Performance enhancing agent

A Performance-enhancing agent (or performance-enhancing drug) is a substance used to improve any form of activity performance in humans. A well-known example involves doping in sport, where physical performance–enhancing drugs are used by athletes and bodybuilders. Use of cognitive performance enhancers by students is sometimes referred to as academic doping. They are also used by military personnel to enhance combat performance.^[1]

Use of performance-enhancing drugs spans the categories of legitimate use and substance abuse.

Definition

The classifications of substances as performance-enhancing agents are not entirely clear-cut and objective. As in other types of categorization, certain prototype performance enhancers are universally classified as such (like anabolic steroids), whereas other substances (like vitamins and protein supplements) are virtually never classified as performance enhancers despite their effects on performance. As is usual with categorization, there are borderline cases; caffeine, for example, is considered a performance enhancer by some but not others.^[2]

Types

The phrase has been used to refer to several distinct classes of drugs:

• Anabolic drugs build up muscle; examples include steroids^[3] hormones, most notably human growth hormone, as well as some of their prodrugs,^[4] selective androgen receptor modulators^[5] and beta-2 agonists.^[6][7]
• Stimulants improve focus and alertness. Dopaminergic stimulants (e.g., reuptake inhibitors and releasing agents) also affect cognitive and athletic performance by improving muscle strength and endurance while decreasing reaction time and fatigue; some examples of ergogenic (athletic performance-enhancing) stimulants are caffeine,^[8] ephedrine and amphetamine.^{[9][10][11][12][13]}
• Endurance enhancement: methylphenidate increases power output at constant levels of perceived exertion, ^[14] and bupropion increases power output at constant levels of perceived exertion only during short term use'^[14] the effect disappears during chronic use.^[14]

• Nootropics, or "cognition enhancers", benefit overall cognition by improving memory (e.g., increasing working memory capacity or updating) or other aspects of cognitive control (e.g., inhibitory control, attentional control, attention span, etc.).^[15][16]
• Adaptogens result in stabilization of physiological processes and promotion of homeostasis, an example being by decreased cellular sensitivity to stress.
• Painkillers allow performance beyond the usual pain threshold. Some painkillers raise blood pressure, increasing oxygen supply to muscle cells. Painkillers used by athletes range from common over-the-counter medicines such as NSAIDs (such as ibuprofen) to powerful prescription narcotics.
• Sedatives and anxiolytics are sometimes used in sports like archery which require steady hands and accurate aim, and also to overcome excessive nervousness or discomfort. Diazepam and propranolol are common examples; ethanol and cannabis are also used occasionally.
• Blood boosters (blood doping) increase the oxygen-carrying capacity of blood beyond the individual's natural capacity. They are used in endurance sports like long-distance running, cycling, and Nordic skiing. EPO is one of the most widely known drugs in this class.

Usage in sport

In sports, the phrase performance-enhancing drugs is popularly used in reference to anabolic steroids or their precursors (hence the colloquial term "steroids"); anti-doping organizations apply the term broadly.^[17] There are agencies such as WADA and USADA that try to prevent athletes from using these drugs by performing drug tests. WADA was founded on November 10, 1999 by Dick Pound. The World Anti-doping Agency focuses on establishing and enforcing rules and codes of all sports around the world. Their goal is to make all sports played fairly between all athletes in a doping free organization with the power to prevent athletes from using any form of performance-enhancing drugs. USADA started October 1, 2000 as non-profit and was composed of nine members. Five of which were former Olympic athletes with the other four elected from independent companies. This is the United States Anti-doping Agency and have the ability to test athletes across the nation. Steroids and performance-enhancing drugs are used across all sports organizations around the world.^[18][19]

See also

• Ergogenic use of anabolic steroids
• List of doping cases in sport
• Steroid use in American football

