ONLINE DRIVERS MEDIA

Some butter on top of the broccoli would allow for the assimilation of the absorption of the 101.6?g vitamin K 623IU vitamin A (various).

There are a handful of very basic questions in nutrition science, no one appears to have an answer to. One of these questions, which is directly related to the  well-known fact that the vitamins A, D, E & K are "lipid soluble". This means that they are "solved" and thus made absorbable by fats and oils. The general assumption is thus that the vitamins A, i.e. the retinol and carotenoids, all forms of vitamin D, the tocopherols and -trienols (vitamins E) and the two major forms of vitamin K, i.e. phylloquinone (K1) and menaquinone (K2) will only be absorbed, if you consume them with a sufficient amount of dietary fat. Now, the questions obviously are (a) is this correct and (b) how much is sufficient.
In view of the fact that the answers to (a) and be are not necessarily identical for all four vitamins of interest, it appears sensible to tackle them one after the other.


Starting with vitamin A and the various forms of carotenoids, we can already confirm that (a), i.e. the assumption that we need dietary fats to optimally absorb vitamin A is correct. As Karin van het Hof and her colleagues point out, the "amount of dietary fat required to ensure carotenoid absorption [does yet] seem low (?3–5 g per meal), although it depends on the physicochemical characteristics of the carotenoids ingested." (van het Hof. 2000) In spite of the fact that 5g of fat are not exactly much, the classic uncooked vegetarian orthorexic salad often comes with a total of only 5g of fat of which 95% remain at the bottom of the salad bowl. If that sounds like your favorite dish, you should be aware that you are risking that all the good  beta- and other carotenoids in the salad will pass right through.

Figure 1: Changes in hepatic vitamin A (retinol) and carotenoid stores in gerbils after 14 days on high fat (30%) vs. low fat (10%) diet (Deming. 2000)

In that, the concomitant presence of both dietary fat and carotenoids in a meal is a necessary prerequisite for the absorption of vitamin A, also because the fatty acids will trigger the conversion of of beta-carotene into vitamin A and its subsequent absorption via the lymphatic system (Ribaya?Mercado. 2002). It is thus not surprising that animal studies by Lakshman et al. (1996) and Deming et al. (2000; see Figure 1) suggest that low fat diet can lead to a depletion of the vitamin A tissue stores even if the serum levels remain constant. The amount of fiber in the diet, on the other, has no influence the absorption of vitamin A (Mills. 2009).

Interestingly enough, the provision of the fat blocker Orlistat reduces the absorption of vitamin A only insignificantly, as a 1996 paper by Angela T. Melia, Susan G. Koss?Twardy, and Jianguo Zhi would suggest (Melia. 1996).

Which takes us right to vitamin E, the absoprtion which is - in spite of being "blocked" by the fat blocker orlistat (Melia. 1996) - less susceptible to the absence of dietary fat than you may think. Annet JC Roodenburg, Rianne Leenen, Karin H van het Hof,  Jan A Weststrate, and Lilian BM Tijburg do in fact argue that the optimal intake of vitamin E requires only "a limited amount" of dietary fat (Roodenburg. 2000).

Figure 2: Vitamin E serum levels after 7 days on control (low fat, 3g) or high(er) fat (36g) diet with and without supplemental vitamin E (Roodenburg. 2000)

As you can see in Figure 2. A minimum intake of only 3g per day was sufficient to keep the vitamin E levels stable. The short study period of 7-days (each) and the absence of measures of tissue concentration of vitamin E do yet reduce the practical relevance of the data, Roodenburg et al. present in their Y2k paper in the American Journal of Clinical Nutrition.
If you take a look at the high prevalence of vitamin E dieficiency among the fat (and PUFA) "loving", or at least eating, majority of Americans, it does yet become obvious that a lack of dietary fat is not just theoretically, but also practically not exactly the #1 reason you may become deficient in tocopherols and -trienols. That the latter is an increased demand due to chronic inflammation and the (over-)consumption of exactly those PUFAs that come with a shitload of vitamin E in nature, for a reason would yet be a topic for another SuppVersity article and thus something we will skip to fast forward to ...

...Vitamin K, obviously. Vitamin K is a relative newcomer to the publics understanding of the alphabet soup. Aside from being it a good tool to rip customers vitamin K, or rather K1 (plant sources) and K2 (animal sources) are thus also the only fat soluble vitamins not everyone knows. The fact that the amount of phylloquinone (K1) that makes it into your blood stream is ~70% reduced if you eat your spinach without fat (Gijsbers. 1996).

And if we take the results researchers from the Gifu University School of Medicine present in a 1996 paper in the Journal of Pharmacological Sciences, as a reference, the amount of fat you need to optimally absorb your K2 (menaquinones), is not exactly low.

Figure 3: For optimal absorption of K2, there has got to be a huge amount of fat in the meal - but who wonders. K2 comes with a high amount of fat (Uematsu. 1996)

Uematsu et al. had to supply their subjects, who consumed otherwise identical test meals with 8.8, 20.0 and 34.9g of fat in them with the maximal (i.e. 35g) of fat before the K2 absorption maxed out. In that the total area under the curve did not really differ between those subjects who consumed the K2 before and those who took it immediately after the test meal.

Thats a pity, cause a high intake of vitamin K (menaquinone from animal sources) has been associated with a 27% reduced risk of developing heart disease (Geleijnse. 2004), an ailment of which many still believe that it was brought about by the fat they need to optimally absorb their vitamin K.

For vitamin D, our last "V" on the list, things look differently. For one, everybody knows about this miracle vitamin and for two, it may be "fat soluble", but the amount of fat thats required to optimally absorb it turned out to be much lower than previously thought (see "A Fat D-Ficiency! Do You Really Need More Vitamin D or Simply More Fatty Foods? Study Shows, Even 50.000 IU of Vitamin D3 Useless, When You Ingest It Without Fat. " | read more).
In fact, Niramitmahapanya et al. found in 2011 that its not necessarily a high amount, but rather the right type of fat that determines if and how much of the vitamin D you take in capsule form or find in comparably low amounts in your foods that determines how much of the vitamin D actually makes it into your bloodstream:

"The change in plasma 25OHD (nanograms per milliliter) during vitamin D supplementation was positively associated with MUFA, (? = 0.94; P = 0.016), negatively associated with PUFA, (? = ?0.93; P = 0.038), and positively associated with the MUFA/PUFA ratio (? = 6.46; P = 0.014)."

