Cognitive Enhancement IS Cheating

One of my colleagues posted a recent commentary from Nature on how the idea of the smart pill has been oversold.  The basic theme of the commentary is that there is no good evidence that treatment of ADHD with stimulants improves academic outcomes.  The author reviews a few long term studies and contends that differences between the medication and placebo seem to wash out over time and therefore there is no detectable difference.  Her overall conclusions seem inconsistent with her view that:  "For most people with ADHD, these medications — typically formulations of methylphenidate or amphetamine — quickly calm them down and increase their ability to concentrate. Although these behavioural changes make the drugs useful, a growing body of evidence suggests that the benefits mainly stop there..."

A question for any cognitive psychologists out there - is it possible to improve your concentration and have that not improve learning?  I can't imagine how that happens.  If you go from not being able to read 2 pages at a time to suddenly reading chapters at a time, how is that not enhanced cognitive performance?  If you go from staring out the window all day and daydreaming to being able to focus on what the teacher is saying how will that not lead to an improved outcome?  The idea that improved attention - a central factor in human cognition will not affect anything over time suggests to me that the measures being used for follow up are not very robust or that this is a skewed sample of opinion.   

For the purpose of cognitive enhancement, the typical users are students trying to gain an edge by increasing their study time.  Anyone who has experienced college and professional school realizes that here is a large amount of information to be mastered and it is not presented in an efficient way.  I can never recall a professor who advised us of the important guideposts along the way or gave us any shortcuts.  The usual message is study all of this material in depth every day or you will fall behind.  That approach in general is consistent with gaps in the ability to study either through the normal course of life or the competition for intellectual resources by 3 or 4 other professors who regard their courses as important.  That typically results in a pattern of cramming for specific key exams.  Although I have not seen any specific studies, stimulant medications are generally used for this purpose and in many cases the use is widespread.  There is a literature on the number of college students who may be feigning ADHD symptoms in order to get a prescription and that number could be as high as 50% (4,5). 

What  about the issue of stimulants acting as a smart pill in people who don't have ADHD?  In the most comprehensive review I could find on the subject (6) the authors review laboratory studies and conclude that in those settings stimulants enhance consolidation of declarative learning to varying degrees, had mixed effects on working memory, and mixed effects on cognitive control.  On 8 additional tests of executive function, the authors found that stimulant medication enhance performance on two of those tests - non-verbal fluency and non-verbal intelligence.  They have the interesting observation that small effects could be important in a competitive environment.  Their review also provides an excellent overview of the epidemiology of stimulant use on campuses that suggests that the overall prevalence is high and the pattern of use is consistent with cramming for exams.  They cite a reference that I could not find (7) that was a reanalysis of NSDUH data suggesting that as many as 1 in 20 stimulant users may have a problem with excessive use and dependence.     

Getting back to the theme of the Nature commentary, it is ironic that the smart pill theme is being called into question when it was the subject of a Nature article years earlier advocating for the use of cognitive enhancement.  In that article Greely, et al come to the somewhat astounding conclusion: 

"Based on our consideration, we call for a presumption that mentally competent adults should be able to engage in cognitive enhancement using drugs."

They arrive at that conclusion by rejecting three arguments against this practice.  Those arguments include that it is cheating, it is not natural and it is drug abuse.  Their rejection of the cheating argument is interesting because they accept the idea that performance enhancing drugs (PEDS) in sports is cheating.  They reject that in cognitive enhancement claiming that there would need to be a set of rules outlining what forms of enhancement would be outlawed and what would not (e.g. drugs versus tutors).  To me that seems like a stretch.  I think that sports bodies select performance enhancing drugs as a specific target because it clearly alters body physiology in a way that cannot be altered by any other means.  There is also plenty of evidence that the types of PEDS are dangerous to the health of athletes and associated with deaths.  Their conclusion about drug abuse: "But drugs are regulated on a scale that subjectively judges the potential for harm from the very dangerous (heroin) to the relatively harmless (caffeine).  Given such regulation the mere fact that cognitive enhancers are drugs is no reason to outlaw them."   That is a serious misread of the potential addictive properties of stimulants and the previous epidemics that occurred when the drugs were FDA  approved for weight loss, the epidemic of street use in the 1970s and the current and ongoing epidemic of meth labs and methamphetamine use throughout much of the USA.

