Science Round-Up Seconds: Nicotine's Effect on Brain Aromatase & the Consequences, 2D:4D Digit Ratio Predicts Testosterone Response to Sprinting and All the Anti-Obesity & Pro-Brain Effects W/ Just 2 Cups of Coffee per Week?

Wallaby Lachie Turner (left), Greg Inglis (centre) & Jarryd Hayne (Stuff.co.nz) - who would have thought that the relative length of their 2nd and 4th digit could predict their testosterone response after the sprint? Not you? Well, then you got to check out the first of the short-items at the bottom.

Those of you who have listened to yesterday's installment of the SuppVersity Science Round-Up on Super Human Radio, will have realized that the show did - as usual - take a somewhat different direction than originally planned. Before I get to the actual SuppVersity Round-Up Seconds, of which there actually weren't all too many I consider absolutely newsworthy and appropriate for a written format, I thought I would briefly mention the paper on which I based the hypothesis (remember: this is nothing certain) that there may be a link between the calcium-influx into the muscle and the strength and hypertrophy effects of performance enhancing drugs (spec. those with a high anabolic : androgenic effect ratio) - for those of you who may want to follow up on this hypothesis or think Carl and I were just making things up ;-) 

The study I refer to shortly after the last break (download the podcast), was conducted by a group of researchers from the Instituto de Ciencias Biomedicas at the Universidad de Chile in Santiago de Chile, dealt with the modulatory effects of testosterone (and aldosterone) on intracellular calcium response in skeletal muscle cell cultures and not the subsequent consequences on contractile force of hypertrophy and could thus only serve as a point of departure for future investigations to either confirm or refute this idea (Estrada. 2010).

Nicotine exposure, brain aromatase and gender-specific implications

With the advent of new technologies, esp. the direct observation of aromatase activity in primate brains (Lidstrom, 1998; Kim, 2009; Biegon, 2010), our understanding of the peripheral effects of certain substances on hormone metabolism, one of the latest such insights pertains to the effects of nicotine exposure on the expression of the aromatase enzyme in the brain.

Figure 1: Effect of nicotine on brain aromatase availability in the female baboon. Representative baseline PET image coregistered with MRI at baseline and following injection of low dose (0.015 mg/kg) or high dose (0.03 mg/kg) nicotine. PET images show averaged frames acquired between 52.5 and 90 min after tracer injection, pseudocolored using the rainbow spectrum, with purple indicating the lowest density and red indicating the highest density of radioactivity (from Biegon, 2010).

In a recently published paper scientists from the Brookhaven National Laboratory Upton in New York did now connect the dots between the previously observed direct inhibitory effects on the central expression of the CYP19a mediated expression of the aromatase enzyme of nicotine and (potentially) other tobacco alkaloids. Thus, Anat Biegon, Nelly Alia-Klein and Joanna S. Fowler are not only able to explain, why women are more susceptible to the addictive effects of the nicotinic acetylcholine receptor agonist, which accumulates in the leaves of several members of the Solanaceae (nightshade) family, than men, but observations such as the early onset of menopause and lower plasma estrogen levels and correspondingly higher osteoporosis risk in female smokers compared to their non-smoking peers, as well (Daniell. 1972; MacMahon. 1982; Nusbaum. 2000; Pant. 2008; Korkor. 2009).

Table 1: Comparison of the effects of nicotine exposure and the effects of an aromatase inhibitor (at different time points in life) on sexual behavior, anxiety and depression, hot flashes, and weight gain in men and women (Biegon. 2012)

The scientists also list a couple of other ascertained side-effects pertaining which are equally important to men and women: The sexual behavior for example has been shown to drop both in response to prenatal, as well as acute nicotine exposure in male mammals - something those of you who happen to have a prescription for an aromatase inhibitor as an adjunct to their TRT regimen and did not hit the sweet spot between too much and too little estrogen, will certainly be aware of. While anecdotal evidence clearly points into that direction the scientific consensus on the negative impact of aromatase inhibitors on male libido in men (not male rodents), is however not yet clear. Personally, I believe this is partly due to the fact that pertinent studies usually deal with subjects who reduce their estrogen levels to normal, which could in fact lead to increased testosterone and DHT level in the absence of any negative side effects on the patients' libido.

