginine) with a placebo control. However, one of the studies also required participants to consume a post-workout protein supplement, the addition of which may potentiate training adaptations beyond MIPS alone [54]. Regardless, these results suggest that chronic MIPS ingestion either with or without post-exercise protein will potentiate training adaptations resulting from a resistance exercise program. However, another investigator found no benefit of an identical MIPS on strength outcomes in resistance-trained males [55] or aerobically-trained males [56]. Notably, the resistance trained males consuming this specific MIPS also consumed a post-workout protein supplement, which also likely influenced training adaptations.

Interestingly, MIPS ingestion may improve upper-body strength but not lower-body strength despite lower-body resistance training, as evidenced by the work of Shelmadine et al. [53] and Lowery et al. [52], who both noted increases in bench press 1-RM but not leg press 1-RM in both trained and untrained males. Kendall et al. [57] likewise noted increases in leg press but not bench press strength after 4 weeks of supplementation loading without a supervised training intervention. However, due to the lack of supervised resistance training and the high volume of aerobic exercise conducted by the participants, these results are less generalizable and should be interpreted with caution. Conversely, Willems and associates [58] reported that MIPS supplementation resulted in no significant increases in upper or lower-body strength compared to placebo, though effect size analysis suggested that strength may have been increased in muscle groups and movements that were targeted during the resistance training regimen (d = 0.98–1.41, p = 0.07, strong). These results, though inconclusive, suggest that MIPS supplementation may support training-specific adaptations but does not result in systemic increases in muscle strength.

Several unique ingredients not common to all MIPS warrant mention. Kreipke et al. [59] found that resistance-trained participants who consumed a supplement containing long jack root had greater gains in bench press strength relative to placebo (d = 0.05, p = 0.001, very weak). The treatment group also improved deadlift 1RM relative to body mass and lean mass. Another group utilizing a product that has since been discontinued due to containing traces of a methamphetamine derivative [3] found no benefit of added betaine, citrulline, or dendrobium extract compared to placebo on strength-related outcomes. Likewise, Jung and associates [60] found no effect of chronic consumption of a MIPS containing Mucana pruitiens extract (15% L-Dopa) or the same supplement with the addition of synephrine on 1RM bench press when compared to placebo.

Muscular endurance

Limited research has examined the effect of chronic MIPS ingestion on muscular endurance, and the results are challenging to interpret as some studies are comparator controlled, while others are placebo controlled. Several studies conducted in resistance-trained participants utilizing whole-body training regimens reported beneficial results of MIPS relative to a comparator or placebo [51, 58]. Schmitz and colleagues [51] found that subjects who consumed MIPS containing a proprietary blend of ingredients performed more bodyweight bench press RTF compared to those who consumed a creatine, carbohydrate and protein-matched comparator (RE = 131.8, p = 0.004). Similarly, results reported by Willems et al. [58] suggest that repetitions to fatigue were enhanced at 80% pre-intervention 1-RM in participants who consumed a MIPS relative to those who consumed placebo (d = 1.2–1.3, p < 0.05, strong). Conversely, several studies found no effect of long-term MIPS consumption on muscular endurance. Spillane et al. [61] investigated the effect of the same supplement used by Schmitz et al. [51] and found no differences in RTF between those who consumed the experimental supplement relative to a comparator product. However, these differences may be due in part to differences between training interventions, as the program implemented by Spillane and colleagues [61] was shorter (6 weeks vs. 9 weeks) than that used in the experiment by Schmitz et al. [51]. Similarly, Hoffman et al. [36] found no effect of chronic MIPS supplementation on maximum pushups or sit-ups completed during a minute.

Power production

Preliminary evidence suggests that long-term MIPS supplementation may not augment lower-body power production. Ormsbee et al. [55] reported that trained males consuming both MIPS and placebo who participated in resistance training 3 days per week for 6 weeks experienced significant improvements in peak anaerobic power during a Wingate test. Post hoc testing identified MIPS users as having significantly increased their peak power while placebo users remained unchanged. However, these results must be interpreted with caution, as no statistically significant interaction (i.e. group x time) was identified (p > 0.05). Hoffman and colleagues [36] likewise found no effect of 4 weeks of MIPS supplementation on either peak or mean power measured during a Wingate test. Though evidence seems to indicate that MIPS does not affect power production, more research is needed to verify this hypothesis.

