Saturday, March 24, 2018

2.5 mg Nicotine = Ergogenic - 18-21% Increase in Power in Crossover Study | Plus: Are Health or Addiction an Issue?

While cigarettes are neither effective performance enhancers nor safe, nicotine, one of their key ingredients, may be the effective ergogenic aid with a reasonable sides/effects ratio you have been looking for... well, that's at least what the recently published 1st RCT with reliability test and crossover protocol seems to suggest.
Yes, nicotine is the main (psycho-)active ingredient in cigarette smoke. It is, however, - and we tend to forget that in the debate about (ab-)using nicotine as a "supplement" - only one out of many "ingredients" of cigarette smoke; ingredients that ruin the health of our lungs and promote the risk of lung and other cancers.

It would be haphazard, though, to exonerate nicotine completely, as there is "a direct contribution of nicotine to cancer onset and growth" (Grando 2017). The research on the interaction of individual genetic susceptibility and nicotines ability to activate "nicotinic acetylcholine receptors (nAChRs), which are activated by nicotine [and] can activate several signaling pathways that can have tumorigenic effects" (ibid.) is still in its infancy.

Moreover, a detailed evaluation of putative carcinogenic effects of non-cigarette sources of nicotine that are used at comparatively low doses pre-workout to enhance physical performance is simply impossible because possible carcinogenic effects of such regimen have not been investigated at all!
Nicotine is, for a good reason, often 'stacked' with coffee and caffeine.

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For other health-relevant outcomes/side effects, smoking cessation studies w/ nicotine gum as temporary replacement may be used to estimate potential health hazards. This is also what I will do in the following analysis of the randomized, double-blind, cross-over trial, a study that was conducted with sixteen healthy, nicotine naïve male "athletes" (24.1 ± 5.3 years, 179.0 ± 8.8 cm, 81.7 ± 13.5 kg, BMI 25.5 ± 3.0, Body fat% 13.2 ± 5.1%), who were, in this instance, people who exercised for a minimum of 45 min at least three times per week, "with each training session containing a strength or power focus and some element of explosive training" (Johnston 2018).
Table 1: Mean± standard deviation of the Wingate performance measures and the corresponding intra-class correlation coefficients (ICC) during the repeatability condition (REP) and placebo (PLA) condition (Johnston 2018).
The subjects completed two repeated 30 s Wingate tests with 3 min rest between bouts following consumption of either a 5-mg oral-dispersible nicotine strip (NiQuitin® | NIC) or a flavour-matched placebo (PLA) in a randomized, double-blind, cross-over design. Before the Wingate test, resting heart rate and blood pressure were also measured prior to and following PLA and NIC ingestion.
The (ab-)use of nicotine, which is also on the WADA's watch-list, for performance enhancing purposes is already highly prevalent in various sports. This is at least what we have to conclude based on observational data from a 2011 study by Marclay et al. which found that 23% of the analyzed anti-doping samples in 2011 contained significant amounts of nicotine or its metabolites. Why's that significant? Well, this number is comparable to the world smoking rate of 25% but it is considerably higher than smoking rate in athlete populations (Marclay 2011). Accordingly, Marclay et al. conclude that the nicotine in the athletes' blood is most likely coming from "smokeless tobacco consumption for performance enhancement" (ibid).
The study was designed to add to the very limited evidence of nicotine's ergogenic effect in athletes, effects scientists ascribe to one or more of the following mechanisms (Mündel 2017):
  • Nicotine gums are made for smokers. Smokers are leaner than non-smokers. Chewing nicotine gums helps you lean out... broscience? Learn more
    potent psychostimulant effects via activation of central cholinergic receptors nicotine will, for example, bump up the production of dopamine and adrenaline
  • significant peripheral sympathoadrenal effects, particularly on the cardiovascular system including increased heart rate, blood pressure and cardiac output
  • meaningfully increased muscle blood flow via cutaneous vasoconstriction 
  • practically relevant elevation(s) of circulating metabolite levels such as free fatty acids, glucose, glycerol, and lactate + insulin & glucagon. 
As the authors of the study under review rightly point out, "[t]hese cardiovascular and metabolic changes have been reported to assist in meeting the demands of exercise by supplying adequate oxygen and energy substrates to active skeletal muscles" (Johnston 2018), while the "adrenaline-mediated effects of nicotine could [...] increase skeletal muscle contraction force and delay fatigue in fast twitch muscle fibres" (ibid)... or, as the same group wrote in their 2017 review:
"There is strong evidence supporting nicotine’s potential role as an ergogenic aid based on key physiological outcome measures relevant to physical performance, namely heart rate, blood pressure, peripheral blood flow and skin temperature. The significant decrease in heart rate variability establishes the role of nicotine in stimulating the sympathetic adrenergic system, which combined with the central effects of nicotine may underlie improvements in physical performance measures" (Johnston 2017). 
As previously hinted at, there is yet still "insufficient evidence to suggest that nicotine exhibits ergogenic effects" (Johnston 2017); and that despite the fact that experimental investigations of potential mechanisms to explain the hitherto not fully established ergogenic effects of clearly suggests that these effects should exist.
Stable nicotine levels (7-10 ng/ml) in the blood (as they can be achieved w/ nicotine patches | in Pullan et al. 5-15 mg/d administered in increasing doses) can significantly improve the overall Crohn's disease score, stool frequency, urgency, abdominal pain, and histology.
The medicinal use of nicotine demonstrates: nicotine is not the all-bad boogieman you are made to believe. It is beyond the scope of this article to address this in detail, but nicotine (in form of patches, sprays, gums, etc.) is by no means used only as a tool in the smoking cessation toolbox. As Grando points out in his previously referenced paper (free FT), "the therapeutic effects of nicotine-containing products are best characterized in ulcerative colitis and recurrent aphthous stomatitis" (Grando 2017), where smoking cessation can actually trigger the recurrence of the disease. How come?