If you take a look at the overview in table 1, you will however realize that other effects as the anxiolytic effects of acute nicotine exposure in adult women or the weight loss effect (which is certainly another reason women like to smoke) stand in direct opposition to the hypothesis that the majority of nicotines beneficial and negative side-effects were mediated by its effects on the aromatase enzyme. Fortunately, for most smokers, this appears to apply to the pro-Alzheimer's effects of low brain aromatase (Hiltunen. 2006), as well - at least, if we go by the conflicting results of the latest epidemiological studies, which contradict earlier findings that did even suggest that smokers would have a lower risk of Alzheimer's disease.

Alzheimer's, dementia, etc. are yet only examples of the far reaching effects brain aromatase and its regulation by nicotine and other substances such as aromatase inhibiting drugs, but also all sorts of environmental toxins with endocrine side-effects could have - so you can easily expect more interesting study results in the future.

Other news that did not make it into the show

As I have mentioned in the introduction, we did cover a hell lot of ground, so that most of the other studies are directly related to the luteinizing hormone negative feedback and thus no real "news" - I skipped discussing those, since I though that everyone listening will get the main message and did not want to bore those of you who are not interested in this topic with a show solely on the effects of nutrient deprivation and exercise on the endocrine milieu. But enough of the excuses, there is still more:

• Right-left digit ratio (2D:4D) predicts testosterone response to exercise in 79 professional Rubgy players (Kilduff. 2012) - In the analysis, researchers from the Swansea University at the Sports Science, Talbot Building in Singleton Park,  Swansea, UK, found that despite significant differences in basal testosterone levels, the 2D:4D ratio, which is generally regarded as an indicator of in-utero androgen exposure was significantly associated with a lower testosterone response to repeated sprint-agility tests in the 25 subjects who participated in the active arm of the study.

• Caffeine prevents weight gain and cognitive impairment by high fat diet (Moy. 2012) - This is not news? Just read on, you will soon realize that it is news! Firstly, the scientists from the University of Albany identified an ameliorative effect of caffeine on the diet-induced reduction of hippocampal expression of the brain-derived neurotrophic factor (BDNF) as the underlying mechanism behind it's neuroprotective effect (the same stuff that's also increased by exercise, by the way).
  
  

  

  Figure 2: Assuming this is not a mistake in the study caffeine once a week would be enough to boost the BDNF levels of junk-food and normal eaters alike (Moy. 2012)

  And secondly, the rodents received only a single, weekly intraperitoneal injection that would be equivalent to ~250mg in a human being (I double checked, the study says: "All animals received either caffeine (20 mg/kg) or saline (volume-matched), i.p., once weekly."; my emphasis in Moy. 2012). If that's not a mistake, chronic caffeine consumption may not even be necessary to see a hell-lot of the anti-diabetes and anti-neurological damage effects of coffee - just 2 cups once per week that's it!
  
  And if you look closely at the data in figure 2 you see that even "normal" people may benefit from this regimen.

Since tomorrow is an official installment of "On Short Notice" due, I will leave you on that flabbergast caffeine study and just remind you that there is - as everyday (guaranteed even on Christmas ;-) tons of interesting new stuff on the SuppVersity Facebook Wall, as well - let's see what we have today:

• Insulin has anti-Alzheimer's effect - Yeah you read me right. It reduces the formation of ameliod beta plague (read more)
• Yet more plant extracts with natural anti-cancer activity: Chamaejasmenin B and neochamaejasmin C isolated from the root of Stellera chamaejasme L known in TCM as Rui Xiang Lang D (read more)
• Want to father a Nobel Laureate and in your early to late 30s? Than its about time you procreate! Study finds U-shaped curve for father's age and intellectual abilities of the offspring peaking at 32-37 years or so (read more) 
   
• ...plus the rest I did not mention (read all)

