Capsaicin - 'Hot' New Ergogenic With Profound Metabolic and Health Benefits!? Recent Study + Older Data Reviewed

Red peppers - too hot for you? CH-19 Sweet is non-pungent pepper w/ similar metabolic effects (Ohnuki 2001a)
You will probably have encountered capsaicin in one or another kitchen-sink supplement in the past. Probably without knowing if and how much it contributed to the fat loss and/or performance effects of said product. I promise: After reading this extended review of a recent study by de Freitas, Cholewa, Freire et al. (2017) your perspective on this "ah, it also contains ... wtf" ingredient may change significantly. Why's that? Well, next to previously cited, latest and greatest research on the ergogenic effects of capsaicin, there's also a bunch of quite exciting papers on its ability to help you lose body fat and promote your metabolic and overall health.
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Figure 1: Pharmacokinetics of capsaicin showing absorption, metabolism, and distribution after oral application of capsaicin in humans (O'Neill 2012).
So, where do I start? With a PubMed search yielding 13611 results for capsaicin, it may be smart to start with what PubMed tells us was the "most relevant" result, a paper on the "Bioavailability of capsaicin and its implications for drug delivery" (Rollyson 2014), which shows that capsaicin, unlike the active ingredients of other 'super herbs' like curcumin from turmeric, has an outstanding (oral) bioavailability of 50-90% and is rapidly cleared from the system within 48h.

Now, that's good news for a pre-workout booster, after all, you don't want to "enjoy" the effects of 12mg of capsaicin for the rest of your life - and that's despite the fact that, according to the previously cited paper in the Journal of Strength and Conditioning Research (de Freitas 2017), include a ...
  • significant increase in total weight lifted (3919.4 +/- 1227.4 kg vs 3179.6 +/- 15 942.4 kg, p=0.002 | that's +23% total volume) on a standardized exercise test (four sets until movement failure in the squat exercise at 70% of 1RM w/ 90s rest in-between sets).
  • significant reduction in the reported rate of perceived exertion (-6% RPE | p = 0.048) immediately after the 4 sets of squats.
that you will get on top of previously observed beneficial effects on energy expenditure, lipolysis, and fatty acid oxidation (Ohnuki 2001a,b; Lejeune 2003; Inoue 2007).
Figure 2: 10mg/d of capsaicin yield sign. increases (+23%) in total volume (reps x weight) while simultaneously reducing the rate of perceived exertion (RPE) of ten young men (age, 22.7±4.0 yr, height, 175±0.07 cm, weight, 82.3±9.6 kg) with at
4 least 1 year of resistance training experience at a frequency of 3 days per week by 6% (de Freitas 2017).
As de Freitas et al. (2017) point out in the introduction to their paper, capsaicin has been found to activate the transient receptor potential vanilloid-1 (TRPV1) in the mouth, stomach, and small intestine of mammals, which, in turn, will "increase mitochondrial heat production via regulation of uncouple protein (UCP) expression and induce mitochondrial biogenesis".
Having a relatively low amount of capsaicin in their diet (0.01%) significantly enhanced the exercise endurance and reduces blood lactic acid and triglycerides of rats through TRPV1 activation in a 3-months study by Lou et al. (2004), which appears to refute the assumption that the chronic use of capsaicin by grown-up mammals (like humans ;-) will desensitize TRPV1 and thus ameliorate its effects.
Will capsaicin lose its efficacy over time? With the study at hand being an acute response study and in view of the fact that a previous human studies in trained individuals showing no increase in repeated sprint performance in response to the chronic supplementation with capsaicin (albeit in form of cayenne pepper, not pure capsaicin) it is, as de Freitas et al. (2017) point out, well possible that "chronic capsaicin ingestion may result in a 'desensitization effect' that blunts the performance benefits" (de Freitas 2017). Support for their hypothesis comes from rodent studies, in which the chronic supplementation of capsaicin led to a desensitization of the TRPV1 receptor and thus not just a reduction in the ergogenic effects of capsaicin, but a reduction in exercise performance! Before you freak out, though, it should be mentioned that this ergolytic effect was observed in rodents that received capsaicin for the first 4 months of their lives. Therefore, the results of the corresponding studies by Dousset, et al. (2014) and Hudson, et al. (2016) have questionable practical relevance. Moreover, scientists from China and Belgium report sign. increases in the time to exhaustion following 3 months of 6 capsaicin ingestion in rats as well as mitochondrial adaptations that would explain the improved endurance capacity (Lou 2004).
What is particularly interesting, here, is the fact that this increase is not just statistically significant, but also practically relevant, as it has been found that this increase in mitochondrial oxidative capacity (and the uncoupling protein UCP-1) translates to ...
  • enhanced abdominal fat loss (an extra −1.11 ± 1.83% reduction in belly fat) in overweight men and women - Snitker et al. (2009), 12 weeks of 6 mg per day of mixed capsinoid supplementation
    Figure 3: 6mg/d of capsaicin target belly fat in 12-week study in overweight men + women (Snitker 2009)
    very similar results have previously been observed in pair-fed + exercised rodents (Yoshioka 2000), where capsaicin added to the diet-induced + exercise-mediated fat loss, specifically in the visceral adipose tissue depots (-10% extra reduction);
  • enhanced skeletal muscle glycogen retention during exercise (32% reduced glycogen depletion in white and 10% reduced glycogen depletion in red gastrocnemius muscle) as it was observed by Oh, et al. in 2003 in a rodent model of exercise;
  • marginally increased post-prandial energy expenditure (see Figure 4) as it has been observed by Yoshioka, et al. in eight male long-distance runners in 1995 in response to a standardized meal containing either no or 10 g of red pepper,
    Figure 4: An analysis of the energy expenditure in healthy subjects 150-min after Ingesting a standardized meal with or without red peppers shows increases in the early postprandial phase (Yoshioka 1995).
    as you can see in Figure 4 the effect that goes hand in hand with a significant decrease in the ratio of glucose/fat that's used and can be abolished by the means of a beta-blocker is yet by no means strong enough to expect to lose weight just by eating peppers with every meal;