In plain English this means, that the "good" seed and vegetable oils with their high PUFA content will effectively inhibit the absorption of vitamin D - an observation that adds to the many reasons the modern sedentary, sun-avoiding, sun-screen using, soybean oil (MUFA:PUFA = 0.4) guzzling American is low in or  quasi devoid of vitamin D.

Figure 4: 25(OH)D levels of 30 healthy men and women after ingestion of 50.000IU vitamin D3 supplement in conjunction with a normal or low fat breakfast (Raimundo. 2011)

Against that background its not surprising that you will not find a conclusive answer to the question how much fat you actually need. In a study that used a fatty meal with soybean oil in it, the effect would be totally different from one in which the subjects consumed meals that were made with sunflower oil, an oil with a MUFA:PUFA ratio >1. In view of the results Gnadinger et al present in a recent appear it does still seem appropriate to consume at least some fat alongside your vitamin D supplements. As far as the food-borne vitamin D is concerned, you dont have to worry, anyways. Foods that are high in D3 usually come with all the fat you need to absorb it.

How much fat, exactly you would need to make the most of dietary and supplemental vitamin D, on the other hand, is still not known. The previously mentioned data from the study by Raimondo et al. (see Figure 4, to the right) I wrote about in "A Fat D-Ficiency" is obviously still valid. The extremely high amount of vitamin D (50,000IU!) could yet require a correspondingly high amount of fat to be optimally absorbed and the fact that the fat in the study came from a "vegetable margarine" with an undisclosed ratio of MUFA:PUFA does not make the real-world effects any more predictable.
References:

• Chitchumroonchokchai, Chureeporn, et al. "Dietary fats with increased ratio of unsaturated to saturated fatty acids enhance absorption of carotenoid and vitamin E by increasing both efficiency of micellarization and lipoprotein secretion." FASEB J 24 (2010): 539-3.
• Deming, Denise M., et al. "Amount of dietary fat and type of soluble fiber independently modulate postabsorptive conversion of ?-carotene to vitamin A in Mongolian gerbils." The Journal of nutrition 130.11 (2000): 2789-2796. 
• Geleijnse, Johanna M., et al. "Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study." The Journal of nutrition 134.11 (2004): 3100-3105.
• Gijsbers, Birgit LMG, Kon-Siong G. Jie, and Cees Vermeer. "Effect of food composition on vitamin K absorption in human volunteers." British Journal of Nutrition 76.02 (1996): 223-229.
• Goodman, Dew S., et al. "The intestinal absorption and metabolism of vitamin A and beta-carotene in man." Journal of Clinical Investigation 45.10 (1966): 1615.
• Jayarajan, P., Vinodini Reddy, and M. Mohanram. "Effect of dietary fat on absorption of ? carotene from green leafy vegetables in children." Indian journal of medical research 137.5 (2013).
• Kris-Etherton, P. M., et al. "Polyunsaturated fatty acids in the food chain in the United States." The American journal of clinical nutrition 71.1 (2000): 179S-188S.
• Lakshman, M. R., et al. "The effects of dietary taurocholate, fat, protein, and carbohydrate on the distribution and fate of dietary ??carotene in ferrets." (1996): 49-61.
• Melia, Angela T., Susan G. Koss?Twardy, and Jianguo Zhi. "The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers." The Journal of Clinical Pharmacology 36.7 (1996): 647-653.
• van het Hof, Karin H., et al. "Dietary factors that affect the bioavailability of carotenoids." The Journal of nutrition 130.3 (2000): 503-506.
• Raimundo, Fabiana Viegas, et al. "Effect of high-versus low-fat meal on serum 25-hydroxyvitamin D levels after a single oral dose of vitamin D: a single-blind, parallel, randomized trial." International journal of endocrinology 2011 (2011).
• Ribaya?Mercado, Judy D. "Influence of Dietary Fat on ??Carotene Absorption and Bioconversion into Vitamin A." Nutrition reviews 60.4 (2002): 104-110.
• Roodenburg, Annet JC, et al. "Amount of fat in the diet affects bioavailability of lutein esters but not of ?-carotene, ?-carotene, and vitamin E in humans." The American journal of clinical nutrition 71.5 (2000): 1187-1193. 
• Uematsu, Toshihiko, et al. "Effect of dietary fat content on oral bioavailability of menatetrenone in humans." Journal of pharmaceutical sciences 85.9 (1996): 1012-1016.

The only truly ergogenic addiction is a SuppVersity addiction ;-)

I am not sure if you remember my detailed elaborations on the effects of sexual intercourse on exercise performance from May 30, 2012 [see "Will Sex Before a Competition Hamper Your Performance?" | more], but if you dont Id suggest you start out with this SuppVersity Classic before you devote yourself to RocknRoll by reading up on that in my article "Acoustic Gear" [read more] and return here for the missing third part of the triumvirate: Drugs!