Well, the often derided alkaloid possesses significant anti-inflammatory properties and both of the previously hinted at diseases are inflammatory diseases.

Next to observational data showing that smoking can actually prevent/revert the recurrence of ulcerative colitis and other inflammatory diseases, there are clinical and experimental studies to support the "anti-inflammatory effects of nicotine-containing products [ - ] for example, nicotine facilitates healing of both cutaneous174–176 and oral ulcers in humans, as well as skin blisters in rats and excisional skin wounds in mice" (Grando 2017) - even if it's administered systemically, in form of a chewing gum (Kawabata 1999)... but as I wrote before: a full evaluation of its pharmacological effects is beyond the scope of this SuppVersity article, sorry!
Practical nicotine for performance research is not just scarce, the majority of the ten pertinent studies Toby Mündel analyzed in his 2017 review yielded only non-significant effects. The authors of the study under review even report ergolytic (=performance reducing effects) in one of the six studies they included in their 2017 review of the literature (Johnston 2017) - the very same review that had them conclude that "future studies should also consider a different route of administration to minimize possible side effects attributed to [snus usage, in particular], and consider further parameters relevant to physical performance such as repeated exercise bouts - two improvements that were made for the study at hand" (Johnston 2017).
Figure 1: In view of the fact that you can expect the Tmax time, i.e. the time to reach maximal nicotine levels in the level, of the nicotine stripes used in the study at hand to be similar to the nicotine gum or the sublingual tablet, the timing (~15 min before the test) in the study at hand may have been suboptimal. It is also worth noting that, with a Tmax of 6-9h, nicotine patches are probably not an option for athletic performance (based on the review of studies in Mündel 2017).
With the "current evidence base [being] limited both in the quantity and quality" (Mündel 2017), it is all the more important that Johnston et al. were able to find significant increases in peak and average power output in response to the 2.5mg of nicotine that were administered 7 minutes (+5 minutes of warm-up) before the Wingate tests via oral strips (i.e. the oral mucosa).
Figure 2: Peak and average power were significantly improved by 2mg of nicotine administered in form of oral strips (=via the oral mucosa) ~15 minutes before the repeated Wingate test (Johnston 2018).
No significant effect, on the other hand, was observed for other effects you might expect based on the previously listed mechanism(s) of action, i.e. reaction times, rates of perceived exertion or post-exercise blood lactate levels (P > 0.05).
A 2003 study, I discussed in my 2014 article about using nicotine to get jacked, showed that nicotine naive subjects will experience a sign. increase in resting energy expenditure w/ 1 mg and add. side effects with 2 mg of nicotine from nicotine gums.
What's the most effective and safe form of nicotine? On our quest for the optimal source(s) of nicotine, we can exclude both, cigarettes (regular cigarettes as well as e-cigarettes) and water pipes, right away. Theit side-effect vs. effect ratio simply sucks. If you're aiming for immediate effects - and when we want to improve athletic performance, that's exactly what we do, nicotine patches have to be excluded as well. With a mean time to maximal serum concentrations of 6-9h, they're delivering the nicotine load simply way too slowly to see the desired effect. This leaves us with nicotine gums, inhalers, and sublingual tablets (see Figure 1)... ah, and the stripes that were used in the study at hand, obviously.

