Thursday, June 27, 2013

Future Policy for Pharmaceutical Neuroenhancement

The idea of enhancing intelligence is not a modern concept as various agents have been experimented with throughout history from various herbs in ancient times to modern drugs like cocaine and amphetamines in the 20th century. However, with increasing pressures on high school and college students as well as young professionals in a global environment that becomes more and more competitive every year there is a concern that the use of certain drugs for the purpose of “increasing brain power” will steadily increase. The problem with this potential increase in use is that these individuals who are now utilizing these types of drugs do not have a diagnosed medical condition that validates or normalizes the drug use, which may increases the probability of detrimental side effects associated with drug consumption.

Overall the term “neuroenhancement” typically refers to the practice of individuals with normal functioning brains consuming medications for the purpose of augmenting cognitive function. The most common modern neuroenhancement agents include methylphenidate (MPH or Ritalin), modafinil, donepezil and Adderall. The general understanding that the media portrays regarding neuroenhancement to the populous is that usage rates are rapidly increasing among younger individuals and that neuroenhancement provides a significant short-term increase in intelligence and focus. However, this understanding is only supported by unscientific small population college student survey data or online polling and is not supported by larger population studies of wider age ranges or clinical studies creating widely differing estimates of use (from 1% to 30+%).1-3

Apart from the hype, the biggest problem with neuroenhancement is whether or not it actually works.4-9 The working theory is that drugs that are effective neuroenhancers for individuals suffering from neurological condition x should also enhance cognitive ability in individuals not suffering from neurological condition x, albeit at some smaller percentage. However, this theory does not take into account characteristic neurological deficiency. For example donepezil is a cholinesterase inhibitor4 that increases the residence time of neurotransmitter acetylcholine in the synaptic cleft by reducing cholinesterase (which catalyzes acetylcholine degradation) activity. While useful to certain individuals who may have limited acetylcholine release or overactive cholinesterases, donepezil is not useful to individuals who have near saturated to saturated acetylcholine release, thus there is no significant positive benefit to be had, but may produce negative side effects. Adding to the debate of neuroenhancement utility is the lack of a standard for defining neuroenhancement in how much of an improvement in a given test or examination or some other measurement tool is due to enhancement versus randomness.10

Clearly there is a valid health concern with the use of these agents regardless of whether or not there is a positive benefit. The agents are inducing a chemical change in the brain and possibly elsewhere in the body to offset ineffective natural operation. Notable in this discussion are supposed neuroenhancers from the past like cocaine and amphetamines. Pharmaceutical companies were not shy about professing the ability of these agents to increase cognitive abilities, yet various studies demonstrated that there was little to zero actual neuroenhancement; almost all of the significant positive changes were associated with placebo effects due to increased confidence.11,12 There are eerie parallels between the use of amphetamines in the 60’s and 70’s and the use of drugs like Ritalin and Adderall in the 90s and 00s.13

When discussing policy issues associated with neuroenhancement the following questions are important: 1) What level of autonomy should be applied to patients seeking neuroenhancement from physicians? 2) Should neuroenhancement be regarded as a form of cheating similar to PEDs in sports? 3) What are the medical legalities associated with prescribing neuroenhancement agents? 4) How does neuroenhancement differ from other forms of societal enhancement like cosmetic surgery? 5) What regulatory policies should be assigned to neuroenhancers?

Some may argue that the most important element in this issue is a potential conflict between patient autonomy versus doctorial duty. The traditional role of a physician is to diagnose and treat injury/disease, reduce short-term and long-term suffering from detrimental conditions and potential treatments, comfort the patient’s friends and family and finally educate patients about treatment options and disease prognosis. This last element relates most to the issue of neuroenhancement. As previously mentioned there will be negative side effects to taking these specific types of agents, thus it is up to physicians to communicate the potential risks and possible benefits.