References

1. Anon. Better Fighting Through Chemistry? The Role of FDA Regulation in Crafting the Warrior of the Future. Food and Drug Law: Final Paper. March 8, 2004.
2. "Caffeine and Sports Performance". Vanderbilt.edu. Retrieved 2012-03-04.
3. "What are anabolic steroids?". National Institute on Drug Abuse. August 2006. Retrieved 2016-04-11.
4. McKelvey Martin, Valerie. "Drugs in Sport". Retrieved 15 April 2013.
5. Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, Hwang DJ, Dalton JT, Miller DD (June 2009). "Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit". Journal of Medicinal Chemistry 52 (12): 3597–617. doi:10.1021/jm900280m. PMID 19432422.
6. Drug Enforcement Administration. November 2013 Clenbuterol
7. Pluim BM, et al. β₂-Agonists and physical performance: a systematic review and meta-analysis of randomized controlled trials. Sports Med. 2011 Jan 1;41(1):39-57. PMID 21142283
8. Pesta DH, Angadi SS, Burtscher M, Roberts CK (2013). "The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance". Nutr Metab (Lond) 10 (1): 71. doi:10.1186/1743-7075-10-71. PMC 3878772. PMID 24330705. Caffeine-induced increases in performance have been observed in aerobic as well as anaerobic sports (for reviews, see [26,30,31]). Trained athletes seem to benefit from a moderate dose of 5 mg/kg [32], however, even lower doses of caffeine (1.0–2.0 mg/kg) may improve performance [33]. Some groups found significantly improved time trial performance [34] or maximal cycling power [35], most likely related to a greater reliance on fat metabolism and decreased neuromuscular fatigue, respectively. Theophylline, a metabolite of caffeine, seems to be even more effective in doing so [36]. The effect of caffeine on fat oxidation, however, may only be significant during lower exercise intensities and may be blocked at higher intensities [37]. ... For both caffeine-naïve as well as caffeine-habituated subjects, moderate to high doses of caffeine are ergogenic during prolonged moderate intensity exercise [61]. ... In summary, caffeine, even at physiological doses (3–6 mg/kg), as well as coffee are proven ergogenic aids and as such – in most exercise situations, especially in endurance-type events – clearly work-enhancing [26]. It most likely has a peripheral effect targeting skeletal muscle metabolism as well as a central effect targeting the brain to enhance performance, especially during endurance events (see Table 1). Also for anaerobic tasks, the effect of caffeine on the CNS might be most relevant. ... Muendel et al. [93] found a 17% improvement in time to exhaustion after nicotine patch application compared to a placebo without affecting cardiovascular and respiratory parameters or substrate metabolism. In this sense, nicotine seems to exert similar effects as caffeine by delaying the development of central fatigue as impaired central drive is an important factor contributing to fatigue during exercise. ... The physiological effects of the above mentioned substances are well established. However, the ergogenic effect of some of the discussed drugs may be questioned and one has to consider the cohort tested for every specific substance. However, only caffeine has enough strength of evidence to be considered an ergogenic aid.
9. Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic Aids". Prim. Care 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID 23668655. Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
   Physiologic and performance effects [of amphetamines]
    • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
    • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
    • Improved reaction time
    • Increased muscle strength and delayed muscle fatigue
    • Increased acceleration
    • Increased alertness and attention to task
10. Parr JW (July 2011). "Attention-deficit hyperactivity disorder and the athlete: new advances and understanding". Clin. Sports Med. 30 (3): 591–610. doi:10.1016/j.csm.2011.03.007. PMID 21658550. In 1980, Chandler and Blair⁴⁷ showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise. ... In 2008, Roelands and colleagues⁵³ studied the effect of reboxetine, a pure NE reuptake inhibitor, similar to atomoxetine, in 9 healthy, well-trained cyclists. They too exercised in both temperate and warm environments. They showed decreased power output and exercise performance at both 18 and 30 degrees centigrade. Their conclusion was that DA reuptake inhibition was the cause of the increased exercise performance seen with drugs that affect both DA and NE (MPH, amphetamine, and bupropion).
11. Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Med. 43 (5): 301–311. doi:10.1007/s40279-013-0030-4. PMID 23456493.
12. Rattray B, Argus C, Martin K, Northey J, Driller M (March 2015). "Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?". Front. Physiol. 6: 79. doi:10.3389/fphys.2015.00079. PMC 4362407. PMID 25852568. Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)
13. Parker KL, Lamichhane D, Caetano MS, Narayanan NS (October 2013). "Executive dysfunction in Parkinson's disease and timing deficits". Front. Integr. Neurosci. 7: 75. doi:10.3389/fnint.2013.00075. PMC 3813949. PMID 24198770. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or “clock,” activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing.