Which of these means of administration is actually 'optimal', however, will have to be established in future trials. Since nicotine gums are the most widely available and probably most convenient nicotine containers, they are what I would try first [I have indeed experimented with 1-2 mg and personally felt performance improvements and, since I was dieting at that time, more importantly, appetite suppression (learn more about using nicotine gums for weight loss)].
The likewise expected increases in heart rate and blood pressure, on the other hand, were significant and could be an issue for those of you who suffer from hypertension or cardiovascular disease, in general.

Is (ab-)using nicotine as an ergogenic aid even safe?

Since the results of the plethora of long-term studies on cigarette smoking don't give us any valid information to answer the previous safety question, I cannot really tell you if nicotine is a safe ergogenic. When used at the recommended (low) dosage of 1-3 mg it is probably safer than the formerly popular DMAA (Jack3D & Co). In the absence of true long-term studies (several years), it is yet difficult to tell if its sides are as transient as those of caffeine which can - as you as a SuppVersity reader will know - have quite severe acute side effects if it's taken in excess.
More won't help more, but it will significantly increase the risk of side effects! As it was the case with the previously discussed putative weight loss benefits, the sweet spot for nicotine is pretty low and more than 1-3 mg shouldn't be necessary - especially in non-smokers. With that being said, it is hitherto unknown if, but not unlikely, that the effective dosage will have to be increased upon continuous use. Plus: If you're asking yourselves why nicotine has not yet found its way into popular pre-workouts, the answer is easy: regulations and the gastric side effects you will get from swallowing too much nicotine at once prohibit the use of nicotine in classic pre-workouts.
Studies investigating the effects of smoke-free sources of nicotine, most prominently nicotine gums, during successful (and failed) smoking cessation do yet suggest an excellent safety profile. The 1996 "Lung Health Study", for example, investigated the effects of chewing 2mg gums (on average 10 pieces/d) in almost 4000 subjects over a period of three years and found the nicotine replacement "to be safe and unrelated to any cardiovascular illnesses or other serious side effects" (Murray 1996); and Moore et al. conclude in their 2009 review and meta-analysis that "[u]sing NRT [nicotine replacement therapy] while smoking did not lead to serious health problems".

With respect to the immediate effects of reasonably dosed + occasional nicotine use, the study at hand even reports reduced side effects in the first 5 minutes after the Wingate tests: "Post hoc analyses showed that the side effect scores were significantly greater for the PLA (5.31 ± 2.80) compared to the NIC (3.00 ± 2.70) condition immediately post the Wingate test (P<0.01)" (Johnston 2018) - a result that should remind of the important question whether any of the previously reported data from smoking cessation trials is even remotely relevant with respect to the use of non-cigarette sources of nicotine for performance enhancement. In the absence of specific research on its long-term effects, this will simply remain an unanswered question.

Is (ab-)using nicotine as an ergogenic aid going to make you addicted?

While studies indicate that smoking is highly addictive, the evidence that the same goes for nicotine replacement therapy with gums & co is less convincing. While there is experimental evidence that there can be withdrawal symptoms including increased irritability, difficulty in concentrating and a drop in heart rate with nicotine gums  (Hughes 1986), it seems to be far less addictive than regular cigarettes.

A short period of dose-dependent side effects can be an issue if you stop chewing (high dose) nicotine gums 'cold turkey'. 
With respect to their addictive potential, nicotine gums and related oral nicotine preparations are probably comparable to caffeine, of which those of you who have tried to stop drinking their 4 cups of coffee 'cold turkey'/overnight will have found that it produces significant withdrawal symptoms that can last for 2-14 days. In that it is important to note that most people will not experience any problems if they reduce their intake gradually). Something similar can be expected for nicotine gum, where the administration of 2mg vs. 4mg gums resulted in a highly significant reduction of withdrawal symptoms (from 3 to 1 symptom) over 4 days.