Drug #1: Caffeine - From your coffee mug to the doping list

I am actually 100% confident that 99% of you have already trained "on drugs". Most of you probably do it regularly. Either with caffeine, about which Tony Chou reported in a 1992 paper that it is consumed on a daily basis by ~90% of the adult population (Chou. 1992). With average amounts of "only" 200 mg or 2.4 mg/kg/day (about 2 cups of coffee).
2 year suspensions (maximum penalty, usually only 2–6 months; cf. Pesta. 2013).
In view of the fact that its ergogenic effects are so well established as with hardly any other substance, I will stick to a very brief overview of the surprising benefits the worlds "drug" #1 will have on preformance:

• Antagonism of adenosine ? analgesic effects (reduced perception of pain; Derry. 2012)
• Increased fatty acid oxidation ?  higher endurance (Spriet. 1992)
• Decreased respiratory ration ? increased use of fat, decreased use of glycogen (Rush. 2001)
• Increases cAMP by inhibiting phospodiesterase ? increase lipolysis = more fuel (Umemur. 2006)
• Activation of protein kinase A ? s. above + increase in gluconeogenesis = more fuel (Graham. 2001)
• Increases glycogen storage ? faster recovery (Pedersen. 2008; learn more)
• Modulation of muscular calciusm flux ? increase contractile forces (Tarnopolsky. 2000)

In view of its various beneficial health effects and the insufficient evidence of significant side-effects, when it is consumed in moderation, exercise performance should thus not be a reason to give up drinking coffee (and as you remember, contrary to the claims of certain "fad brands" the same is true for mycotoxins, as well).

Drug #2: Alcohol - From the track to the bar and into the gutter

While caffeine made it from everyones coffee mug onto the WADA list of prohibited substances for all sports, alcohol is prohibited in-competition only and only in the following sports: aeronautic, archery, auto mobile, karate, motorcycling and powerboating (until 2010, modern pentathlon was also included in this list; Pesta. 2013).
In view of its effects on exercise performance and the generally reckless approach to the #2 on the list of the most diligent killers among all, not just the freely available drugs the decision of the World Anti Doping Association appears not reasonable, but at least consequent.

For many cyclists at the Tour de France, it was common practice to drink one, two or three glasses, sometimes even a bottle of wine before during and after a race, but that was in the (good?) old days and its ergogenic effects are certainly questionable. Nevertheless, it took some time until the wine that was often laced with strychnine to help ease the pain and decrease the feeling of fatigue (Fife. 2000) got replaced by EPO, glucocorticoids & co [note: the cyclists also used cocaine or sympathomimetic drugs in order to attenuate the feeling of fatigue associated with such a prolonged exercise; cf. Lucia. 2003].

Now, aside from certain analgesic (=pain reducing) effects, alcohol has little to offer to the average athlete. It may still be the "the most commonly consumed drug in athletic communities" (Pesta. 2013), but in moderation and certainly not for ergogenic purposes.

Table 1: Summary of the effects of alcohol on performance (adapted from Pesta. 2013)

It has after all been shown to adversely affects psychomotor skills and exercise performance. The beneficial reductions in maximal oxygen consumption (~greater muscular efficiency), on the other hand are pathetic, so that the American College of Sports Medicine (ACSM) rightly recommends that "if an athlete must consume alcohol, that they should refrain from alcohol consumption for at least 48 hours prior to competition." (ACSM)

Remember the irony in the article " Ultimate Post-Workout Testosterone Booze" [more] - Dont use hard liquor to increase your post-workout testosterone levels by almost 100%,  unless figures on a lab report are more important to you than health & performance.

If you stick to this recommendation even on training days, this will probably eliminate alcohol from your diet altogether or restrict its consumption on the weekend; and thats certainly a good thing. Chronic alcohol abuse will after all

• lead to significant impairments in cardiac and skeletal muscle structure and function in 99% of the cases
• slow down post-exercise recovery, and 
• inhibit protein synthesis 

There is obviously no debating: Alcohol is a uniformly ergolytic agent, It has significant detrimental effects on exercise performance and its use must be minimized not just for performance, but also, and more importantly, for health reasons.

Apropos health! I am sure all of you will be aware that the government of Colorado believes that marijuana should be part of a healthy lifestyle... ah, I mean medical protocol to deal with pain and other issues and decided to legalize the renown preparation of the Cannabis plant thats intended for use as a psychoactive drug and as medicine.

Drug #3: Cannabis, Mariuhana, Pot, Weed

As we have learned from the Tour de France athletes of the past, pain obviously is a major issue for athletes. So, wouldnt it make sense to switch from wine + strichnine to marijuana? Ok, you cant consume it "intra-workout", but maybe before and after the Queens stage at L’Alpe d’Huez?!
To answer that question, it may be useful to take a closer look at the structure of THC, which enables it to dock with the cannaboid receptors in the central nervous system (CNS). As Anand et al. point out (Anand. 2009):

• The centrally expressed CB1 receptors trigger the psychotropic effects of marijuana.
• The CB2 receptors in the periphery (spec. the sensory tissue) mediate the analgesic effects.

For the average Tour de France cyclist a selective CB1 receptor modulator (a "SCBRM", so to say ;o) could thus be the drug of choice. In view of the fact that some of the beneficial effects of exercise are also mediated by endogenous cannabinoid receptor antagonists (Hill. 2010), the analgesic effects could potentially be complemented by additional physiological benefits or side effects that are unrelated to the psychotropic effects of marijuana.

If these effects exist is yet probably almost as uncertain as the general usefulness of marijuana as an ergogenic, of which Pesta et al. write that if there were any, they would yet have to be established (Pesta. 2013).

• You dont have to smoke the weed to mess yourself up: Bird et al. demonstrated in 1980 that the previously mentioned detrimental effects on other aspects of performance occur with orally administered THC (215 µg/kg), as well. So dont even think of it ;-)
  Reduced work capacity of the heart at elevated heart rates -- Steadward and Singh (Steadward. 1971) were probably among the first scientists to test the effects of marijuana on exercise performance. In their study that was published as a dissertation at the University of Alberta in 1971 they found significant elevations in resting heart rate and both systolic and diastolic blood pressure at rest after marijuana consumption compared to both control and placebo. This lead to a highly significant decrease in physical work capacity at a heart rate of 170 (-25%) 
• Decrease in time to exhaustion -- Renauds and Cormiers finding from a 1986 study appear to confirm the earlier results Steadward and Singh present in their thesis paper. The researchers  tested subjects 10 min after smoking a marijuana cigarette (containing 1.7% of ?9-THC) of 7 mg/kg of body weight, and noted a slight, but significant decrease in cycle ergometry time to exhaustion. Avakian et al. [156] demonstrated that double.

