ORIGINAL PAPER

Will There Ever Be a Drug with No or Negligible Side Effects?Evidence from Neuroscience

Sylvia Terbeck & Laurence Paul Chesterman

Received: 4 May 2013 /Accepted: 10 September 2013# Springer Science+Business Media Dordrecht 2013

Abstract Arguments in the neuroenhancement debateare sometimes based upon idealistic scenarios involv-ing the assumption of using a drug that has no ornegligible side effects. At least it is often implicitlyassumed – as technology and scientific knowledgeadvances - that there soon will be a drug with no ornegligible side effects. We will review evidence fromneuroscience, complex network research and evolutiontheory and demonstrate that - at least in terms ofpsychopharmacological intervention – on the basis ofour understanding of brain function it seems inconceiv-able that there ever will be a drug that has the desiredeffect without undesirable side effects. We will illus-trate this by reference to enhancing edge detection inV2 in monkeys and demonstrate that even for thislocalised single neuron coded function there wouldbe numerous side effects. Taking the more realisticcase of pharmacological enhancement that is inevitablyassociated with side effects will change consequential-ist arguments for neuroenhancement and have impli-cations for the conception of autonomy, specifically inthe case of performance enhancement. We concludethat a neuroethics debate that aims to inform policydecisions should take these findings into account. We

hope that our article will precipitate more interdisci-plinary research in neuroscience and philosophy.

Keywords Pharmacological enhancement . Neuronalnetworks . Side effects

Introduction

“In a way reading a book is like deep brainstimulation since both are enhancement, alteringthe brain.” 1

This statement might at first glance, and for a layperson, seem wrong, sounding something like “In away a dog is like a table since they both have fourlegs.”Following the current neuroethics debate it be-comes clear however that there are a number ofarguments that may support this conclusion. Itcould thus be too easy to declare something asunethical, unnatural, or unauthentic, just becauseit involves medication or surgery, but is in itsessence the same as already existing and widelyuse enhancing methods. Indeed, one recent paperargued on this basis that it was morally appropri-ate to use deep brain stimulation for enhancementpurpose [1]. We will not take as a standpoint thatit is its intrinsic nature that makes biological en-hancement unethical, but that safety issues may beof ethical concern.

NeuroethicsDOI 10.1007/s12152-013-9195-7

1 (Personal conversation: Neuroenhancement conference Uni-versity of Mainz, Germany, 2011).

S. Terbeck (*)University of Oxford, Oxford Uehiro Centrefor Practical Ethics,Suite 8, Littlegate House, St Ebbes Street,Oxford OX1 1PT, UKe-mail: sylvia.terbeck@psy.ox.ac.uk

L. P. ChestermanSchool of Psychology, University of Bangor,North Wale, UK

Current arguments in the ethical debate onneuroenhancement are often based on the assumptionthat there is - or soon will be - neuroenhancement withno or negligible side effects. We will demonstrate that –at least in terms of pharmacological enhancement - onthe basis of our understanding of brain function it isextremely unlikely that this will ever be the case. Thismay therefore require modification of some of the ethicalarguments. Increased interest in cognitive and emotionalenhancement, might have been triggered by increasedpublic awareness of the proliferation of these technolo-gies. For example, selective serotonin reuptake inhibitors(SSRIs) are now increasingly prescribed for patientswhose problems might not meet the threshold for mentalillness.2 In terms of mood enhancement, Elliot [2] statedthat healthy people who took antidepressants reportedthat they felt energized, more alert, andmore able to copewith the world. Also, Kramer [3] suggested that individ-uals, who had no recognised mental illness, recoveringfrom depression, asked to remain on the treatment sinceantidepressants made them feel better then well.

The scientific evidence for the effectiveness of phar-macological mood enhancement remains, however, in-consistent. In an extensive meta-analysis Repantis et al.[4] reviewed 65 studies using antidepressant drugs inhealthy volunteers and concluded that there was noconsistent evidence for enhancing effects onmood, emo-tional processing, wakefulness, attention, memory, orexecutive functions. Also a recent meta- analysis foundthat antidepressant treatment was only more effectivethan placebo in severe but not mild or moderate depres-sion [5]. Thus, the available evidence does not indicatethat enhancing mood in mentally well individual is likelyto be achieved with pharmacological interventions. Inaddition to mood enhancement, Savulescu et al. [6]suggested that other attributes such as “… memory,self- discipline, patients, empathy, a sense of humour,optimism, and just having a sunny temper”, “… mayhave some biological and psychological basis that wouldbe capable of manipulation with technology.” (p. 11).

Consequentialist arguments in favour ofneuroenhancement fol low the not ion thatneuroenhancement ultimately has beneficial effects suchas: “… a world in which people have greater intellectualskills, have sharper memories, and can control theirmoods is a world in which people are more productiveand happier.” ([6], p. 373). Further, it was suggested by a

spokesperson from the US Military that “… even asmall enhancement of cognitive capacity would proba-bly have an impact on the world economy rivalling thatof the internet.” ([6], p. 54). Another argument for themoral permissibility of neuroenhancement, and also thepractical implication of its free availability, are claimsbased on human autonomy. For example Dees [7] ar-gued that it should be an individual’s free choice toenhance themselves, as long as others are not harmed.Also, Berghmans et al. [8] posed the question if phar-macological enhancing drugs should be “… partof personal choice and available over the counter ....”(p. 21.). Since cigarettes and alcohol, which are poten-tially harmful, freely available for adults the sameargument based on autonomy might suggest thatneuroenhancement should also be the individual’schoice even if it would harm the individual but notothers. In addition, Dees [7] discussed concerns aboutcoercion associated with neuroenhancement. The authorargued that enhancing drugs, if widely used in theworkplace, might force others to take these drugs aswell. The author suggested that individuals are alsoobliged to make other sacrifices for job success suchas socialising, attending a certain school etc. The authorhimself however acknowledges that this argumentagainst the coercion claim might only be valid in thecase of a safe drug. Subsequently in this paper, we willdemonstrate that the autonomy claim and consequen-tialism arguments might have to be reviewed if theassumption of a drug with no side effects is not valid.