This educational role is the only authoritative ability that a physician has in this situation with regards to the patient. In the past when access to medications was more guarded and controlled a physician could deny a patient a prescription if he/she felt it would not be appropriate for the patient. Unfortunately in modern times the advent of the Internet eliminates this bottleneck of control. If a patient wants drug x he/she can acquire it with little effort from various online pharmacies or even less reputable sources regardless of physician approval.

However, despite being undercut by the Internet and globalization, the educational aspect is still critically important because physicians typically have a perception of harm probability that is more seasoned and profound than their patients, which allow them to understand genuine problems that could stem from use that patients would otherwise minimize in their zeal to claim the potential benefits. Utilizing appropriate educational techniques not only can physicians refuse to prescribe neuroenhancers, if deemed appropriate, through respectable and meaningful dialogue, but also reduce the probability that patients run to the Internet or doctor shop out of scorn for not getting their wish from their primary physician. Overall while physicians should have the ultimate say in whether or not a patient should take a neuroenhancer, the logistics of drug supply in modern society marginalizes that reality to one of an educational nature, thus both patients and physicians must take the role of education seriously.

The chief moral aspect of using neuroenhancers is similar to the morality surrounding the use of performance enhancing drugs (PEDs) in sports. Use of PEDs in sports is largely driven by the fact that the consumption of steroids, HGH and similar type components will allow the user to increase certain important abilities related to participation in a particular sport, thus increasing the probability of success and artificially shifting the balance of success between competitors. Rebalancing success probabilities demands widespread PED use creating an environment of collusion where because of the natural restrictions of time the advantages provided by PEDs force numerous other potential participants to consume PEDs.14 Unfortunately there are significant and reliable health detriments associated with PED consumption, which creates the moral question of fairness in that “is it fair to force individuals that do not initially want to take PEDs to take them to have a fair probability of success at their chosen athletic endeavor?”

This question embodies the very moral issue surrounding neuroenhancement, but on a greater scale. Where PED morality only touches on the issue of sport, which for most is recreational and only to a very select few a career possibility, neuroenhancement touches almost all occupations because of the so-called importance of grades and other examination evaluation metrics undertaken in the educational process along with the increased level of global competition for occupational opportunities. The morality issue for neuroenhancement becomes murkier in that there is questionable information on both whether or not they actually work and what type of negative side effects are associated with their use.

Some attempt to argue, similar to PEDs, that simply taking neuroenhancers will not increase an individual’s intelligence. Individuals still have to study, but because neuroenhancers augment certain passive traits like focus and attention to detail, studying should be easier and thus more enjoyable creating a positive feedback loop leading to even more studying and eventually higher grades; thus because the act of studying is still essential for receiving “enhancement” from neuroenhancers there is little reason to accuse individuals taking these agents of “cheating” or not earning their grades. In this vein supporters of neuroenhancement like to classify it as an alternative learning strategy similar to existing behavioral modification like psychotherapy. Unfortunately this classification is inappropriate because unlike typical learning enhancement methods there are potential medical risks associated with neuroenhancement as well as questions to existing benefits. Also this argument does not address potential collusion elements associated with widespread neuroenhancement use largely due to time constraints.

One interesting argument in favor of widespread neuroenhancement use is “the limited ceiling”. PEDs create a collusive environment because play is the principle and direct element that determines success. In the educational environment grades and other evaluation metrics are only a component of the portfolio that determines success. It is notable that in this situation poorer students would more than likely see more benefit from neuroenhancement. Therefore, if everyone has high grades then grades become irrelevant as an evaluation metric. An interesting potential irony of such a situation is that mitigating the importance of grades may increase the randomness of evaluation, which would create an inversely proportional relationship between benefits from neuroenhancement and usefulness of neuroenhancement in improving success probability. Basically those who would receive Bs without enhancement and get As with it actually have their success probability decrease because a number of C/D students are now getting higher grades saturating the attractive candidate selection pool.

