BOTOX FOR THE BRAIN
If one believes that the central issue is risk vs. benefit rather than philosophical and ethical, then it is necessary to examine the drugs in current use. Unfortunately, the list is long and studies on use prevalence in various populations are very limited. The major performance enhancing drugs currently in use off-label or illegally include modafinil (Provigil), methylphenidate (Ritalin) and a combination of amphetamines (Adderall). The street name for amphetamines including Ritalin is "Speed". Ritalin and other amphetamines are used extensively to treat attention deficit/hyperactivity disorder (ADHD) in both children and adults. Modafinil, which not only goes by the name Provigil but several others, is an analeptic drug approved in the US for treatment of narcolepsy, shift-work sleep disorders and excessive daytime sleepiness associated with sleep apnea. Thus it appears to address the problem of staying awake but also operates to some extent as a smart drug. Modafinil appears to operate via a number of complex mechanisms.2 Other drugs include 2-oxo-1-pyrrolidine acetamind (Piracetam, a GABA derivative), anti-dementia drugs (acetylcholinesterase inhibitors donepezil, galantamine, rivastigmine) and the glutamate receptor blocker memantine. This non-stimulant group presumably joined the neuroenhancer family for use by well individuals because of evidence of inducing improvements in patients who were cognitively impaired. However, these cognitive enhancers mainly improve performance, primarily or exclusively, in individuals with significant impairment.2,3 This list is probably not complete but indicates the problems with risk-benefit analysis since we are dealing with a number of drug classes.
If these drugs are really benign, then one of the strongest arguments against neuroenhancement disappears. Short term studies of adverse side effect of stimulants are limited and long-term studies virtually non-existent. Furthermore, for many of the drugs in use, only a few very small, short-term studies, if any at all, have been carried out on healthy, normal individuals and the important questions regarding long-term harm and serious adverse effects have never been systematically studied. As regards stimulants used for ADHD, studies do not differentiate between those who really do not have ADHD and those that do when studying an ADHD cohort for side effects, since overdiagnosis and overtreatment is in general ignored or denied. Some hold the view that ADHD is seriously over diagnosed and over-treated, which gives added importance to adverse side effects. Nor are there any studies of adverse side effects for those who manage to get drugs such as Ritalin from friends or off the street and use them for recreational or enhancement purposes. Finally individuals taking stimulants or other psychiatric drugs often quickly stop taking them because they cannot tolerate the side effects. These cases do not generally enter into the databases for side effects.
Finally, there is the issue of the impact of any of these drugs on brain development and brain changes, which extend from conception to roughly the end of the teenage period. The design of such studies would constitute a profound challenge, and financing such studies would require deep pockets indeed. The large number of drugs that are eligible for study underscores the general conclusion that the required risk information will never be acquired. One can fall back on generalities. The complex biochemistry, pathways, receptors, networks, etc. in the brain are only partially understood. Furthermore, the mind-brain connection is not understood at a level where the information is useful. The general consensus among those who do not have an agenda is that the mechanisms of mental disorders are poorly understood, if at all. Thus one can conclude on general principles that it is not a good idea to mess around with the brain by introducing chemicals never before encountered. While the justification that someone is really acutely sick and needs treatment of course has merit, neuroenhancement is a different matter entirely which is at the other end of the spectrum and involves mentally and physically healthy individuals where the goal is to make them smarter, brighter, more focused, more able to engage in sustained intellectual efforts, stay awake and able to compete more effectively and successfully in the modern world. The obvious question then becomes, are unknown long-term risks of neuroenhancers, some potentially involving permanent brain alteration, worth taking for the perceived benefits some derive?
Women of childbearing age present a special situation. Psychiatric drugs use, especially during the first trimester, can have profound effects on fetal development and the risk of permanent abnormalities.4,5 But the lag time between conception and awareness of being pregnant, as well as the wash-out time for some drugs can put the fetus at risk for a period well into the first trimester, and the first month has been shown in many studies be especially critical in the context of adverse effects. Recall that this argument is used successfully to justify the suggestion that all women of childbearing age take folic acid and governments even mandate fortification of foods with this in mind. There are also serious issues with withdrawal from psychiatric drugs when pregnancy is confirmed since the process must be tapered over a period of time or very serious effects are likely.
Some insight into risk can be obtained by examining what is known about the side effects of stimulants since this class has a long history of use in both children and adults and there is considerable information available, especially regarding Ritalin, Concerta and Focalin and the amphetamine mixture called Adderall. Note that these are all classed in the US as so-called Schedule II drugs. The nature of the list can be discerned by the company they keep, which includes cocaine, opium, morphine, codeine, methadone, oxycodone, and hydromorphone! Addicts "snort" stimulant drugs just as they snort other Schedule II drugs in the process of achieving a high. Drugs are on this list because they have the potential for leading to severe psychological or physical dependence and abuse. Thus high on the list of adverse side effects for stimulants is the risk of addiction, independent of whether they are used for AHDH or as neuroenhancers. Parents should be made aware of this.