Endurance exercise performance

Limited research exists investigating aerobic performance following long-term MIPS ingestion, and results of these studies are contradictory. Stout and colleagues [62] found that peak oxygen consumption (VO 2peak ) and time to exhaustion during a graded cycling exercise test significantly increased by 8.4% and 5.7%, respectively, among sedentary men and women who consumed a MIPS containing caffeine, green tea extract, and glucuronolactone but not in those who consumed placebo during a 10-week resistance and aerobic exercise regimen (NA). However, Smith et al. [63] found no between-group differences in maximal oxygen consumption (VO 2max ) after 3 weeks of HIIT training in recreationally-trained males who consumed MIPS or placebo. Surprisingly, Kendall et al. [57] found that 4 weeks of supplementation with a MIPS containing caffeine, creatine, and β-alanine in recreationally-trained males resulted in decreased relative VO 2max , though no such change was found in those who consumed a placebo (d = − 0.51, p < 0.05, moderate). However, the percent of VO 2max at which ventilatory threshold occurred significantly increased in the treatment but not placebo group (d = 1.21, p < 0.05, strong). The contrasting results offered by Kendall and colleagues may be explained by the lack of a specific training intervention, as all participants reported physical activity levels via questionnaire. However, given the body of research it appears that long-term MIPS consumption may augment aerobic performance in sedentary individuals beginning an exercise program or among aerobically fit individuals beginning a high-intensity protocol. However, more research is needed in this area.

Muscle damage

Early evidence suggests that long-term MIPS consumption has little effect on soreness, inflammation, and biomarkers of muscle damage resulting from exercise. Ormsbee et al. [56] found no effect of 4 weeks of MIPS consumption on perceived soreness, post-damage muscle function, or biochemical measures of muscle damage in endurance-trained males who performed a damaging downhill running bout. These results were mirrored in a trained female population by Köhne et al. [64], who reported that participants who consumed MIPS for 28 days prior to and 3 days after a bout of downhill running had no significant changes in soreness, muscle function, biomarkers of muscle damage, or inflammation, though effect size analysis suggested that MIPS slightly attenuated the inflammatory response to exercise. Clearly, more information is required, though initial results do not appear promising.

Body composition

The effect of MIPS on body composition appears to be promising, though differences in study design and the reliance on self-reported dietary intake make conclusions challenging. Several studies have found that the long-term consumption of MIPS in resistance trained males leads to greater increases in fat-free mass (FFM) following six [55, 65] (d = 0.18–0.22, p < 0.05, weak) or 8 weeks [52] (RE = 104.1, p < 0.01) of resistance training (three sessions per week) compared to a placebo. While the aforementioned investigations used the same brand of MIPS, participants also consumed a protein-based post-workout supplement during each of the six-week interventions, thus potentially confounding the conclusions regarding the isolated effect of MIPS supplementation that can be drawn from these studies. Chronic MIPS consumption has also been shown to improve body composition in untrained populations, as Shelmadine et al. [53] (d = 0.24, p = 0.001, weak) and Spillane et al. [54] (d = 0.17, p = 0.023, weak) noted greater gains in FFM after 28 days of resistance training in non-resistance trained males consuming MIPS compared to placebo. Additionally, Spillane and colleagues found a significantly greater decrease in fat mass (FM) in the treatment group (d = − 0.08, p = 0.026, very weak), though these effects may be due in part to post-exercise protein ingestion in addition to any chronic effect of MIPS supplementation. Stout and coworkers [62] examined the effect of MIPS ingestion on body composition in sedentary men and women during a 10-week resistance and endurance training program and found that MIPS users lost significantly more FM (NA) relative to placebo users at the end of the intervention. Interestingly, the MIPS formulation employed in this investigation was the only supplement to result in positive changes in body composition that did not contain creatine.

Few placebo-controlled studies have found MIPS to have no influence on body composition. Jung et al. [60] examined the effects of a MIPS containing Mucana pruitiens extract (15% L-Dopa), an identical MIPS with added synephrine, or a placebo in 80 resistance-trained males and found no effect of either MIPS formulation on body composition relative to placebo after four or 8 weeks of training. Smith et al. [63] also found no differences in body composition between MIPS and placebo users after 3 weeks of high-intensity interval training. Similarly, one of the only studies to exclusively use female subjects [66] found no change in body composition in females who consumed MIPS while participating in 7 weeks of resistance training. Thus, it seems that long-term supplementation of MIPS that contain creatine, β-alanine, whey protein, or BCAAs may exert a favorable effect on body composition in males participating in resistance training.

Several comparator-controlled studies have investigated the effect of long-term MIPS consumption on body composition, with contrasting results. Kedia et al. [3] and Spillane et al. [61] both found no improvements in body composition after 6 weeks of resistance training and supplementation among resistance-trained individuals assigned to consume MIPS as opposed to comparator product. However, another study reported significantly increased FFM (RE = 102.1, p = 0.049) and decreased FM (RE = 87.1, p = 0.023) after 9 weeks of resistance training in resistance trained males who consumed a MIPS with a proprietary blend of amino acids compared to subjects who consumed a carbohydrate, whey, and creatine-matched comparator [51]. It is important to note that the MIPS formulation used by Kedia and colleagues [3] was primarily focused on promoting energy, with the comparator matched for energy and caffeine, while the comparator products used by Spillane et al. [61] and Schmitz et al. [51] were matched for carbohydrate, whey, and creatine. The results of these studies support the idea that creatine and protein are likely the primary ingredients driving increases in fat-free mass accretion.