However, while some may argue that widespread neuroenhancement will be a boon to all parties (the above paragraph seems to contradict that argument), the problem before even debating this issue is the attainment of an environment of widespread use is nearly impossible. Whether or not neuroenhancement works is debatable (probably not at the moment), but if it does work the effects are short-term; therefore, one must procure and consume a steady supply to ensure a continuation of any positive effect. Lower income students, especially those who have to work simply to pay current or future tuition, will not be able to continuously engage in this procurement, thus eliminating their involvement in neuroenhancement creating a wider gap between poor and rich educational scores. Some may argue that wealthier students have always had an advantage over poorer students typically having a better home environment, the ability to hire tutors and other resources, etc., but while that is the case why should society freely allow richer students another advantage over poorer students?

One of the obstacles for physicians in their responsibility to education patients regarding the administration of neuroenhancers is that almost all of them will be off-label prescriptions. Off-label is typically defined as using a drug in an unapproved manner or for a non-targeted population group. In the United States off-label prescriptions are legal, but because FDA approval is not required the safety aspects associated with using a given drug in an off-label manner are unclear.15,16 When the FDA approves a drug for use, multiple tiers of clinical studies must be conducted to demonstrate that the drug is both safe and at least as effective as existing alternatives (ignore the fact that a number of drugs are approved because companies conceal the negative studies, but that is what typically occurs when foxes are allowed to guard the proverbial hen house). Safety analysis is dependent on the inherent biological characteristics of the principle target group for the drug; changing those characteristics will change the identified safety profile of the drug with the magnitude of this change unknown.

Another problem with off-label prescriptions is that originally pharmaceutical companies were not allowed to promote off-label uses to physicians or prospective patients. The rationality of the regulation was that promotion of off-label drugs were inherently false and misleading because those claims did not have the support of the FDA and this support was important because of the aforementioned safety profile change in use alteration. This regulation has found conflict with First Amendment supporters since its inception and a recent appeals court ruling has raised questions regarding the scope of government regulatory power concerning off-label advertisement and promotion where a sales representative was criminally prosecuted in violation of his First Amendment right when promoting off-label uses.17 If drug companies begin to view neuroenhancement as potential big business then large-scale promotion activities could create conflict between honest evaluations of effectiveness and marketing hype even more so then they already have.

A secondary important issue is the liability concerns for physicians that prescribe off-label drugs. Once a drug has been approved by the FDA for sale to treat a given condition physicians are allowed to prescribe it for another condition if it is determined to be safe and effective. However, what if the drug has limited available safety information and the physician is simply prescribing blind? One precedence is seen in elective cosmetic surgery where the courts have typically defined injuries from that field similar to those along the lines of traditional medical negligence.18 Unfortunately one major uncertainty in this liability issue is proving cause and effect. Most medical negligence, including elective cosmetic surgery, is easy to identify and rather simple to connect back to the sequence of events that created the negligence. Most detrimental neurological damage that could be caused by neuroenhancement will usually occur later in life and could be difficult to separate from other lifestyle choices or simple genetic mutations brought on by aging.

Supporters who believe that pharmaceutical companies will “look out” for the well being of users do not understand history. Some argue that examples like Vioxx demonstrate why companies need to be careful due to the protracted litigation leading to large settlements/jury verdicts, which cast negative light on the company and hurt stock valuation. However, this argument is foolish because of the aforementioned difficulty in establishing a cause (taking neuroenhancer A produced by company A) and resultant effect (unforeseen negative neurological condition brought on by neuroenhancer A). If neuroenhancement becomes popular the profit made by participating companies, especially because of the collusion element described above, will dwarf any associated legal costs, if there are any in the first place. Regulation is the only appropriate means to create an environment of appropriate distribution.

One of the most common arguments in favor of neuroenhancement is that society already allows physical enhancement from various cosmetic surgery to even sillier things like penis enlargement; therefore, if these physical enhancements are allowed and numerous studies have demonstrated that social interaction and career advancement are bolstered by a high-quality physical appearance why should society place any significant restrictions on neuroenhancement? Initially this position seems convincing because there are similar parallels between the two.