Other adverse mental effects reported in clinical trials of stimulants include drowsiness, loss of alertness, convulsions, dopey behavior, depression, agitation, restlessness, and irritability. Rates range from 5% to about 40% depending on the effect.6 FDA post-marketing adverse event reports concerning methylphenidate products such as Ritalin and Concerta include suicidal ideation, aggression and violent behavior. A March 2006 FDA report indicated that every type of stimulant drug potentially could cause psychosis or mania, particularly hallucinations at the usual doses employed to treat ADHD, and these results included confirmation by rechallenge (administration for a second time caused recurrent psychosis).6 Another side effect is termed being "hung up" which translates roughly into compulsive behavior including over focusing and repetitive behavior. Of course, if these side effects occurred in the majority of users, the drugs would no longer be on the market.
In his recent (second edition) medical textbook Brain Disabling Treatments in Psychiatry, Dr. Peter Breggin points out that experts generally agree that Ritalin affects normal children in the same way as those diagnosed with ADHD. Breggin lists and documents a number of stimulant effects commonly misidentified as therapeutic or beneficial which include obsessive-compulsive behavior, social withdrawal effects, and behaviourally suppressed effects. He also discusses at length brain damage and dysfunction caused by stimulants including atrophy, gross brain dysfunction, abnormalities in brain chemistry and microscopic pathological changes. One serious problem he emphasizes throughout the book is that the drugs also impair an individual's ability to detect adverse effects but rather confuse them with benefit. He terms this "spellbinding" although it has a fancy medical name as well.6 Spellbinding presents a serious obstacle to those trying enhancers to see if they work and if there are adverse effects. Since the drugs being used have never undergone long-term testing with normal, healthy cohorts with the object of uncovering adverse effects which include brain disabling and spellbinding, and since those trying these drugs for neuroenhancement may never be able to detect subtle and perhaps permanent damage, it is hard to emphasize strongly enough that real and very complex risks are indeed involved. They are also risks easily dismissed by advocates of neuroenhancement, especially those who only believe in the most compelling evidence-based arguments. After all, these risks are routinely dismissed or downplayed when the drugs are used for therapy, a fact of life which complicates decision making for the layperson desirous of valid and complete information concerning risks, but generates books full of case histories which can be profoundly alarming.7-9 The information really needed is either not available, nonexistent or ignored. Part of the driving force behind this situation, including denial and suppression, is simply that benefits are emphasized for the sake of profits, and the profits are huge by any standard.
If one is doing a risk/benefit analysis, it would seem that little more needs to be said. For a normal individual with no real mental illness to attempt neuroenhancement with stimulant drugs does not appear to be a good idea. Thus the enhanced ability to focus and settle down to a task, which some equate to being smarter or better able to function at certain tasks, comes at a high price of risk of known side effects. Long-term risks that would apply to continuous use over a number of years of stimulant uses to reach a permanent higher-level performance have never been studied. However, in groups where continuous use has occurred, there is obviously a selection process since those who experience some adverse effects will simply stop taking the drug. At the other extreme, addiction will occur, perhaps along with psychosis, which will then lead to additional medication. This is an all too common scenario.
With respect to the other classes of drug used off-label for neuroenhancement, side effect information is variable. The following include examples of three different classes of drug also used off-label for neuroenhancement. More details can be found in the Physicians Desk Reference and drug company and other websites.
Modafinil (Provigil). From the drug label information:
Memantine. Common adverse reactions observed include confusion, dizziness, drowsiness, headache, insomnia, agitation and hallucinations.
Donepezil (Aricept). Nausea, vomiting, diarrhea, loss of appetite, dizziness, drowsiness, weakness, trouble sleeping, shakiness and muscle cramps.
This information must be interpreted with caution. Treatment was on-label and thus for conditions that were indications for treatment, rather than for well individuals. Also, one can conclude from the evidence uncovered in court cases that side effects may be significantly and intentionally understated or suppressed in industry supported trials.
THE ETHICAL DILEMMA
At present, neuroenhancers are prescription drugs or illegal street drugs and thus the physician asked for a neuroenhancer prescription has a problem since a drug is being given off-label, not to treat any disorder, but purely for anticipated enhancement of performance or to gain a competitive advantage. Couple this with the lack of information in general regarding long-term adverse effects on patients of all ages, and one can easily appreciate that for most doctors, there will probably be (or should be) a fairly high level of discomfort. Remember the oath that emphasized "first do no harm". Exactly the same situation occurs with sport performance enhancers. Those seeking neuroenhancer prescriptions may solve this problem by faking the appropriated disorder, e.g. ADHD or a sleeping or wakefulness problem, and in come cases this will work. Students do it all the time. If the past is any guide, there will always be physicians willing to play along with the request for such off-label prescriptions, and how this will be treated in terms of legality or professional misconduct remains to be seen. The whole ethical issue is now the subject of ongoing debate and there is a large relevant literature.