Skeletal muscle adaptations

Three studies have utilized muscle biopsy techniques to identify changes in skeletal muscle after extended exposure to MIPS. Shelmadine and colleagues [53] found MIPS to increase myofibrillar protein content (d = 1.78, p = 0.014, strong), total DNA (d = 2.96, p = 0.041, strong), as well as myogenic regulatory factors Myo-D (NA) and MRF-4 (NA) relative to placebo. Similarly, Spillane et al. [54] found MIPS to increase myofibrillar protein content (d = 0.32, p = 0.049, weak) as well as Myo-D (d = 0.51, p = 0.038, moderate) and MRF-4 (d = 1.37, p = 0.001, strong). In a later study, the same research group observed increased total muscle creatine and total muscle protein in both MIPS users and those who consumed a protein, carbohydrate, and creatine-matched comparator during 6 weeks of heavy resistance training [61]. In summary, as all of these experiments found beneficial effects of long-term supplementation of MIPS that contained whey protein, creatine, and BCAAs, these ingredients likely lead to favorable skeletal muscle adaptations.

Subjective measures

Several long-term MIPS studies have utilized the profile of mood states (POMS) assessment to measure psychological responses to MIPS exposure. Ormsbee et al. [65] investigated the subjective effects of MIPS consumption and found no between-groups differences in mood state, as training led to increased vigor in both those who consumed MIPS or placebo. Similarly, Kreipke and colleagues [59] did not witness any between-group differences in mood state, as an increase in anger was found in both participants who consumed placebo and participants who consumed a MIPS containing long jack root. Kedia and coworkers [3] documented the only difference in subjective measures between MIPS and comparator users and reported that MIPS led to increased energy and focus during endurance testing as well as significantly higher self-perceived energy, concentration, and focus (NA). The MIPS group also reported reductions in self-perceived fatigue. However, the product utilized in this experiment was later recalled for containing methamphetamine analogs, which may explain many of the alterations in subjective measures. Hoffman et al. [36] likewise reported that recreationally-active subjects who consumed MIPS for 4 weeks were able to maintain focus after a bout of exhaustive exercise, while those who consumed placebo experienced declines in focus (NA).

Reaction time and cognitive processing

It appears that chronic MIPS supplementation has little effect on reaction time, as Hoffman and colleagues [36] found no effect of a caffeine-containing supplement on reaction time after a bout of exhaustive exercise. Jung et al. [60] found that those who consumed a MIPS containing caffeine, L-tyrosine, and L-Dopa (derived from Mucana puritens extract) with or without synephrine had better performance during a Stroop test (d = 0.12–0.16, p < 0.05, very weak). However, as only a single study using a unique ingredient has investigated cognitive functioning after more than 10 days of MIPS exposure, more research is needed to bolster any conclusion drawn from these findings.

Hormonal response

The hormonal response to long-term MIPS use has only been evaluated in resistance trained males. In several resistance-training studies which used the same MIPS formulation, no changes were found in cortisol [65], GH [55], or insulin-like growth factor-1 (IGF-1) [55] relative to placebo. A similar product containing whey, creatine, BCAAs, and taurine also had little effect on insulin, IGF-1, cortisol, or GH relative to placebo [61]. While testosterone has been shown to increase following training among both MIPS and placebo users [55], no study has yet demonstrated an effect of chronic MIPS supplementation on testosterone concentration relative to placebo. Furthermore, consumption of a MIPS containing long jack root had no effect on bioavailable testosterone, free testosterone, total testosterone, sex-hormone binding globulin, or estradiol compared to placebo [59].

Gender

Four long-term supplementation studies included in this review examined the effects of MIPS on both males and females, while an additional two investigations only examined female participants. Stout et al. [62] included 20 males and 18 females in their study but did not control for menstrual cycle or assess the effect of gender on any outcome variable. Similarly, Kedia and colleagues [3] enrolled men and women into their 6-week long study, though the authors did not disclose the ratio of females to males or assess gender as a covariate. However, the researchers controlled for the menstrual cycle. The sample obtained by Hoffman et al. [36] was only 11% female (2/19 total participants) and researchers did not control for menstrual cycle or include gender in their analysis, likely due to the discrepancies in sample size. Köhne and colleagues [64] explored the effects of a MIPS on flexibility, muscle damage, and power in female runners who performed a single bout of downhill running during the mid-follicular phase following 28 days of supplementation. Though Köhne and colleagues did not find any differences between MIPS and placebo with regard to any outcome measure, these results are very similar to a study performed in men using a nearly identical study design and the same supplement [56]. Another study using only female participants found that MIPS did not influence RMR or body composition when compared to placebo [66], though menstrual control was not mentioned in the manuscript. No consensus can be drawn from these data on the effect of gender on long-term MIPS consumption. Future studies should simultaneously compare men and women following the same training protocol and using the same supplement while controlling for hormonal status in female participants.