These authors go on to outline four policy mechanisms that they believe would "support fairness, protect individuals from coercion, and minimize enhancement related socioeconomic disparities."  At first glance these lofty goals might seem reasonable if society had not already had in depth experience with the drugs in question.  The clearest example was the FDA approved indication of amphetamines for weight loss.  What could be a more equitable application than providing amphetamines to any American who wanted to use them for weight loss?  The resulting epidemic and reversal of the FDA decision is history.  A similarly equitable decision to liberalize opioids in the treatment of chronic pain had resulted in another epidemic of higher lethality due to differences in the toxicology of opioids and amphetamines. 

The contrast between these two commentaries in Nature also highlight a couple of the issues about the way medical problems and treatment is portrayed in the media.  This first is that you can't have it both ways.  Quoting a researcher or two out of context does not constitute an accurate assessment of the science involved.   Some of the authors in the first commentary are highly respected researchers in cognitive science and they clearly believe that cognitive enhancement occurs and it should be widely applied.  Nature or any other journal cannot have it both ways.  A more realistic appraisal of the problem is addressed in reference 6.   The second issue is that in both cases the authors seem blind to the addictive properties of stimulants and they are ignorant of what happens when there is more access as exemplified by the FDA misstep of approving stimulants for weight loss.  Do we really need a new epidemic to demonstrate this phenomenon again?  Thirdly, all of this comes paying lip service to non - medication strategies for cognitive enhancement.  We can talk about the importance of adequate sleep - a known cause of ADHD like symptoms and if we are running universities and workplaces in a manner that creates sleep deprived states, the next step is reaching for pills to balance an unbalanced lifestyle.  The new rules for residency training are a better step in the right direction.  Fourth, college is a peak time for alcohol and substance use in the lives of most Americans.  These substances in general can lead to a syndrome that looks like ADHD.  It is highly problematic to make that diagnosis and provide a medication that can be used in an addictive manner.  It is also highly problematic to think that treating an addicted person with a stimulant will cure them of the addiction and yet it happens all of the time.

There is plenty of evidence to suggest that cognitive enhancement is cheating.   Much of my career has been spent correcting the American tendency of trying to balance one medication against another and using medications to tolerate a toxic lifestyle or workplace.  It does not work and the current group of medications that are being put forward as cognitive enhancers are generally old drugs with bad side effect profiles particularly with respect to the potential for addiction.

If you want safe cognitive enhancers that can be made widely available, they have not been invented yet.  

George Dawson, MD, DFAPA




References:

1: Sharpe K. Medication: the smart-pill oversell. Nature. 2014 Feb 13;506(7487):146-8. doi: 10.1038/506146a. PubMed PMID: 24522583.

2: Greely H, Sahakian B, Harris J, Kessler RC, Gazzaniga M, Campbell P, Farah MJ.

Towards responsible use of cognitive-enhancing drugs by the healthy. Nature. 2008 Dec 11;456(7223):702-5. doi: 10.1038/456702a. Erratum in: Nature. 2008 Dec 18;456(7224):872. PubMed PMID: 19060880.

3: Feldman HM, Reiff MI. Clinical practice. Attention deficit-hyperactivity disorder in children and adolescents. N Engl J Med. 2014 Feb 27;370(9):838-46. doi: 10.1056/NEJMcp1307215. PubMed PMID: 24571756.  

4: Green P, Lees-Haley PR, Allen LM., III The word memory test and the validity of neuropsychological test scores. J Forensic Neuropsychol. 2002;2:97–124. doi: 10.1300/J151v02n03_05

5: Suhr J, Hammers D, Dobbins-Buckland K, Zimak E, Hughes C.  The relationship of malingering test failure to self-reported symptoms and neuropsychological findings in adults referred for ADHD evaluation.  Arch Clin Neuropsychol. 2008 Sep; 23(5):521-30.

6: Smith ME, Farah MJ. Are prescription stimulants "smart pills"? The epidemiology and cognitive neuroscience of prescription stimulant use by normal healthy individuals. Psychol Bull. 2011 Sep;137(5):717-41. doi: 10.1037/a0023825. Review. PubMed PMID: 21859174 

7: Kroutil LA, Van Brunt DL, Herman-Stahl MA, Heller DC, Bray BM, Penne MA. Nonmedical use of prescription stimulants in the United States. Drug and Alcohol Dependence. 2006; 84:135–143.10.1016/j.drugalcdep.2005.12.011 [PubMed: 16480836]

"Anything worth winning is worth cheating for."