However, there are dramatic differences between physical injury and mental injury. The safety uncertainty of neuroenhancement creates possibilities that such treatments could lead to societal negative neurological conditions like bipolar disorder, schizophrenia, Alzheimer’s, etc. Clearly the potential to significantly change the mental state of an individual must be measured against a person becoming slightly less attractive because of a botched nose job or saggy breast implants when considering possible differences in regulation. Another concern with comparing neuroenhancement to cosmetic surgery is that cosmetic surgery has a long-standing track record for actually providing a benefit to the user either societal (with the way people treat the cosmetic surgery patient) or psychological (self-esteem) whereas neuroenhancement has no long-standing track record for providing benefit and little short-term evidence for providing any benefit with possible positive and negative side effects.

While the principle function of neuroenhancers is to influence cognition, there is also reason to believe that they impact emotional and motivational functions as well; for example modafinil influences the functionality of a wide range of neurotransmitters including dopamine, norepinephrine, GABA and glutamate along with histamine and orexin/hypocretin.19,20 Cognitive benefit studies have demonstrated that MPH has a large positive effect on memory, but no statistically significant influence on attention, mood, rectifying negative effects associated with sleep deprivation or executive function.21 Negative short-term side effects were a slightly increased heart rate, headache, anxiety, nervousness, dizziness and insomnia.22-25 A single dose of modafinil unsurprisingly increased wakefulness and attention (because that is what it is designed to do), but had no effect on mood, memory or motivation and slightly increased levels of anxiety. Negative short-term side effects of modafinil typically were headache, dizziness, gastrointestinal problems, heart issues (diuresis, tachycardia and palpitations) and restlessness which may affect long-term sleep rates.26-29

The weakness of existing neuroenhancement studies should raise numerous red flags. Almost all existing studies only utilize a single administration dosage methodology, which is less than half the story in society.21 If student A is taking a neuroenhancer with the intent of increasing his/her grade there is one of two possible outcomes. Clearly student A has a certain expectation to how he/she will perform in a given exam; suppose student A projects a C for the next test and takes a neuroenhancer to attempt to increase that grade. After the test the student either improves or does not improve on the projection. If no improvement occurs it is unlikely that the student will continue to take the neuroenhancer. However, if an improvement occurs then it is likely that the student will entertain the idea of continuing to take the neuroenhancer.

The expected behavior of student A based on the outcome of the test limits the usefulness of the single administration dosage studies because either the student stops taking the neuroenhancer or takes it multiple times over a longer period of time. Of the few existing repeated dosage studies MPH increases feelings of energy, somewhat proportional to age (older people felt more energetic), but yields no other statistically relevant benefits.30,31 Long-term dosing of modafinil increased wakefulness, but also increased anxiety.32 Therefore, new studies need to be conducted with parameters focusing on long-term use with various dosage amounts to actually determine potential benefits as well as detrimental neuronal outcomes, which typically do not have a standardized method of assessment limiting the level of understand regarding rate of occurrence, reinforcing effects, dependence development and drug tolerance.

Another problem is that a number of studies fail to report raw data, which makes it difficult for outside parties to review the assumptions that went into producing the given conclusions of the study.21,33,34 Also the studied dosage can be a problem in that without a standard protocol some studies may miss operational windows. For example a number of drugs operate under a “mountain” activation curve (or inverted U-shape) where too much or too little of a drug impairs performance. Therefore, if a study uses a dosage on the wrong area of this activation curve the study could create erroneous results.