I guess with the podcast to listen to and some food for thought on once-weekly caffeine administration (on a side note, injecting into the intraperitoneal cavity is, for most substances, only minimally different from oral ingestion and done only to assure that the animals don't spit whatever you want them to ingest back out) you will survive the next couple of hours until the facebook news will receive another update and the next installment of "On Short Notice" is going to be published? If not, complain in the comment area ;-)
 
References:

• Biegon A, Kim SW, Alexoff DL, Jayne M, Carter P, Hubbard B, King P, Logan J, Muench L, Pareto D, Schlyer D, Shea C, Telang F, Wang GJ, Xu Y, Fowler JS. Unique distribution of aromatase in the human brain: in vivo studies with PET and [N-methyl-11C]vorozole. Synapse. 2010 Nov; 64(11):801-7. 
• Biegon A, Alia-Klein N, Fowler JS. Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain. Front Pharmacol. 2012;3:185.
• Daniell HW. Osteoporosis and smoking. JAMA. 1972 Jul 31;221(5):509.
• Estrada M, Liberona JL, Miranda M, Jaimovich E. Aldosterone- and testosterone-mediated intracellular calcium response in skeletal muscle cell cultures. Am J Physiol Endocrinol Metab. 2000 Jul;279(1):E132-9.
• Hiltunen M, Iivonen S, Soininen H. Aromatase enzyme and Alzheimer's disease. Minerva Endocrinol. 2006 Mar;31(1):61-73.
• Korkor AB, Eastwood D, Bretzmann C. Effects of gender, alcohol, smoking, and dairy consumption on bone mass in Wisconsin adolescents. WMJ. 2009 Jul;108(4):181-8.
• MacMahon B, Trichopoulos D, Cole P, Brown J. Cigarette smoking and urinary estrogens. N Engl J Med. 1982 Oct 21;307(17):1062-5.
• Moy GA, McNay EC. Caffeine prevents weight gain and cognitive impairment caused by a high-fat diet while elevating hippocampal BDNF. Physiol Behav. 2012 Dec 6.
• Nusbaum ML, Gordon M, Nusbaum D, McCarthy MA, Vasilakis D. Smoke alarm: a review of the clinical impact of smoking on women. Prim Care Update Ob Gyns. 2000 Sep 1;7(5):207-214.
• Pant S, Shapiro CL. Aromatase inhibitor-associated bone loss: clinical considerations. Drugs. 2008;68(18):2591-600.
• Roselli CE, Abdelgadir SE, Ronnekleiv OK, Klosterman SA. Anatomic distribution and regulation of aromatase gene expression in the rat brain. Biol. Reprod. 1998; 58, 79–87.
• Roselli CE, Resko JA. Cytochrome P450 aromatase (CYP19) in the non-human primate brain: distribution, regulation, and functional significance. J. Steroid Biochem. Mol. Biol. 2001; 79, 247–253.

 

Honey, Smoke & Testosterone: One Tablespoon of Honey Protects Your Leydig Cells From Oxidative Damage

Image 1: A beehive in one of the beehives Koompassia excelsa (‘Tualang’) trees which grow in the Rain Forest of Kedah, Malaysia.

"Have you already had your tablespoon of honey, Honey?" If that's what your girlfriend or wife asked you this morning, she is probably concerned about your testicular health... A group of Malaysian scientists has recently been able to show that 1.2g/kg/day (human equivalent: 0.2g/kg/day or about 1 tablespoon for an average adult man) of a off-the-shelf Malaysian Tulang honey protected the testis of rats, who had been exposed to cigarette some for 8 minutes three times per day, from damage and oxidative stress (Mohamed. 2011).

Before the experiment, the scientists had conducted FRAP and DPPHI assays to determine the in-vitro antioxidant activity of the sweet gummy superfood from "beehives built on a tall tree, Koompassia excelsa (locally named as ‘Tualang’ tree) that grows in the Rain Forest of Kedah".

Figure 1: Total phenolic content (Eq/kg), antioxidant activity (FRAP; µmol of Fe Eq/L), free radical scavenging activity (DPPH assay % inhibition of DPPH radicals) and sugar composition of the Tulang honey used in the study (data adapted from (Mohamed. 2011).