I used to speedskate in pack style races.  For a while one of my competitors would come to the line and make that statement just before we all took off.  Most of us thought that it was hilarious.  One day I was intentionally sandbagging, and told several people that I was really fatigued and did not anticipate that I would be very competitive.  When the gun went off I broke for the first turn as fast as everyone else.  They gave me a hard time for sandbagging after that race and I reminded them: "Anything worth winning is worth cheating for."

That brings me to the recent Lance Armstrong saga.  The Oprah interview followed by endless opinion pieces and man on the street interviews focused on the emotional response to his doping confessions.  That has continued this week with a skewering by comedians, indignant responses by journalists, endless analyses of his interviews, the looming threat of ongoing legal action, and the expected outrage from the process of being lied to.  But I wonder if there is not a lot more going on that just cheating and lying. 

A little context is important.  Bicycle racing has been associated with cheating for decades.  Most people don't realize it but one of the most widely used antipsychotics,  haloperidol was invented as an antidote to amphetamines by Paul Janssen in response to the following observation he made in the 1950s:

“Even when he was pulled off his bike and congratulated by a reporter, he tried to continue cycling” Janssen said. It was obvious, he added, that “finding a treatment for amphetamine intoxication would provide a cure for paranoid schizophrenia”.  Ivan Oransky.  The Lancet - 17 January 2004 ( Vol. 363, Issue 9404, Page 251 )

Haloperidol was invented in 1959.  A British cyclist allegedly under the influence of amphetamines died in 1967 during the Tour de France while ascending Mt. Ventoux.

Over the intervening decades doping has become more sophisticated and the anti-doping authorities have become more sophisticated.  Epo was probably introduced to cycling as early as the 1980s.  There were 18 deaths of young professional cyclists in the late 1980s and 8 additional deaths since 1993.  The commonest compounds in the news that are thought to give a competitive advantage include testosterone and testosterone derivatives and the cytokine - erythropoietin or Epo for short.  Erythropoietin the primary regulator of human red blood cell production, survival, and differentiation of bone marrow derived blood cells.  It has been known for some time that is also has potential performance enhancing characteristics in elite athletes:

“Administration of Epo, by increasing haemoglobin and haematocrit, increases the oxygen carrying capacity of the blood, thereby improving the athlete’s endurance.  The use of Epo in this manner can be dangerous, increasing the risk of heart failure, strokes and thrombosis.  A number of high profile cases have been reported in the press, including in 1998, the arrest on drugs charges of the doctors of the Tour de France cycling Team, Festina.   One of the Festina riders ……has only recently returned to competition after a ban after admitting to regularly taking Epo.”  The Cytokine Handbook. Volume 2, p 1267.

Testosterone and its derivatives referred to as anabolic steroids first appeared in 1954. The use of anabolic steroids or anabolic androgenic steroids (AAS) has increased significantly across the population over the past 20 years.  In the 1990s about 1% of high school students used these compounds.  This increased to 3% recently with as many as 10% of 15-19 year old boys (4).  Pope, et al (5) reviewed the evidence that AAS use resulted in addiction and came up with a figure of 30% across seven studies with the qualifier that selection bias may be a factor.  The most recent review of the evidence (6,7) indicates that AAS are widely abused and that most AAS users are engaged in polypharmacy.

The actual effects of performance enhancing drugs are very difficult to evaluate largely because of the secrecy surrounding their use and the inability to investigate them on an systematic basis.  As I hear stories about what has been used a lot of it does not seem to make any sense.  For example, there was the famous incident where a Tour de France cyclist tested positive for testosterone after gaining 4 minutes on the field.  In the subsequent discussion he said initially that alcohol may have been the reason but eventually acknowledged using a testosterone patch.  The stage occurred well into the race and it made no sense to me why he thought that testosterone would be effective overnight.  An alternative explanation is that he was using more testosterone and the testing done was not accurate .  I have also heard recent comments on taking “hydrocortisone pills.”  I don’t understand how anyone would expect a glucocorticoid to lead to performance enhancing effects when it has a catabolic effect on muscle tissue.  There is some more clear cut documentation showing potential performance advantages from anabolic steroids, but much of it is anecdotal with little attention paid to minimum doses.  In fact some of the literature describes a natural tendency for escalation and uncontrolled use – a hallmark of addiction.  The literature on AAS use and whether or not they do enhance performance is varied.  The original literature originated in secret classified documents from the German Democratic Republic (GDR) and their Olympic efforts from 1966 through the late 1980s.  In over 150 documents, specific programs and dosing regimens were noted on thousands of athletes and hundreds of physicians and scientists.  An observation of the performance enhancing effects from this paper: 

“Performances could be improved with the support of these drugs within 4 years as follows: Shot-put (men) 2.5-4 m,  Shot-put (women) 4.5-5 m, Discuss throw (men) 10-12 m. Discuss throw (women)11-20m, Hammer throw 6-10 m, Javelin throw(women) 8-15 m, 400 m (women) 7-10 sec, 800 m (women) 5-10 sec, 1500 m (women) 7-10 sec….”