14. Roelands B, De Pauw K, Meeusen R (June 2015). "Neurophysiological effects of exercise in the heat". Scand. J. Med. Sci. Sports. 25 Suppl 1: 65–78. doi:10.1111/sms.12350. PMID 25943657. Retrieved 10 March 2016. Physical fatigue has classically been attributed to peripheral factors within the muscle (Fitts, 1996), the depletion of muscle glycogen (Bergstrom & Hultman, 1967) or increased cardiovascular, metabolic, and thermoregulatory strain (Abbiss & Laursen, 2005; Meeusen et al., 2006b). In recent decennia however, it became clear that the central nervous system plays an important role in the onset of fatigue during prolonged exercise (Klass et al., 2008), certainly when ambient temperature is increased  ... 5-HT, DA, and NA have all been implicated in the control of thermoregulation and are thought to mediate thermoregulatory responses, certainly since their neurons innervate the hypothalamus (Roelands & Meeusen, 2010). ... Strikingly, both the ratings of perceived exertion and the thermal sensation were not different to the placebo trial. This indicates that subjects did not feel they were producing more power and consequently more heat. ... Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort. ... The combined effects of DA and NA on performance in the heat were studied by our research group on a number of occasions. ... the administration of bupropion (DA/NA reuptake inhibitor) significantly improved performance. Coinciding with this ergogenic effect, the authors observed core temperatures that were much higher compared with the placebo situation. Interestingly, this occurred without any change in the subjective feelings of thermal sensation or perceived exertion. Similar to the methylphenidate study (Roelands et al., 2008b), bupropion may dampen or override inhibitory signals arising from the central nervous system to cease exercise because of hyperthermia, and enable an individual to continue maintaining a high power output
15. Frati P, Kyriakou C, Del Rio A, Marinelli E, Vergallo GM, Zaami S, Busardò FP (January 2015). "Smart drugs and synthetic androgens for cognitive and physical enhancement: revolving doors of cosmetic neurology". Curr Neuropharmacol 13 (1): 5–11. doi:10.2174/1570159X13666141210221750. PMC 4462043. PMID 26074739. Cognitive enhancement can be defined as the use of drugs and/or other means with the aim to improve the cognitive functions of healthy subjects in particular memory, attention, creativity and intelligence in the absence of any medical indication. ... The first aim of this paper was to review current trends in the misuse of smart drugs (also known as Nootropics) presently available on the market focusing in detail on methylphenidate, trying to evaluate the potential risk in healthy individuals, especially teenagers and young adults.
16. Ilieva IP, Hook CJ, Farah MJ (January 2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". J. Cogn. Neurosci.: 1–21. doi:10.1162/jocn_a_00776. PMID 25591060. The present meta-analysis was conducted to estimate the magnitude of the effects of methylphenidate and amphetamine on cognitive functions central to academic and occupational functioning, including inhibitory control, working memory, short-term episodic memory, and delayed episodic memory. In addition, we examined the evidence for publication bias. Forty-eight studies (total of 1,409 participants) were included in the analyses. We found evidence for small but significant stimulant enhancement effects on inhibitory control and short-term episodic memory. Small effects on working memory reached significance, based on one of our two analytical approaches. Effects on delayed episodic memory were medium in size. However, because the effects on long-term and working memory were qualified by evidence for publication bias, we conclude that the effect of amphetamine and methylphenidate on the examined facets of healthy cognition is probably modest overall. In some situations, a small advantage may be valuable, although it is also possible that healthy users resort to stimulants to enhance their energy and motivation more than their cognition. ... Earlier research has failed to distinguish whether stimulants’ effects are small or whether they are nonexistent (Ilieva et al., 2013; Smith & Farah, 2011). The present findings supported generally small effects of amphetamine and methylphenidate on executive function and memory. Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ...
    
    The results of this meta-analysis cannot address the important issues of individual differences in stimulant effects or the role of motivational enhancement in helping perform academic or occupational tasks. However, they do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
17. "Performance-Enhancing Drug Resources". Drug Free Sport. Retrieved 14 April 2013.
18. "Who we are". World Anti-Doping Agency. Retrieved 2015-11-03.
19. "U.S. Anti-Doping Agency - USADA". U.S. Anti-Doping Agency (USADA). Retrieved 2015-11-03.