More importantly and in contrast to smoking cessation, stopping nicotine gums cold turkey after 1 month of continuous usage did not produce a sign. increase in total symptom scores (irritable/angry, anxious/tense, difficulty concentrating, restless, impatient, excessive hunger, somatic symptoms (e.g., sweating, dizziness, and stomach problems), insomnia, increased eating, and drowsiness.) - even if the high dose of 4mg is used (Hatsukami 1991). Moreover, addiction can be almost excluded with occasional use during training/competition.
Just like caffeine, nicotine may help you to keep your metabolism running while dieting. You can learn more about this in this and potential side effects in the following 2017 SuppVersity Classic: "Role of Muscle and CNS in Diet-Induced Decline of Exercise-Induced Energy Expenditure | Caffeine & Nicotine May Help!" | read it
Bottom line: The main take-home message of the study at hand (methodologically probably the best we have today) is that the ingestion of 2.5 mg of nicotine in form of a sublingual stripe (NiQuitin®) will significantly improve practically relevant performance markers. Whether the increases in peak (~21%) and average power (~18%) in the Wingate test translate to relevant increases in athletic performance in specific sports (e.g. weightlifting, Crossfit, sprinting, cycling, running, etc.) is yet difficult to predict.

More research is also necessary to determine the long-term safety of nicotine "supplements", the best form of administration, optimal dosage, and proper timing (previous pharmacokinetic experiments suggest that the <15 minutes the study at hand left between the administration of nicotine and the exercise test may be suboptimal because the level of nicotine is probably going to peak after 30-60 minutes).

For the former, i.e. the safety-related parameters, as well as the addictive potential of alternative (=non-smoking + non-tobacco) sources of nicotine (see Figure 1), the clearly insufficient evidence seems to suggest a very reasonable safety profile. As long as nicotine is used only occasionally and in low(-ish) dosages of 1-3 mg per day it may indeed be similar to that of medium-dose caffeine, which has similar acute cardiovascular side effects (increased heart rate and blood pressure) and mild withdrawal effects. In the absence of exercise-specific long-term safety data, I can still not recommend the use of nicotine as a standalone ergogenic or as part of the popular nicotine + caffeine stack | Comment on Facebook!
References:
  • Grando, Sergei A. "Connections of nicotine to cancer." Nature Reviews Cancer 14.6 (2014): 419.
  • Hatsukami, Dorothy K., et al. "Signs and symptoms from nicotine gum abstinence." Psychopharmacology 104.4 (1991): 496-504.
  • Hughes, John R., Dorothy K. Hatsukami, and Kelli P. Skoog. "Physical dependence on nicotine in gum: a placebo substitution trial." Jama 255.23 (1986): 3277-3279.
  • Johnston, Robert, M. Crowe, and K. Doma. "Nicotine effects on exercise performance and physiological responses in nicotine in naive individuals: A systematic review." Journal of Science and Medicine in Sport 20 (2017): e47.
  • Johnston, Robert, Melissa Crowe, and Kenji Doma. "Effect of nicotine on repeated bouts of anaerobic exercise in nicotine naïve individuals." European journal of applied physiology 118.4 (2018): 681-689.
  • Kawabata, H., et al. "Successful treatment of digital ulceration in Buerger's disease with nicotine chewing gum." The British journal of dermatology 140.1 (1999): 187-188.
  • Marclay, François, et al. "A one-year monitoring of nicotine use in sport: frontier between potential performance enhancement and addiction issues." Forensic science international 213.1-3 (2011): 73-84.
  • Mündel, Toby, and David A. Jones. "Effect of transdermal nicotine administration on exercise endurance in men." Experimental physiology 91.4 (2006): 705-713.
  • Mündel, Toby. "Nicotine: Sporting Friend or Foe? A Review of Athlete Use, Performance Consequences and Other Considerations." Sports Medicine 47.12 (2017): 2497-2506.
  • Murray, Robert P., et al. "Safety of nicotine polacrilex gum used by 3,094 participants in the Lung Health Study." Chest 109.2 (1996): 438-445.
  • Pullan, Rupert D., et al. "Transdermal nicotine for active ulcerative colitis." New England Journal of Medicine 330.12 (1994): 811-815.
  • West, R. J., and M. A. H. Russell. "Effects of withdrawal from long-term nicotine gum use." Psychological Medicine 15.4 (1985): 891-893.