    and that's in line with follow-up studies like Inoue et al. (2007), who observed non-sign. increases in EE only in overweight subjects, and Smeets et al. (2009) and Galgani et al. (2010), whose studies showed no effect of capsaicin on healthy subjects' energy expenditure with different dosages of capsaicin (3mg/kg, 10mg/kg and 1, 3, 6 or 12 mg in Smeets et al. and Galgani et al., respectively);
  • improved glucose management, mainly by a sign. augmentation insulin production in rodent models of T2DM, as it was observed by Islam et al. in 2008;
    Figure 5: Glucose (left) and insulin (right) response in health 12 healthy volunteers  0-120 minutes after an oral glucose tolerance test (Weerapan 2009).
    and, via a similar mechanism (i.e. increased insulin response to glucose) in 12 healthy volunteers who underwent an oral glucose tolerance test (results in Figure 5) after ingesting 5 grams of capsicum or placebo (Weerapan 2009);
  • other health benefits ranging from the well-known analgesic effects of capsaicin-loaded patches, its gastroprotective influence in GERD, gastric ulcers and H. pylori, its anti-cancer effects, which have been observed in colorectal cancer, pancreatic cancer, bladder tumor, gastric cancer, breast cancer, hepatocellular carcinoma, melanoma. pancreatic cancer, lung cancer, or prostate cancer (Szydełko 2017 | download this recent review)
It should be highlighted, though that capsaicin is by no means a wonder-drug. In a 2003 RCT by Lejeune et al., for example, the whopping dose of 135 mg capsaicin/d did not reduce the weight the ninety-one moderately overweight subjects regained in the weeks after a modest weight loss intervention - and that despite significant increases in fat oxidation (remember: calories count!).
Is capsaicin even safe? Capsicum fruit is GRAS by the US Food and Drug Administration's Center for Food Safety and Applied Nutrition for use in foods. Capsaicin is rapidly absorbed from the stomach and small intestine. It is then quickly metabolized in the liver by cytochrome P450 enzymes (note: it also inhibits CYP1A2, -2C9, -2C19, as well as CYP3A4 (Babbar 2010), albeit only at very high serum concentrations of >1µM; still keep in mind that interaction with drugs, supplements and hormones could occur) which may limit systemic, pharmacological effects of enterally absorbed capsaicin (Singletary 2011). What you must not forget, though, is that even water becomes toxic if you ingest too much of it... and you bet that the amount of capsaicin that's needed to get into the danger zone for capsaicin is significantly lower than for water ;-)
Furthermore, reviews like Diepvens et al. (2007) highlight that capsaicin, "when it is used clinically it requires a strong compliance to a certain dosage, that has not been shown to be feasible yet" - a problem that may be tackled in future studies, though, by using capsaicin from "CH-19 Sweet", the fruit of a non-pungent cultivar of pepper.
Figure 6: Graphical summary of capsaicin's beneficial cardio-metabolic effects (Sun 2016).
How exactly capsaicin does what it does is still not 100% clear. With respect to its ergogenic effects, the previously cited study by Lou et al. (2012; see red box) seems to suggest that they are a result of PGC-1a-mediated effects on the mitochondria, which trigger improvements in the oxidative capacity and rate of fatty acid oxidation in skeletal muscle mitochondria.
Is it possible to use foods and/or food extracts instead? In vivo data from Caterina et al. (1997) compared the TRPV activity of extracts from Habanero, Thai Green, Wax and Poblano verde peppers to capsaicin. They found that the extremely hot Habanero outperform even pure capsaicinoids - a result that is clearly in line with the various studies showing that people who eat spicy food tend to have a reduced risk for various cardiometabolic diseases.