Regulation of neuroenhancers is a somewhat tricky question. Some would argue that off-label prescriptions, doctor shopping and Internet pharmacies may mitigate most of the protections offered by any regulation creating a general free-for-all arms race and collusion environment. However, such a possibility should not force the elimination of regulation. Otherwise it would be akin to agreeing that because speed limits cannot stop all individuals from speeding, speed limits are inherently pointless, a conclusion that is clearly false. Neuroenhancers should be regulated through physicians in that they should require a physician’s prescription with possible coordination with the DEA because of their potential for being addictive. In addition close attention should be paid to any physician prescribing large amounts of neuroenhancers. A secondary strategy for indirect regulation could involve opponents of neuroenhancement seeking to create an environment where any of the theorized useful elements of neuroenhancement are mitigated.

As stated above the two chief advantages that have been attributed to neuroenhancement are improved memory and improved focus/attention, especially within a sleep deprived state. These advantages are useful in the current educational environment because of its focus on memorization and long simplistic examinations that concentrate on one-dimensional concepts rather than problem solving and comprehension. If the educational evaluation environment changes from one-dimensional concepts to problem solving and comprehension the preparation methodology changes from straight memorization through cramming where time is an important factor to complex application where time is not an important factor, but instead learning strategy is the important element. Eliminate time and memorization as limiting factors in education and the value of neuroenhancers disappears, which would dramatically limit their use.

In modern society truth is often obfuscated by rumor, hype and singular circumstance; in the case of neuroenhancement such a scenario is currently occurring and is likely to continue, especially in the collusive “keeping up with the Jones” mindset society has created backed by promotion from pharmaceutical companies in effort to make more money. It is likely that neuroenhancement will attempt to become a lifestyle augmentation similar to cosmetic surgery and sexual dysfunction drugs like Viagra. Therefore, the widespread introduction of neuroenhancement will perpetuate a “rich get richer, poor stay poor” society for neuroenhancement will demand long-term use, which will require a steady stream of money, thus equal access to enhancement cannot be guaranteed or even expected. An underlying problem is that neuroenhancement may not even work over the long-term, which will result in wasting money by spending it on an ineffective product and giving it to pharmaceutical companies that do not need it in addition to possibly increasing healthcare costs associated with negative side effects.

While the above prediction is rather sarcastic, it is quite probable. The best strategy for neutralizing the expansion of neuroenhancement and the further expansion of inequality in society is to focus on the double layer of standard regulation and changing the usefulness of neuroenhancement in academia and the work force by changing the expectations and evaluation methodology from rote memorization to comprehension and problem-solving ability. Such a change should not only limit the importance of neuroenhancement, as it is currently understood, but also naturally, without negative consequence, improve intelligence and the ability to succeed in the future. Instead of looking for the quick-fix shortcut drug, society needs to actually address the problem.

Citations –

1. Maher, B. “Poll results: look who’s doping.” Nature. 2008. 452:674–675.

2. Sahakian, B, and Morein-Zamir, S. “Professor’s little helper.” Nature. 2007. 450:1157–1159.

3. Hall, W, and Lucke, J. “The enhancement use of neuropharmaceuticals: more scepticism and caution needed.” Addiction. 2010. 105:2041–2043

4. Gron, G, et Al. “Cholinergic enhancement of episodic memory in healthy young adults.” Psychopharmacology. 2005. 182:170 –179.

5. Mehta, M, et Al. “Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain.” J Neurosci. 2000. 20:RC65.

6. Greely, H, et Al. “Towards responsible use of cognitive enhancing drugs by the healthy.” Nature. 2008. 456:702–705.

7. de Jongh, R, et Al. “Botox for the brain: enhancement of cognition, mood and pro-social behavior and blunting of unwanted memories.” Neurosci Biobehav Rev 2008. 32:760–776.

8. Academy of Medical Sciences. Brain Science, Addiction and Drugs. London: Academy of Medical Sciences. 2008.

9. Lucke, J, et Al. “Weak evidence for large claims contribute to the phantom debate.” Biosocieties. 2010. 5:482–483.

10. Sackett, D, et Al. “Evidence-based medicine: what it is and what it isn’t.” British Medical Journal. 1996. 312(7023):71-72.