In 1977, already Tashkin et al. (1977) hypothesized that the decrease in exercise performance may be due to itschronotropic effects, which would lead to achievement of maximum heart rate at reduced workloads.It goes without saying that - as long as you dig long enough - you will always find studies with conflicting results. The beneficial effects Tashkin et al. (1975) report in their paper, for example, occured in patients with asthma benefit from the bronchodilating effects of cannabis. For healthy individuals similar benefits are thus more than unlikely.

If there even is a benefit for pot-heads, its probably a psychological one that could be brought about by anxiety reducing and euphorigenic effects of cannabis... but lets be honest: Isnt a healthy amount of pre-competition anxiety a necessary prerequisite for world-class performance?

Drug #4: Nicotine - Better smoke tobacco than pot?

If alcohol doesnt help and pot is downright bad for you what else could you add to your beloved caffeine? Of course! Cigarettes. I mean, nicotine and caffeine that does even sound alike! Plus: Some "experts" say that they synergistically promote weight loss (which is a non-verified hypothesis that is often supported by a single short-term human trial by Jessen et al. (2003) and entails the risk of developing diabetes; cf. Attvall. 1993).
With its CNS stimulating and dopaminergic effects 3-(1-methyl-2-pyrrolidinyl)pyridine aka nicotine does at first appear to be a very likely candidate for every pre-workout supplement. Unfortunately, it does also enhance the effect of serotonin and opiate activity and will thus override its own stimulatory with a calming and depressing effect (Silvette. 1962). Against that background it sounds funny that nicotine will still increase the heart rate and blood pressure (Narkiewicz. 1998), as well as cardiac stroke volume and output and coronary blood flow (Bargeron. 1957).

The question is thus: Which effects prevail? The stimulatory or the the sedating effects? The WADA apparently doesnt believe that nicotine doping is worth it. 3-(1-methyl-2-pyrrolidinyl)pyridine is currently on the watch list, but its neither banned or officially tested for. That does yet not mean that  it cannot yield small but significant benefits for endurance athletes (17% improvement in time to exhaustion in Mündel et al. 2006) or sports where dexterity / skills play an important role (improvement in the degree in a real-life motor task, Tucha et al. 2004; positive effect on fine-motor abilities, West et al. 1986; cf. Martin. 2009). None of these effects was observed with cigarettes, though, but with a 7mg nicotine patch, a  2mg nicotine chewing gum and 2mg intranasal nicotine, respectively.

Figure 1: Cigarette smoking and risk of diabetes among 41 810 men during six years follow up (Rimm. 1995)

Whether the 17% endurance increase in the Mundal study qualifies as an incentive to "go on the patch" is yet questionable. Nicotine is not just addictive (Stolerman. 1995), going off of it will also trigger declines in motor performance that wont come handy for any athlete (Burtscher. 1994). This as well as the previously cited potential of developing insulin resistance that has been reported for both cigarettes and nicotine gums (Taskinen. 1996; the downside of the Taskinen study is that the increased diabetes risk may be a result of previous cigarette smoking - we can thus not be totally sure that chewing nicotine gums regularly increases your diabetes risk).
References:

• Anand, Praveen, et al. "Targeting CB2 receptors and the endocannabinoid system for the treatment of pain." Brain research reviews 60.1 (2009): 255-266.
• Attvall, S., et al. "Smoking induces insulin resistance—a potential link with the insulin resistance syndrome." Journal of internal medicine 233.4 (1993): 327-332. 
• Burtscher, M., et al. "Motor symptoms similar to parkinsonism in heavy smokers." International journal of sports medicine 15.04 (1994): 207-212.
• Margeron, L., et al. "Effect of cigarette smoking on coronary blood flow and myocardial metabolism." Circulation 15.2 (1957): 251-257.
• Bird, K. D., et al. "Intercannabinoid and cannabinoid-ethanol interactions and their effects on human performance." Psychopharmacology 71.2 (1980): 181-188.
•  Chopra, Gurbakhsh Singh. "Man and marijuana." Substance Use & Misuse 4.2 (1969): 215-247.
• Chou, Tony. "Wake up and smell the coffee. Caffeine, coffee, and the medical consequences." Western Journal of Medicine 157.5 (1992): 544.
• Derry, Christopher J., Sheena Derry, and R. Andrew Moore. "Caffeine as an analgesic adjuvant for acute pain in adults." Cochrane Database Syst Rev 3 (2012). 
• Fife W, eds. Tour de France – The History, the Legend, the Riders, Vol. 100. Edinburgh and London: Mainstream Publishing, 2000: 1–255.
• Graham, Terry E. "Caffeine and exercise." Sports medicine 31.11 (2001): 785-807. 
• Gawryszewski V.P., and Monteiro M.G. "Mortality from diseases, conditions, and injuries where alcohol is a necessary cause in the Americas, 2007-2009". Addiction (2014) [ahead of print].
• Jessen, Anna B., Søren Toubro, and Arne Astrup. "Effect of chewing gum containing nicotine and caffeine on energy expenditure and substrate utilization in men." The American journal of clinical nutrition 77.6 (2003): 1442-1447.
• Hill, Matthew N., et al. "Endogenous cannabinoid signaling is required for voluntary exercise?induced enhancement of progenitor cell proliferation in the hippocampus." Hippocampus 20.4 (2010): 513-523.
• Lucia, Alejandro, Conrad Earnest, and Carlos Arribas. "The Tour de France: a physiological review." Scandinavian journal of medicine & science in sports 13.5 (2003): 275-283.
• Martin, Laura F., Deana B. Davalos, and Michael A. Kisley. "Nicotine enhances automatic temporal processing as measured by the mismatch negativity waveform." Nicotine & Tobacco Research 11.6 (2009): 698-706.
• Mündel, Toby, and David A. Jones. "Effect of transdermal nicotine administration on exercise endurance in men." Experimental physiology 91.4 (2006): 705-713.
• Murray, Christopher JL, and Alan D. Lopez. "Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study." The Lancet 349.9063 (1997): 1436-1442.
• Narkiewicz, Krzysztof, et al. "Cigarette smoking increases sympathetic outflow in humans." Circulation 98.6 (1998): 528-534.
• Pesta, Dominik H., et al. "The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance." Nutrition & metabolism 10.1 (2013): 71.
• Pedersen, David J., et al. "High rates of muscle glycogen resynthesis after exhaustive exercise when carbohydrate is coingested with caffeine." Journal of Applied Physiology 105.1 (2008): 7-13. 
• Renaud, A.M., and Cormier, Y. "Acute effects of marihuana smoking on maximal exercise performance." Medicine and science in sports and exercise 18.6 (1986): 685-689. 
• Rimm, Eric B., et al. "Prospective study of cigarette smoking, alcohol use, and the risk of diabetes in men." Bmj 310.6979 (1995): 555-559.
• Rush, James WE, and Lawrence L. Spriet. "Skeletal muscle glycogen phosphorylase akinetics: effects of adenine nucleotides and caffeine." Journal of Applied Physiology 91.5 (2001): 2071-2078. 
• Silvette, H., et al. "The actions of nicotine on central nervous system functions." Pharmacological reviews 14.1 (1962): 137-173.
• Spriet, L. L., et al. "Caffeine ingestion and muscle metabolism during prolonged exercise in humans." American Journal of Physiology-Endocrinology And Metabolism 262.6 (1992): E891-E898.
• Steadward, R. D-, and Singh M. The effects of smoking marihuana on physical performance. Diss. University of Alberta, 1971. 
• Stolerman, Ian P., and M. J. Jarvis. "The scientific case that nicotine is addictive." Psychopharmacology 117.1 (1995): 2-10.
• Taskinen, Marja-Riitta, and Ulf Smith. "Long-term use of nicotine gum is associated with hyperinsulinemia and insulin resistance." Circulation 94.5 (1996): 878-881.
• Tarnopolsky, Mark, and Cynthia Cupido. "Caffeine potentiates low frequency skeletal muscle force in habitual and nonhabitual caffeine consumers." Journal of applied physiology 89.5 (2000): 1719-1724. 
• Tashkin, Donald P., et al. "Effects of smoked marijuana in experimentally induced asthma." Am Rev Respir Dis 112.3 (1975): 377-86.
• Tashkin, D. P., et al. "Cannabis, 1977." Annals of Internal Medicine 89.4 (1978): 539-549. 
• Tucha, Oliver, and Klaus W. Lange. "Effects of nicotine chewing gum on a real-life motor task: a kinematic analysis of handwriting movements in smokers and non-smokers." Psychopharmacology 173.1-2 (2004): 49-56.
• West, R. J., and M. J. Jarvis. "Effects of nicotine on finger tapping rate in non-smokers." Pharmacology Biochemistry and Behavior 25.4 (1986): 727-731.
• Umemura, Takashi, et al. "Effects of acute administration of caffeine on vascular function." The American journal of cardiology 98.11 (2006): 1538-1541.

If you want to know how to get of pubertal acne, you got to ask professional pubescents ;-)

The study at hand is not only the first experimental verification of the efficacy of omega-3 + gamma linoleic acid supplementation in acne treatment, its also "paleo approved", because it cites a study by no one else but Loraine Cordaine himself ;-) Dont worry, I am just kiddin around. In spite of the fact that Cordains study "Acne vulgaris: a disease of Western civilization" (Cordain. 2002) is in fact the #1 on the reference list, the scientists from the Seoul National University College of Medicine refrain from (paleolithic) dairy bashing in their evaluation of "the clinical efficacy and safety of omega-3 fatty acids and of GLA for the treatment of mild to moderate facial acne." (Jung. 2014)

If you google "natural acne treatment" it will usually not take long until you find a reference to fish oil and gamma linoleic acid (as in borage or starflower oil). Against that background it is surprising that the Korean scientist are obviously the first to scrutinize the efficacy of 2,000 mg of eicosapentaenoic acid and docosahexaenoic acid and 400 mg ?-linoleic acid (from borage oil) in a parallel design dietary intervention study.

Long-standing "natural acne cure" now scientifically proven

The 45 participants with mild to moderate acne, were allocated to either of the intervention groups for 10 weeks, after which the effect on their skin was evaluated visually and via heamatoxylin, eosin and immunohistochemical staining of the lesions.
And what the scientists observed was ... positive, at least in the omega-3 group, the mean inflammatory acne lesion count was significantly reduced (from 10.1 ± 3.2 in week 0 to 5.8 ± 3.4 in week 10; p < 0.05).

Figure 1: Changes in inflammatory acne lesion counts with time (left, top), noninflammatory acne lesion counts with time (left, bottom), and changes in patients subjective assessment (VAS) with time (right; Jung. 2014)

As you can see in Figure 1, a similar change was observed in the GLA (9.8 ± 5.2 before vs. 8.0 ± 4.6 after 5 weeks vs. 6.6 ± 3.7 after 10 weeks, p < 0.05), but not in the control group (9.9 ± 4.3 before to 10.2 ± 6.2 after 10 weeks).

Figure 2: Before (top) and after (bottom) photos (Jung. 2014)

"Mean non-inflammatory acne lesion counts were also reduced by omega-3 and GLA supplementation (23.5 ± 9.2 to 18.9 ± 8.3, p < 0.05, and 22.8 ± 8.4 to 19.2 ± 7.2, p < 0.05, respectively) at final visits, whereas mean lesion count in the control group was unchanged (from 21.8 ± 9.7 to 22.0 ± 8.6). Significant differences were evident between the treatment groups and the control group after 10 weeks (p < 0.05)." (Jung. 2014)

In the end, there was no no significant difference between the two treatments for any of the measured parameters, so that it is probably up to you, whether you try to control the "fire within your skin" with GLA or DHA + EPA supplements.
References:

• Cordain, Loren, et al. "Acne vulgaris: a disease of Western civilization." Archives of Dermatology 138.12 (2002): 1584-1590.
• Jung, Jae Yoon, et al. "Effect of Dietary Supplementation with Omega-3 Fatty Acid and gamma-linolenic Acid on Acne Vulgaris: A Randomised, Double-blind, Controlled Trial." (2014).
• Wolf, Ronni, Hagit Matz, and Edith Orion. "Acne and diet." Clinics in dermatology 22.5 (2004): 387-393.