Without access to the original documents it is difficult to say exactly how carefully this was studied but I doubt that it was an A-B-A design with comparisons to placebo.  Nonetheless, if all of the performance enhancement was due to AAS, it would provide a clear advantage in events decided by meters or seconds and could potentially move an athlete from very good to world class.  Subsequent controlled studies like the first study (8) of the anabolic effects of supraphysiological doses of testosterone documented increases in both muscle diameter and strength during the administration of 10 weeks of testosterone injections.  They also commented that the widespread use of AAS at the time (1996) was unsubstantiated.  The authors documented strength increases of 22 – 38% during that experiment.

Another interesting document (3) of the widespread use of AAS by athletes and people interested in the body building aspects of these drugs was based on a hearing on the matter where doctors prescribing steroids were questioned.  The initial focus of this article was the 1988 disqualification of Ben Johnson after he won the 100 m event in the Olympics in Seoul, South Korea.  The physician in that case described a 5 year program of AAS use.  An estimated 20% of AAS were prescribed by physicians and one of the physicians in the report estimated that the size of his practice was 2000 patients and he thought there were 70 other physicians in the Los Angeles area prescribing these drugs.  At the time AAS use in international track and field competition and a “drug free athlete was considered a losing athlete.”

The politics and limited memory of the scope of this problem is also interesting.  Armstrong responded to the rhetoric of the officials who went after him and described his doping operation as the largest and most sophisticated.  A cycling team would not seem large compared with estimates of one million AAS users in the 1990s, 300 thousand of them active in any given year.  From previous estimates that number may be three times as large right now and chances are that many of these people are also using growth hormone and other polypharmaceutical approaches that they believe will enhance their performance.

The bottom line for me is that Lance Armstrong used performance enhancing drugs by his own admission.  Like practically all users of these drugs he lied about using them.  He used the legal system and his resources to his advantage to defend his positions.  None of this is very surprising given a culture that has used performance enhancing drugs for decades and one that is expanding to the use of cognitive enhancers (9).  So be irate with him if you want, but there is clearly a large segment of the population that practices performance enhancement and the population is also expanding into enhancers for intellectual performance as well as athletic performance.  It is not likely that either of these practices will be going away any time soon.

 

George Dawson, MD, DFAPA

1.  Lewis JL, Lotze GM (2003) Haemopoietic cytokines. In: The Cytokine Handbook, vol. 2 (Thompson AW, L. M., ed), p 1267 London: Academic Press.

2.  Franke WW, Berendonk B. Hormonal doping and androgenization of athletes: a secret program of the German Democratic Republic government. Clin Chem 1997;43:1262-1279.

3.  Breo DL.  Of MDs and muscles--lessons from two 'retired steroid doctors'. JAMA. 1990 Mar 23-30;263(12):1697, 1699, 1703-5. PubMed PMID: 2407878.

4.  Lukas SE. (2009) The pharmacology of anabolic steroids.  In:  Principles of Addiction Medicine, Fourth Edition, p 252, Philadelphia: Lippincott, Williams, and Wilkins.

5.  Kanayama G, Brower KJ, Wood RI, Hudson JI, Pope HG Jr. Treatment of anabolic-androgenic steroid dependence: Emerging evidence and its implications.  Drug Alcohol Depend. 2010 Jun 1;109(1-3).

6.  Kersey RD, Elliot DL, Goldberg L, Kanayama G, Leone JE, Pavlovich M, Pope HG Jr. National Athletic Trainers' Association position statement: anabolic-androgenic steroids. J Athl Train. 2012 Sep-Oct;47(5):567-88.

7.  Kanayama G, Pope HG Jr. Illicit use of androgens and other hormones: recent advances. Curr Opin Endocrinol Diabetes Obes. 2012 Jun;19(3):211-9.

8.  Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996 Jul 4;335(1):1-7.

9.  Greely H, Sahakian B, Harris J, Kessler RC, Gazzaniga M, Campbell P, Farah MJ. Towards responsible use of cognitive-enhancing drugs by the healthy. Nature. 2008 Dec 11;456(7223):702-5.