11. Rasmussen, N. On Speed: The Many Lives of Amphetamine. New York: New York University Press. 2008.

12. Hall, W. “Feeling ‘better than well’—can our experiences with psychoactive drugs help us to meet the challenges of novel neuroenhancement methods?” EMBO Rep. 2004. 5:1105–1109.

13. Svetlov, S, et Al. “Performance enhancing, non-prescription dose of Ritalin—a comparison with amphetamines and cocaine.” J Addict Dis. 2007. 26: 1–6.

14. “Addressing Performance Enhancing Drugs in Sports”. Bastion of Reason Blog. February 26, 2013.

15. 21 USCA sec 360e(d) (1)(A).

16. 21 CFR sec 314.50–54, 807.92(a)(5), 807.100(b)(1)(1999).

17. Thomas, K. “Ruling Is Victory for Drug Companies in Promoting Medicine for Other Uses.” NY Times. December 3, 2012.

18. Kirsten Brukamp and Dominik Gross (2012). Neuroenhancement - A Controversial Topic in Contemporary Medical Ethics, Contemporary Issues in Bioethics, Dr. Peter A. Clark (Ed.), ISBN: 978-953-51-0169-7, InTech, Available from:

19. Minzenberg, M, and Carter, C. “Modafinil:. A review of neurochemical actions and
effects on cognition.” Neuropsychopharmacology. 2008. 33(7):1477–502.

20. Ballon, J, and Feifel, D. “A systematic review of modafinil: potential clinical uses and
mechanisms of action.” J Clin Psychiatr. 2006. 67:554–66.

21. Repantis, D, et Al. “Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review.” Pharmacological Research. 2010. 62(3):187–206.

22. Bray, C, et Al. “Methylphenidate does not improve cognitive function in healthy sleep-deprived young adults.” J Invest Med. 2004. 52:192–201.

23. Clark, C, Geffen, G, and Geffen, L. “Role of monoamine pathways in attention and effort: effects of clonidine and methylphenidate in normal adult humans.” Psychopharmacology (Berl). 1986. 90:35–9.

24. Peloquin, L, and Klorman, R. “Effects of methylphenidate on normal children’s mood, event-related potentials, and performance in memory scanning and vigilance.” J Abnorm Psychol. 1986. 95:88–98.

25. Volkow, N, et Al. “Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D2 receptors.” J Pharmacol Exp Therapeut. 1999. 291:409–15.

26. Caldwell, J, et Al. “Modafinil’s effects on simulator performance and mood in pilots during 37 h without sleep.” Aviat Space Environ Med. 2004. 75:777–84.

27. Whitmore, J, et Al. “A double-blind placebo controlled investigation of the efficacy of modafinil for maintaining alertness and performance in sustained military ground operations.” AFRL-HE-BR-TR-2006-0005 ed. United States Air Force Research Laboratory. 2006.

28. Gill, M, et Al. “Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study.” Acad Emerg Med. 2006. 13:158–165.

29. Pigeau, R, et Al. “Modafinil, damphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature.” J Sleep Res.
1995. 4:212–28.

30. Gilbert, J, et Al. “Effect of magnesium pemoline and methylphenidate on memory improvement and mood in normal aging subjects.” Int J Aging Hum Dev. 1973. 4:35–51.

31. Gobbi, G, et Al. “Neurochemical and psychotropic effects of bupropion in healthy male subjects.” J Clin Psychopharm. 2003. 23:233–9.

32. Taneja, I, et Al. “A randomized, double-blind, crossover trial of modafinil on mood.” J Clin Psychopharm. 2007. 27:76–9.

33. Egger, M, Smith, G, and Altman, D. “Systematic reviews in health care: metaanalysis in context.” London: BMJ Books. 2001.

34. Higgins, J, and Green S, editors. “Cochrane handbook for systematic reviews of interventions 4. 2. 6. Chichester, UK: The Cochrane Library, John Wiley & Sons, Ltd; 2006. Issue 4.

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