As the data in figure 2 shows, the anti-inflammatory, anti-oxidant effects of the honey (cf. figure 1), were so pronounced that the +234% increase in TBARS (thiobarbituric acid reactive substance) cigarette exposure induced in the unsupplemented group was completely abolished by the Tulang honey "supplement" (I deliberately put this into quotation-marks, because I would not consider the "human equivalent", i.e. putting a tablespoon of honey in the tea you have with breakfast as "supplement").

Figure 2: Effect of 13 weeks of honey supplementation (H: 1.2g/kg/day), exposure to cigarette smoke (CS: 8 min, 3x daily) or both (H+CS) on oxidative stress markers from rat testis (Mohamed. 2011).

Accordingly, the Leydig cell sections from the "smoking rats" that received supplemental honey (H+CS; -15% Leydig Cell count), did not show similarly pronounced degenerations as their standard fed peers in the CS (8min 3x daily exposure to cigarette smoke; -23% Leydig cell count) group (cf. figure 3).

Figure 3: Representative photomicrographs of testicular sections showing Leydig cells in intertubular space from the control, the cigarette smoke and the honey + cigarette smoke groups (graphic is based on photos from Mohamed. 2011).

Even if, as I would hope, you have not yet seen how "damaged" Leydig cells look like, the photomicrographs in figure 3 leave no doubt that even with the protective effect of honey, 13 weeks of only 24 minutes cigarette smoke exposure wreak havoc on the morphology of those cells of your best parts that are responsible for the production of testosterone.

Image 2: Believe it or not, despite the fact that it has carbs (you could also argue that it is pure sugar!) honey is not only good for your testis, but for your blood sugar levels as well (photo from readmyreview.com)

Just a quick note to all you sugar-haters out there who are afraid that the one tablespoon of honey will give you diabetes, heart attacks and strokes (let alone all those unaesthetic body fat you will gain ;-): A very recent review on the health effects of honey consumptions comes to the conclusion that (Cortes. 2011)

compared to glucose and sucrose, the consumption of honey decreases glycemic levels and blood lipids in healthy, diabetic and hyperlipidemic individuals. Moreover, long periods of honey intake seem to reduce fasting glucose levels in humans, suggesting that honey consumption influences plasma glucose regulation, mainly through a normo- or hypoglycemic effect.

Digest this before you pass on the honey, because "it has carbs in it!" *scary*

So, while we all know that testosterone won't make you aggressive (ScienceDaily. 2009), there is another sort of "testosterone-related" issue that always has me close to freaking out: Male and female tobacco junkies who dare to light their weeds right next to their own kids... and I bet you, those poor little buggers won't be fed a teaspoon (that should be enough given their smaller body weight) of Malaysian Tulang honey a day.

True or False: You Can (Ab-)Use Nicotine Chewing Gums to Get Shredded Without Compromising Your Health

Nicotine gums are made for smokers. Smokers are leaner than no-smokers. Chewing nicotine gums helps you lean out... broscience? Logic? Or bullshit?

It's one of the better-known pieces of broscience: "Nicotine chewing gums will promote weight loss!" Aside from being "better-known", it's yet also highly controversial. In that, people usually don't question the fact that nicotine chewing gums may promote weight loss (we do all know that smokers, are leaner, don't we?), but rather that they do so in the absence of significant ill-health effects.

Since this is the SuppVersity and not the bb.com bulletin board, I am not going to restrict today's analysis on the health issues. Instead, I will start by looking for scientific evidence that would confirm the common sense assumption that chewing nicotine gums does in fact promote weight loss -- in humans, not in rodents (Lupien. 1988).

You can find more True or False articles at the SuppVersity

Pasta "Al Dente" = Anti-Diabetic

Vinegar & Gums for Weight Loss

Teflon Pans Will Kill You!