Nigella sativa is available in form of seeds, oils and all sorts of ointments and for many of them there are studies suggesting that they work.

SuppVersity reader Amaan Mueen asks on Facebook: "In traditional Oriental medicine its said that blackseed is a cure for everything except death, is there any truth to that?" I probably dont give away too much, when I tell you that blackseed (also "black seed") aka "nigella sativa" is not going to cure everything, but death, but that does not mean that modern Western medicine has not been able to confirm what Oriental "doctors" have known for centuries.

In the following I am going to present an allegedly cursory overview of the existing evidence with a focus on those health benefits that could be relevant for the average and extra-ordinary SuppVersity reader.

• General anti-oxidant effects - The complete oil of N. sativa, as well as thymoquinone (the main compound of the essential oil) have been shown to significantly reduce non-enzymatic lipid peroxidation in liposomes (Houghton. 1995). Significant anti-oxidant effects have also been observed for other compounds isolated from N. sativa, uncluding thymoquinone, carvacol, t-anethole and 4-terpineol.
  
  

  Figure 1: The tymoquinone rich fraction of blackseed (TQRF-X) has dose dependent (L,M,H) effects on antioxidant enzyems in hypercholesterolemic (Ismail. 2010).

  These compounds were found in a series of other in vitro tests to have variable antioxidant, but no pro-oxidant properties.
  
  Most importantly, though, the different compounds in the oil were found to act in a synergistic manner (i.e. more than the mere summation of the actions of the individual compounds). This stresses the importance of using the whole oil (or the crude extract) of the seeds in pharmacological studies.
  
  As Ali and Blunden point out in their review of the literature, "the antioxidant property of N. sativa is multifactorial, [but] it does not seem to involve iron-complexing activity (Ali. 2003). It rather appears as if its general ability to scavenge free radicals, which may be, at least partially, the basis of many human diseases and conditions, could be at the heart of its ability to protect, for example, against CCl4 hepatotoxicity (Nagi. 1999), liver fibrosis and cirrhosis (Türkdogan. 2000), and hepatic damage induced by Schistosoma mansoni infection (Mahmoud. 2002).
• Antiinflammatory and analgesic actions -Its one thing to scavenge free radicals. Its yet a completely different thing to effectively reduce the inflammation thats often, but not always triggered by the presence of free radicals. Against that background its important to note that an aqueous extract from nigella sativa exhibits strong anti-inflammatory effects, as well (Al-Ghamdi, 2001). Using carrageenan-induced paw oedema as a model of inflammation, and the hot plate reaction time as a model of nociception, the extract was found to possess significant antiinflammatory and analgesic (=pain reducing) action.
  
  As Ali & Blunden (2003) point out, this finding lends some credence to the folk medicinal use of the plant as an antiinflammatory and analgesic substance, and also confirms previous reports on the antinociceptive (Abdel-Fattah. 2000) and antiinflammatory (Mutabagani. 1997) effects of N. sativa oil and its major component, thymoquinone, in mice.
  
  The possible mechanism by which N. sativa exerts its antiinflammatory action has been studied. Thymoquinone has been shown to be a potent inhibitor of eicosanoid generation, namely thromboxane B2 and leucotrienes B4, by inhibiting both cyclooxygenase and lipooxygenase, respectively (Houghton. 1995). Interestingly, it was found that the fixed oil of N. sativa had both antioxidant and anti-eicosanoid effects greater than thymoquinone, which is its active constituent (Houghton. 1995)

• Anti-Cancer Effect - In an in-vitro study from the late 1990s researchers from the Tobacco and Health Research Institute in Lexington were able to show that the thymoquinone (TQ) and dithymoquinone (DIM) content of nigella sativa have the astonishing ability to kill several parental and multi-drug resistant (MDR) human tumor cell lines (Worthen. 1997).
  

  Figure 2: A schematic diagram showing major molecular targets of TQ. As an anticancer agent, TQ inhibits the activity of CYP enzymes, which are involved in metabolic activation carcinogens, and induces the expression and activities of cytoprotective enzymes by activating Nrf2 signaling. TQ selectively induces tumor cell death in an ROS-dependent manner following both intrinsic and extrinsic pathways of apoptosis. TQ exerts anti-proliferative, anti-inflammatory, anti-migratory, anti-invasive and anti-metastatic effects by blocking the activation of NF-?B- and STAT3-regulated gene products (Kundu. 2014).

  In spite of the fact that there are as of yet no studies that show that humans were cured with blackseed, recent studies have shown that Thymoquinone, a component of Nigella sativa, decreases oxidative DNA damage in a rat model of mammary cancer (Sindi. 2014) and protect the brain, liver and other organs from radiation induced damage during cancer therapy (Ahlatci. 2014; Cikman. 2014). So, even if it were not for its established cytotoxic effects in various human cancer cells (e.g. Liver, Khan. 2014; Kidney, Tabasi. 2014; Prostate & Breast Cancer, Schneider-Stock. 2014; Cervix, Ichwan. 2014; etc.), it would still make sense to use black seed extracts as antioxidants during radiation and as studies indicate also chemotherapy (Pace. 2003; Almog. 2014).
• Anti-allergic effects - In a study from 2003 Kalus et al. observed significant reductions in subjective feeling of allergic symptoms in 152 patients with allergic diseases (allergic rhinitis, bronchial asthma, atopic eczema) who were treated with Nigella sativa oil, given in capsules at a dose of 40 to 80 mg/kg/day.
  