The growing use of neuroenhancers has prompted the formation of the Neuroethics Society (www.neuroethicssociety.org) representing a subfield of bioethics. Its mission is to address the ethical aspects of developments in neuroscience and neuropsychiatry. There is no doubt that the current activity in the field of cognitive enhancement, and especially the research on new drugs targeted at healthy individuals, will challenge this organization. Another challenge will be to determine if the organization is biased by industry ties.
The two sides to the ethical issue are clearly seen in the recent literature. In a commentary in Nature Henry Greely from Stanford Law School was joined by other academics from various medical science disciplines to argue that society must respond to the growing demand for cognitive enhancement.10 We are told that "We should welcome new methods of improving our brain function." They present a comprehensive agenda addressing issues such as fairness and socioeconomic disparities inherent in cognitive enhancement, research into effectiveness of drugs in healthy individuals, full dissemination of information on risks, benefits and alternatives, and legislative action to protect the effort and use. A tacit assumption appears to be that benefit far outweighs risk ands that long-term risk can and will be determined. The article is illustrated with a picture of some Adderall pills. A similar position is advanced by Steven Hyman from Harvard.11 In dealing with the risks of stimulant drugs he argues that these drugs have been used for decades and long-term cohorts have been followed for a variety of reasons, "making it unlikely that we are missing some truly awful long-term side effect." He should read what Peter Breggin has to say in two chapters on stimulants and check out the references!6 But Hyman does admit to the absence of "solid empirical knowledge" regarding risks.
Sahakian and Morein-Zamir from the University of Cambridge have recently provided a good discussion of what they call the "rights" and "wrongs" of the use of cognitive enhancers in healthy adults.2 They discuss many of the observations detailed above concerning alleged or real benefits in healthy individuals and describe a survey of academics who took modafinil. Those who used this drug spoke highly of the experience with global effects on attention, working memory, word finding, improved sustained hard thinking and increased mental energy. The authors also cite applications in the military and even for surgeons. College students report similar levels of satisfaction.1
Sahakian and Morein-Zamir also provide a lengthy discussion of concerns. Some of these have been mentioned above. They included the absence of long-term studies, the potential dangers to the developing brains of children and teenagers, inequalities and fairness associated with access to these drugs, unfair advantages in many settings, and that some aspects of the development of a successful and intelligent work ethic could be replaced by taking a pill. Also, they point out that intelligence is complex and no one knows what these drugs do in general and advocates are simply looking at certain manifestations which can be manipulated. They quote Anjan Chatteerjee from the University of Pennsylvania as saying that "No one has conducted thorough studies about how brain-boosting drugs would affect healthy people after weeks or months (how about years?) of use." Finally, they discuss surveys that indicate that a significant fraction of some populations (e.g. students and parents) held a favourable view of the underlying philosophy of using cognitive enhancing drugs.
Along with all of these calls, both radical and conservative, for increased use or consideration of cognitive enhancers, the one thing ignored is the almost complete impossibility of demonstrating long-term safety in large controlled studies. Will university ethics committees approve giving powerful drugs with documented side effects to healthy individuals? True, healthy individuals can no doubt be paid to participate, but those who experience early side effects would no doubt drop out, and compliance over say several years is hard to imagine. Proponents look forward to targeted drugs for cognitive enhancement in healthy individuals that have been proven safe. But arguments have been presented repeatedly in the above discussion and in the literature that proof of low or no risk is near impossible, and in fact simply fantasy, just like the Brave New World.
Neuroenhancement and cosmetic neurology are completely consistent with the modern philosophy that there is a pill for almost everything and if you have a problem, Big Pharma is always there to offer a helping hand. In the academic setting, if you want an advantage, or in fact avoid being disadvantaged, enhance your intellectual powers and your ability to focus, or if it is desired to combine an active and time consuming social life with the need to do some studying and writing, then talk to your buddies down the hall or find someone who sells enhancers. Parents take note of what may be necessary to get your kid in an Ivy League school. If you are an ER doctor and have trouble working at 100% for the whole shift or a professor desperate to achieve tenure, follow the example of some of your peers and take modafinil. It is said to be a wonder drug.
Twenty or thirty years ago the above paragraph would be considered somewhat absurd. Those who view it as a valid description of the present, and an indication of the future can feel secure in that the negative arguments are doomed to never get off the ground because of the near impossibility of doing studies which will define the real long-term risks. It is interesting that serious, concerned people are suggesting that urine samples should be required before students take important exams such as SATs.