Yohimbine Burns Stubborn Fat

You Can Wash Pesticides Away

High Volume Diet = Success

Let's first take a look at the connection between nicotine and body weight management in general. In 2006 Chen et al. published an intriguing paper the title of which could in fact explain why smokers tend to be lighter than non-smokers (for US citizens that's ~ 3.7% leaner; cf. Albanes. 1987): "Cigarette Smoke Exposure Reprograms the Hypothalamic Neuropeptide Y Axis to Promote Weight Loss" (Chen. 2006)

According to Chen et al., the anorexic effects they observed in a 4 week rodent study are behind the anti-obesity effects of smoking. Similar effects on appetite in general and reductions in sugar cravings (Grunberg. 1982) in human studies as well. Nevertheless, if a reduction in appetite was the only beneficial effect of nicotine would be limited to phases of ad-libitum dieting. A direct effect on fat loss, as it is implied by broscience, on the other hand, would not exist.

Beware of becoming skinny fat! While the average smoker may be lighter, he is not necessarily leaner. The results of a 1989 study by Shimokata et al. show that smokers have higer waist-to-hip ratios and "indicate that there are harmful effects of cigarette smoking on the pattern of distribution of body fat" i.e. away from the harmless body parts, i.e. the extremities and right to the epicenter of unhealthy fat: the waist! Due to the fact that cigarette smoking is also associated with unhealthy eating habits (Dallongeville. 1998), it's yet difficult to tell, whether this effect is (solely) due to the cigarettes.

If it was not for Schechter et al. and other scientists who report "nicotine-induced weight loss in rats without an effect on appetite" (Schechter. 1976), I could stop here and tell you that (a) you obviously don't want to chew nicotine gums for the rest of your life to benefit from its appetite suppressing phases and that (b) it wouldn't make sense to chew them in a phase, where you're counting calories, anyway (if you want the appetite suppressing effects, anyway, add caffeine, this will enhance them; Jessen. 2005).

Figure 1: Body weight and food intake in 13 week rodent study with 0.4mg/kg and 0.8mg/kg (right) of nicotine administered in solution or saline control thrice daily (Schechter. 1976)

Thanks to the impressive reduction in body weight Schlechter et al. observed in the previously cited rodent study in the absence of statistically significant reductions in food intake (graphs at the bottom of Figure 1), it's worth to keep digging further.

Figure 2: (a) Male body weights before, during, and after nicotine or saline administration; (b) Female body weights before, during, and after nicotine or saline administration (Grunberg. 1987)

Ladies, beware! The non-food related weight loss could be a "male only thing"! According to Grunberg et al. "the nicotine-related changes in body weight were accompanied by changes in bland food and water consumption" in female rodents - as the authors point out, a significant difference to previous studies (Grunberg. 1986). Accordingly, a follow-up study showed: "The body weight of females that had received nicotine were indistinguishable from controls up to 4 months after cessation of nicotine. The body weight of males that had received 12 mg nicotine per kg per day remained lower than controls." (Grunberg. 1897). Notably, the dreaded weight regain occured in male & female rodents (Figure 2)!

If you take a close look at the results you will yet realize that there is a big caveat to the impressive weight loss (specifically in the 3x0.8mg/kg group | human equivalent ~ 3x4mg or three high dose nicotine chewing gums). Yes, I am talking about the the nasty weight regain that occurred - likewise in the absence of increased food intakes - when the nicotine administration was seized.

Against that background, it's all the more important to find evidence from human studies. Unfortunately, the majority of studies on nicotine gums is not relevant to the topic, because they are (a) dealing with the success of smoking cessations, or (b) dealing with weight regain after smoking cessation. We will therefore have to resort to ostensibly unrelated results such as...

• 

  Figure 3: Plasma leptin levels in non-smokers, long-term nicotine gum users and smokers after adjustment for age and body composition (Eliasson. 1999)

  the increase in leptin levels researchers from the Sahlgrenska University Hospital in Göteborg (Sweden) observed in a 1999 study in 73 subjects: 23 non-smokers, 31 smokers and 19 long-term nicotine gum chewers (NGCs) with similar ranges of age, body mass index (BMI) and per cent body fat. As the authors of the corresponing paper point out, "[t]he increased leptin levels may be an important reason for the lower body weight in smokers." (Eliasson. 1999). Unfortunately "long-term" is nothing you would associate with the use of nicotine gums as diet adjuvant.
  