  

  Figure 3: The addition of blackseeds at a dosage of 2g/day propels the beneficial effects of subcutaneous allergen-specific immunotherapy on polymorphonuclear leukocyte (PMN) function in 24 patients sensitive to house dust mites with allergic rhinitis (I??k. 2010)

  Other studies confirm that Nigella sativa can reduce the peripheral blood eosinophil count, IgG1 and IgG2a, cytokine profiles and lung inflammation in murine model of allergic asthma (Abbas. 2004) that are equal to the corticosteriod dexamethasone and scientists from the Gaziosmanpasa University Medical Faculty say that "N. sativa display its antioxidant and regulatory effects via inflammatory cells rather than the host tissue (brain and medulla spinalis)" in a rodent model of experimental allergic encephalomyelitis (Ozugurlu. 2005). Effects that were also observed in a 2010 human study which indicates that "N. sativa seed supplementation during specific immunotherapy of allergic rhinitis may be considered a potential adjuvant therapy" (I??k. 2010 | see Figure 3).
• Anti-diabetes effects: The volatile compounds in nigella sativa oil have been shown to exert potent glucose lowering effects in healthy and diabetic animals (Al-Hader. 1993). Effects that occured in the absence of changes in insulin levels and are almost unsettlingly pronounced.
  

  Figure 4: Reduction in fasting blood glucose in the hours after the administration of 50mg/kg volatile oil extract to normal and diabetic rodents (Al-Hader. 1993).

  For those of you who are hovering around in the netherlands of glucose levels, anyway, the 14% reduction Al-Hader et al. observed in the healthy rabbits in their 1993 could in fact be enough to induce mild hypoglycemia and side effects such as ravenous appetite, feeling cold, cold sweat, being irritable and so on - an effect thats going to be particularly pronounced, because blacksee will at the same time inhibit the production of glucose in the liver that would otherwise compensate the drop in blood glucose (Al-Awadi. 1991).
  
  With comparatively lower doses of only 5ml of nigella sativa oil, Mohtashami et al. have recently demonstrated that the beneficial effects on blood glucose are not rodent specific.
  
  

  Figure 5: Blackseed consumed in 2x2.5ml servings everydy improves blood glucose management in healthy humans, too (Mohtashami. 2011)

  In their randomized clinical trial with 70 healthy subjects who received either 2.5 ml Black seed oil or a similarly looking mineral oil two times a day, the scientists observed achieved less pronounced, but still significant reductions in fasting blood glucose and the long(er)-term glucose marker HbA1c within only two months.
  
  In view of the comparatively small reductions in blood sugar (see Figure 5), its also not surprisng that the only side effect was an occasional case of transient nausea. Notable changes in liver enzyme and kidney functional adverse effects, on the other hand, were not observed..
  
  Similar results have been reported for subjects with diabetes (Najmi. 2008), intact and diabetic rats (Hawsawi. 2001; Houcher. 2007) and in several cell models, like muscle cells, where it increases AMPK and GLUT4 expression (Benhaddou-Andaloussi. 2011) or the Langerhans cells (Rchid. 2004) of the pancreas of which Fararh et al. (2002) were able to show that they can partly recover their ability to release insulin in a rodent model of diabetes, when nigella sativa is administered in conjunction with nicotinic acid.
• Cardiovascular effects - The results of a 2014 study by Mohammad et al. indicate that "[t]he use of N. sativa as an alternative therapy for hypercholesterolemia could have profound impact on the management of CVD among menopausal women especially in countries where it is readily available." In the corresponding study 1g of nigella sativa powder consumed after breakfast lead to significant improvements in lipid profiles of menopausal women (decreased total cholesterol, low density lipoprotein cholesterol and triglyceride, and increased high density lipoprotein cholesterol)within 2 months. Improvements that were lost almost completely after one month without the capped Nigella sativa supplement.
  
  Rather ambigous - at least at first sight - are the effects of nigella sativa on the physiology of the heart, while Al-Asoom et al. (2014a) were able to show that the IFG-1 boosting effects Nigella sativa exerts on exercising rats could make it a valuable tool for the treatment of heart failure with superior advantages to exercise training alone, the same effects are often mentioned as potential unwanted side effects of Nigella sativa.
  

  Figure 6: In trained rats, the Nigella sativa induced boost in IGF-1 (left) promotes the exercise induced increase in heart weight (right | Al-Asoom. 2014a)

  Whether thats actually a problem is yet questionable. In view of the nature of the cardiac hypertrophy, its rather an augmentation of the beneficial cardiac remodeling due to exercise similar to the one we call "athletes heart" than a pathological increase in the size of the heart. Whether similar effects can be observed for skeletal muscle has, at least as far as I know, yet not been tested - its yet certainly not impossible.