The results of the de Freitas study, however, cannot be explained by either long-term (it was, after all, an acute supplementation study) or acute effect on fatty acid oxidation, because any practically relevant increase in the ratio of fatty acid to glucose oxidation should have lead to a decrease in lactate levels, which were not observed in the study at hand (it should be said, though, that there's a marginal reduction in lactate levels on the latter sets and that the comparison is somewhat unfair, because the total work done in the supplement trial was sign. higher). Accordingly, we are left with two alternative mechanisms that could explain the beneficial effects on squat performance:
  • the analgesic (=pain-reducing) effect capsaicin exerts by activating the TRPV1 receptor - there's a good reason "topical capsaicin has been used as a pain reliever in neuropathic conditions" (de Freitas 2017); what would support this hypothesis is the fact that the researchers observed a sign. reduction in ratings of perceived exertion - and that despite the increased number of reps the subjects performed; alternatively, ...
  • a likewise TRPV1-mediated increase in calcium release by sarcoplasmic reticulum that would lead to a greater interaction of actin-myosin filaments and thus greater tension generation could have synergized with the previously observed increase in central nervous system (CNS) activity in response to capsaicin supplementation.
Ultimately, though, an increase in training volume is only a means to an end, an end that is for both, the researchers and probably most of you, to gain lean mass. I would thus assume that you'll be interested in the author's conclusion that...
"[g]iven that greater resistance training volumes are highly associated with muscular hypertrophy (Schoenfeld 2017), [...] it is possible that chronic pre-training capsaicin supplementation could lead to greater strength and hypertrophic adaptations (de Freitas 2017). 
In view of the fact that this is not more than a hypothesis, the most important message pertaining to potential real-world benefits beyond being able to boast of having done "that extra rep" in the conclusion of de Freitas' paper is that "future research is required to test this hypothesis" (de Freitas 2017).
MCT + Chili = Pretty HOT Pair: 50% Increase in Thermogenesis | more.
Bottom line: Yes, the study at hand demonstrates an acute ergogenic effect of capsaicin in a very specific scenario, i.e. young, previously trained male subjects who are doing four sets of squats for reps after the single administration of 10mg pure capsaicin. All assumptions about (a) chronic effects and its effects in (b) different subjects, during (c) different exercises, exercises for different body parts and types of exercise (endurance vs. strength), as well as speculations about (d) other study outcomes, such as increased skeletal hypertrophy, are hypothetical.

Based on the what we believe to be the mechanism(s) of action, the existing studies in rodents and the little we've learned from human RCTs, though, it is not completely unlikely that benefits could be observed in (a) in the long run, with the previously cited study by Lou et al. (2004) suggesting increases in the adaptative response, (b) in women and less trained individuals, (c) in both, endurance and strength training, and, maybe, even (d) improvements in exercise-induced skeletal muscle hypertrophy.

For less athletic individuals, on the other hand, its (albeit insulin-mediated) anti-diabetic effects and its ability to significantly suppress appetite and the desire to eat (Janssens 2014) could be of interest. Even if the results of the previously cited studies are ambiguous | Comment!
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