  As suggestive as they may be, the increases in leptin are thus probably not relevant for short term decreases in body weight - or even better body fat - as you would expect them, when you're dieting.
• the association with hyperinsulinemia and insulin resistance the same Swedish researchers from the Sahlgrenska University Hospital observed in a previous investigation (Taskinen. 1996) clearly suggest that the chronic consumption of nicotine leads to insulin resistance, metabolic abnormalities associated with the insulin resistance syndrome, and increased cardiovascular morbidity.
  
  On the other hand, we are - I can't repeat that often enough - not talking about the chronic use of nicotine gums, but their (ab-)use for 4-6 weeks to propel your fat loss results. Eventually, the results are thus as irrelevant as the previously mentioned beneficial effects on leptin (see previous bullet-point).

• 

  Figure 4: Thermogenic effect in 150min after the ingestion of nicotine and / or caffeine (Jessen. 2003)

  the "pronounced" thermogenic effect researchers from the The Royal Veterinary and Agricultural University in Denmark observed in their 2003 study. Aside from scientific evidence that the administration of nicotine has thermogenic effects, the second important result of the study at hand is the observation hat the thermogenic effects  of 1 mg nicotine (measured over 150 min after the ingestion) can be (almost) doubled, if the nicotine is administered in conjunction with 100 mg of caffeine (Jessen. 2004).
  
  It's also important to note that "[i]ncreasing the nicotine dose to 2 mg does not increase the thermogenic effect but produces side effects in most subjects." (Jessen. 2003) More is thus, as so often, not better for nicotine (a similar non-linear dose-response effect was observed with cigarettes, as well; cf. Collins. 1996). A previous study by Collinset al. (1994) found a 7.5% increase in resting energy expenditure with 200mg of caffeine and a similarly low amount of nicotine, i.e. 0.8mg of nicotine from cigarette smoke over a 3h period.

If you take a look at the evidence I provided, it supports the previously raised concerns about the long-term use of nicotine gums. On the other hand, the study by Jessen et al., as well as the study Collins et al. who didn't just find a similar synergistic effect of caffeine and nicotine, but were also able to show that the effects occur in both smokers and non-smokers (Collins. 1994; similar results in Perkins. 1989), clearly indicate that the short-term (ab-)use of nicotine gums may in fact promote the loss of body weight and - assuming you're getting your 1.5g/kg protein and lifting heavy objects - body fat, as well.

Figure 5: The increase in thermo- genesis due to 4x20µg intranasal nicotine is impressive in men, non- significant in women (Perkins. 1996)

Do men better sniff their nicotine?! While snuff is obviously not identical to an intranasal nicotine spray, the results Perkins et al. present in their 1996 study which investigated the effects of 4x20µg/kg nicotine that was administered intranasally every 30 minutes for 2h after the consumption of tonic water or alcohol are quite impressive... well, at least in men. In contrast to the male subjects in whom the nicotine only increased the energy expenditure by almost 13%, the 3.8% increase in the female study subjects was not significant! Whether that's a result of the absolutely lower dosage (remember the nicotine was dose per body weight) or a true sex-difference is uncertain.

Unfortunately, it is difficult to say whether these benefits come with significant negative effects on your health. Evidence on short-term effects of nicotine abuse in human beings is scarce. Furthermore studies in non-smokers suggest that healthy people and people with pre-existing problems with glucose management react differently, with the former experiencing no and the latter experiencing severe reductions in insulin resistance in response to the acute infusion of nicotine in a 2001 study by Axelsson et al.

Figure 6: Negative effects of nicotine on insulin sensitivity occur only in diabetics (Axelsson. 2001)

As far as the dreaded increases in insulin resistance are concerned, you could thus argue that the contemporary evidence suggest that healthy athletic individuals have nothing to fear. Since the same appears to be true for the negative effects on platelet count (Mundal. 1995), blood pressure and other markers of cardiovascular health (Benowitz. 2002). For people who belong to one of the classic risk groups, i.e. men and women with metabolic syndrome and / or existing heart condition, the use of nicotine gum may yet easily result in a hospital stay or worse (Rigotti. 1986).