References

• Abbas, Ayman Talatt, et al. "Effect of dexamethasone and Nigella sativa on peripheral blood eosinophil count, IgG1 and IgG2a, cytokine profiles and lung inflammation in murine model of allergic asthma." The Egyptian journal of immunology/Egyptian Association of Immunologists 12.1 (2004): 95-102.
• Abdel-Fattah, Abdel-Fattah Mohamed, Kinzo Matsumoto, and Hiroshi Watanabe. "Antinociceptive effects of< i> Nigella sativa</i> oil and its major component, thymoquinone, in mice." European journal of pharmacology 400.1 (2000): 89-97. 
• Al-Saaidi, J. A. A., A. L. D. Al-Khuzai, and N. F. H. Al-Zobaydi. "Effect of alcoholic extract of Nigella sativa on fertility in male rats." Iraq J Verterin Sci 23 (2009): 123-8.
• Al-Asoom, L. I., et al. "Effect of Nigella sativa Supplementation to Exercise Training in a Novel Model of Physiological Cardiac Hypertrophy." Cardiovascular toxicology (2014a): 1-8. 
• Al-Asoom, Lubna Ibrahim, et al. "Comparison of Nigella sativa-and Exercise-Induced Models of Cardiac Hypertrophy: Structural and Electrophysiological Features." Cardiovascular toxicology (2014b): 1-6.
• Al-Awadi, Fatania, and U. Shamte. "The effect of a plants mixture extract on liver gluconeogenesis in streptozotocin induced diabetic rats." Diabetes research (Edinburgh, Scotland) 18.4 (1991): 163-168.
• Al-Hader, Aqel, M. Aqel, and Z. Hasan. "Hypoglycemic effects of the volatile oil of Nigella sativa seeds." Pharmaceutical Biology 31.2 (1993): 96-100.
• Ali, B. H., and Gerald Blunden. "Pharmacological and toxicological properties of Nigella sativa." Phytotherapy Research 17.4 (2003): 299-305. 
• Ahlatci, Adem, et al. "Radiation-modifying abilities of< i> Nigella sativa</i> and Thymoquinone on radiation-induced nitrosative stress in the brain tissue." Phytomedicine 21.5 (2014): 740-744. 
• Benhaddou-Andaloussi, Ali, et al. "The in vivo antidiabetic activity of Nigella sativa is mediated through activation of the AMPK pathway and increased muscle Glut4 content." Evidence-Based Complementary and Alternative Medicine 2011 (2011).
• Cikman, Oztekin, et al. "Radioprotective Effects of Nigella Sativa Oil Against Oxidative Stress in Liver Tissue of Rats Exposed to Total Head Irradiation." Journal of Investigative Surgery (2014).
• Fararh, K. M., et al. "Isulinotropic properties of< i> Nigella sativa</i> oil in Streptozotocin plus Nicotinamide diabetic hamster." Research in veterinary science 73.3 (2002): 279-282.
• Hawsawi, Zubaida A., Basil A. Ali, and Abdullah O. Bamosa. "Effect of Nigella sativa (black seed) and thymoquinone on blood glucose in albino rats." Annals of Saudi medicine 21.3-4 (2001): 242-244. 
• Houcher, Zahira, et al. "Effects of methanolic extract and commercial oil of Nigella sativa L. on blood glucose and antioxidant capacity in alloxan-induced diabetic rats." Pteridines 18.1 (2007): 8-18.
• Houghton PJ, Zarka R, de las Heras B, Hoult JRS."Fixed oil of Nigella sativa and derived thymoquinone inhibit eicosanoid generation in leukocytes and membrane lipid peroxidation". Planta Med 61 (1995): 33–36.
• Ichwan, S. J., et al. "Apoptotic Activities of Thymoquinone, an Active Ingredient of Black Seed (Nigella sativa), in Cervical Cancer Cell Lines." The Chinese journal of physiology 57.5 (2014).
• Lautenbacher LM. "Schwarzkümmelöl." Dtsch Apoth Ztg 137 (1997): 68–69.
• Khan, Fazal, et al. "Evaluation of the effect of Nigella sativa extract on human hepatocellular adenocarcinoma cell line (HepG2) in vitro." BMC Genomics 15.Suppl 2 (2014): P63.
• Kundu, Juthika, et al. "Mechanistic Perspectives on Cancer Chemoprevention/Chemotherapeutic Effects of Thymoquinone." Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (2014).
• Mahmoud, M. R., H. S. El-Abhar, and S. Saleh. "The effect of< i> Nigella sativa</i> oil against the liver damage induced by< i> Schistosoma mansoni</i> infection in mice." Journal of ethnopharmacology 79.1 (2002): 1-11. 
• Mohtashami, R., et al. "Blood Glucose Lowering Effects of Nigella Sativa L. Seeds Oil in Healthy Volunteers: a Randomized, Double-Blind, Placebo-Controlled Clinical Trial." Journal of Medicinal Plant 10.36 (2011): 90-94.
• Mutabagani, A., and S. A. M. El-Mahdy. "A study of the anti-inflammatory activity of Nigella sativa L. and thymoquinone in rats." Saudi Pharmaceutical Journal 5 (1997): 110-113.
• Nagi, Mahmoud N., et al. "Thymoquinone protects against carbon tetrachloride hetatotoxicity in mice via an antioxidant mechanism." IUBMB Life 47.1 (1999): 153-159. 
• Najmi, Ahmad, et al. "Effect of Nigella sativa oil on various clinical and biochemical parameters of insulin resistance syndrome." International journal of diabetes in developing countries 28.1 (2008): 11.
• Ozugurlu, F., et al. "The effect of Nigella sativa oil against experimental allergic encephalomyelitis via nitric oxide and other oxidative stress parameters." Cellular and molecular biology (Noisy-le-Grand, France) 51.3 (2005): 337-342.
• Pace, Andrea, et al. "Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy." Journal of Clinical Oncology 21.5 (2003): 927-931. 
• Paarakh, Padmaa M. "Nigella sativa Linn.–A comprehensive review." Indian J Nat Prod Resour 1 (2010): 409-29.
• Rchid, Halima, et al. "Nigella sativa seed extracts enhance glucose?induced insulin release from rat?isolated Langerhans islets." Fundamental & clinical pharmacology 18.5 (2004): 525-529.
• Sindi, Abrar, and Karen Carlberg. "Thymoquinone, a component of the Middle East spicy seed Nigella sativa, decreases oxidative DNA damage in a rat model of mammary cancer (693.21)." The FASEB Journal 28.1 Supplement (2014): 693-21.
• Tabasi, Nafise, et al. "Cytotoxic and apoptogenic properties of Nigella sativa and thymoquinone, its constituent, in human renal cell carcinoma are comparable with cisplatin." Food and Agricultural Immunology ahead-of-print (2014): 1-19.
• Türkdo?an, M. K., et al. "The role of antioxidant vitamins (C and E), selenium and Nigella sativa in the prevention of liver fibrosis and cirrhosis in rabbits: new hopes." DTW. Deutsche tierarztliche Wochenschrift 108.2 (2001): 71-73.
• Worthen, David R., Omar A. Ghosheh, and P. A. Crooks. "The in vitro anti-tumor activity of some crude and purified components of blackseed, Nigella sativa L." Anticancer research 18.3A (1997): 1527-1532.