If you want to try it, try this: 200mg caffeine + 1mg nicotine from chewing gums upon rising, another 200mg of caffeine and 1mg nicotine at lunch or pre-workout, additional 2x 100mg caffeine + 1mg nicotine between breakfast and lunch and lunch and dinner.

Bottom line - True! For healthy athletic folks! Just to make that clear. I am not, by any means recommending the use of nicotine gums for weight loss. All I do is to answer the often heard question whether the bro-scientific assumption that they'd help you shed body fat is true.

And, by the way, the study that would confirm that "dieting + nicotine" = greater weight / fat loss than "dieting alone" has not yet been conducted. If you want to do your own N=1 study, do it at your own risk. Next to potential (albeit for healthy people probably controllable health issues), it appears as if there was also a minimal risk of addiction for never-smokers (Etter. 2007) | Comment on Facebook!

References:

• Albanes, Demetrius, et al. "Associations between smoking and body weight in the US population: analysis of NHANES II." American Journal of Public Health 77.4 (1987): 439-444.
• Axelsson, T., et al. "Nicotine infusion acutely impairs insulin sensitivity in type 2 diabetic patients but not in healthy subjects." Journal of internal medicine 249.6 (2001): 539-544.
• Benowitz, Neal L., Anna Hansson, and Peyton Jacob. "Cardiovascular effects of nasal and transdermal nicotine and cigarette smoking." Hypertension 39.6 (2002): 1107-1112.
• Chen, Hui, et al. "Cigarette smoke exposure reprograms the hypothalamic neuropeptide Y axis to promote weight loss." American journal of respiratory and critical care medicine 173.11 (2006): 1248-1254.
• Collins, L. C., et al. "Effect of caffeine and/or cigarette smoking on resting energy expenditure." International journal of obesity and related metabolic disorders: journal of the International Association for the Study of Obesity 18.8 (1994): 551-556. 
• Collins, Lynell C., Jerome Walker, and Bryant A. Stamford. "Smoking multiple high-versus low-nicotine cigarettes: impact on resting energy expenditure." Metabolism 45.8 (1996): 923-926.
• Dallongeville, Jean, et al. "Cigarette smoking is associated with unhealthy patterns of nutrient intake: a meta-analysis." The Journal of nutrition 128.9 (1998): 1450-1457.
• Eliasson, Björn, and Ulf Smith. "Leptin levels in smokers and long‐term users of nicotine gum." European journal of clinical investigation 29.2 (1999): 145-152. 
• Etter, Jean-François. "Addiction to the nicotine gum in never smokers." BMC public health 7.1 (2007): 159.
• Grunberg, Neil E., Deborah J. Bowen, and Suzan E. Winders. "Effects of nicotine on body weight and food consumption in female rats." Psychopharmacology 90.1 (1986): 101-105.
• Grunberg, Neil E. "The effects of nicotine and cigarette smoking on food consumption and taste preferences." Addictive behaviors 7.4 (1982): 317-331.
• Grunberg, N. E., S. E. Winders, and K. A. Popp. "Sex differences in nicotine's effects on consummatory behavior and body weight in rats." Psychopharmacology 91.2 (1987): 221-225.
• 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.
• Jessen, A., et al. "The appetite‐suppressant effect of nicotine is enhanced by caffeine*." Diabetes, Obesity and Metabolism 7.4 (2005): 327-333. 
• Mundal, H. H., K. Gjesdal, and P. Hjemdahl. "Acute effects of low dose nicotine gum on platelet function in non-smoking hypertensive and normotensive men." European journal of clinical pharmacology 47.5 (1995): 411-416. 
• Lupien, John R., and George A. Bray. "Nicotine increases thermogenesis in brown adipose tissue in rats." Pharmacology Biochemistry and Behavior 29.1 (1988): 33-37.
• Perkins, Kenneth A., et al. "Metabolic effects of nicotine in smokers and non-smokers." Problems of Drug Dependence 1989 (1989): 469.
• Perkins, Kenneth A., Joan E. Sexton, and Amy DiMarco. "Acute thermogenic effects of nicotine and alcohol in healthy male and female smokers." Physiology & behavior 60.1 (1996): 305-309.
• Rigotti, Nancy A., and Kim A. Eagle. "Atrial fibrillation while chewing nicotine gum." Jama 255.8 (1986): 1018-1018.
• Schechter, Martin D., and Peter G. Cook. "Nicotine-induced weight loss in rats without an effect on appetite." European journal of pharmacology 38.1 (1976): 63-69.
• 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.

Sex, Drugs and... Exercise? Caffeine, Alcohol, Marihuana and Nicotine - Do All Our Favorite Addictions Clash With Being Healthy, Lean and Athletic?

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 don't I'd suggest you start out with this SuppVersity Classic before you devote yourself to Rock'n'Roll 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).

Why are you laughing? Caffeine was on the WADA's list of banned substances from 1962 to 1972 and again from 1984 to 2003. Whether the average coffee consumer will ever achieve concentrations of 12 μg/ml+ in the urine and thus fail a doping test is obviously a whole different question, but during the second banned period from 1984-2003, a whole host of athletes passed the magic 12 µg/ml line and were tested positive for caffeine. The sanctions ranged from warnings up to

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 world's "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 it's 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 everyone's 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).

Alcohol is a killer: According to WHO, morbidity attributable to alcohol in countries with an established market economy (10.3% of disability adjusted life years) comes second only to that of tobacco (11.7%; Murray. 1997). According to a very recent study by published in the scientific journal Addiction by the Pan American Health Organization, a branch of the World Health Organization alcohol was a 'necessary' cause of death (i.e., death would not have occurred in the absence of alcohol consumption) in an average of 79,456 cases per year in 16 North and Latin American countries (Gawryszewski. 2014).

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] - Don't 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 that's 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 it's 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 that's 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, wouldn't it make sense to switch from wine + strichnine to marijuana? Ok, you can't consume it "intra-workout", but maybe before and after the Queen's stage at L’Alpe d’Huez?!

Cannabis is everywhere and has been used for ages: While the legalization of cannabis in Colorado may be innovative, the sue of cannabis and its principal active ingredient, tetrahydrocannabinol (THC  is only one of 483 known compounds in the plant, including at least 84 other cannabinoids, such as cannabidiol, cannabinol, tetrahydrocannabivarin, and cannabigerol) is not. It has been used for generations by people all over the world (see table to the left, cf. Chopra. 1969). Whether it is "paleo" or not is yet something I can't tell you for sure ;-)

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 don't 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 don't 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 -- Renaud's and Cormier's 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 Δ9-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, it's probably a psychological one that could be brought about by anxiety reducing and euphorigenic effects of cannabis... but let's be honest: Isn't a healthy amount of pre-competition anxiety a necessary prerequisite for world-class performance?

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

If alcohol doesn't 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).

A note on different deliver routes: Both snus and nicotine gums enable nicotine to diffuse across the mucous membranes and are taken up by the bloodstream. The effects are yet still not necessarily identical to what we see, when it is inhaled and diffuses across the alveolar membrane - particularly if the source of the nicotine is a carcinogen-packed cigarette.

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 doesn't believe that nicotine doping is worth it. 3-(1-methyl-2-pyrrolidinyl)pyridine is currently on the watch list, but it's 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 won't 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).

Nicotine + caffeine = heart damage, w/ and without ephedra | more

Bottom line: If you take a look at the results of this mini-summary, caffeine addiction isn't just the only scientifically proven "ergogenic addiction", it's also the only one without certain (alcohol and pot) and almost certain (nicotine) negative side effects.

 If I had to pick my poison I would thus always go for caffeine and ignore alcohol, pot and even nicotine; and that in spite of the fact that the latter may exert (mainly neurological) benefits in certain sports.

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.