Assumptions

Sahakian & Morein-Zamir [9] suggested that in thenear future there might be a drug with increased ben-eficial effects and reduced side effects and that theremight be less objection to take those kinds of drugs.When comparing the side effects of atypical and tradi-tional antipsychotic medication or selective serotoninuptake inhibitors to previous antidepressant drugs, theside effects are clearly less severe in the newer drugs. Itis thus likely that advances in science would lead to adrug with reduced side effects, but this should howevernot lead to the assumption that further research wouldbe able to create a drug that has no or negligible sideeffects. In his chapter on moral enhancement, Douglas[10] creates a fictional scenario. Part of this scenario isthe assumption that: “The only effects of Smith’s2 President’s Council in Bioethics.

S. Terbeck, L.P. Chesterman

intervention will be (a) to alter Smith’s psychology inthose (and only those) ways necessary to bring aboutthe expectably better post-motives ….” (p.473.). Thisargument is based on the assumption that a drug can bedeveloped that has no side effects. Additionally thereare a number of other papers where the authors makethe assumption that there soon will be a drug with no ornegligible side effects (e.g., Berghmans et al. [8]; Dees[7]). For example, in their article Berghmans et al. [8]suggested that so called neuroceuticals for therapy andenhancement will become possible: “Unlike today’spharmaceuticals, neuroceuticals will be efficientneuromodulators with negligible side effects. By beingable to target multiple receptors in specific neural cir-clets, neuroceuticals will create the possibility for dy-namic intracellular regulation of an individual’s neuro-chemistry.” (pp. 128). However when discussing safe-ty issues associated with enhancing drugs, Dees [7]acknowledged that concerns about side effects mightprevent the use of enhancing drugs “right now”.

There is No Drug with No Side Effects

To date no psychotropic drug has been identified that hasno or negligible side effects. For example prominent sideeffects of SSRIs include: headache, nervousness, insom-nia, sweating, dizziness, sexual dysfunction, and tremor.There is also some inconsistent evidence that SSRImightelicit the sudden emergence of intense suicidal preoccu-pations [11]. Indeed, Sahakian & Morein-Zamir [9] stat-ed that currently a main concern of using psychotropicmedication for treatment as well as for enhancing pur-poses are the side effects, which thus have to be weighedagainst the benefits for every case individually. Theauthors also stated that the exact mechanisms and longterm side effects are not yet fully understood.

There Never Will Be a Drug with No Side Effects

Since the 19th century we have understood that thebrain works in complex networks. Thus the brainworks locally and globally, as well as dynamically.Phase locked high- frequency electromagnetic oscilla-tions can make up a functional network, forming thebasis of information processing [12]. In their reviewBullmore and Sporns [12] address the use of graphtheory (a new mathematical tool to analyse complexnetworks, such as the brain) to gain insight into theanatomical and functional complexity of brain

networks. The authors found that, from a network per-spective, the function of an individual node is partlydetermined by its interconnecting notes, such that thefunctional properties are the result of the action of anentire network. One example of this is intelligence. Forexample, da Rocha et al. [13] demonstrated, using EEG,that a distributed network, rather than a localised region,is likely to be the neural basis of intelligence. Thus, it islikely to be a structural entailment of neuroanatomy thatimpacting any system in the brain must impact on others.

For demonstration purpose, we decided to examinea theoretical case of enhancing a seemingly stronglylocalised brain function. One might agree, that en-hancement of complex functions such as empathy,intelligence, or morality might be controlled by numer-ous brain regions and neurotransmitters, but we want todemonstrate that even in the case of enhancing a “pure”and simple function, large neuronal networks are in-volved. Thus, we decided to describe the scenario ofenhancement of visual edge detection to the right cor-ner in stereoscopic vision in monkeys. Using singlecell recordings, Von der Heydt et al. [14] found thatcells in V2 of the visual cortex selectively respond tothe direction of edges during the coding of stereoscopicfigures. Research in molecular biology has shown, thatin V2 62 % of cells possessed the acetylcholine recep-tor subtype M1 AChR-ir and 43 % of acetylcholinereceptor subtype M2 AChR-ir [15]. Importantly, thishowever is not specific to this region; researchconducted for example by Spencer et al. [16] revealedthat the receptor density for muscarinic acetylcholinereceptors was also high in numerous other brain re-gions. For the M1 AChR-ir subtype high density wasalso found in the dentate gyrus, the medial amygdala,the caudate nucleus, and the putamen. In addition toV2, the M2 AChR-ir subtype high density was foundin the putamen, thalamic areas, and brainstem. Addi-tionally, we do not even considered the effect thatmodulating the effects of one neurotransmitter couldhave on numerous other neurotransmitters. It thus be-comes clear that even if a drug was developed thatspecifically targeted the M1 AChR-ir receptor thatwould enhance edge detection in the visual system ofmonkeys, due to the distribution of these receptorsthroughout the brain in various other regions therewould most likely be numerous side effects. Thus anyattempt to pharmacological modify such higher orderbrain functions as “....memory, self- discipline, pa-tients, empathy, a sense of humour, optimism, and just

Will There Ever Be a Drug with No or Negligible Side Effects?

having a sunny temper” ([6], p.11) would be even morelikely to be associated with significant side effects.

Additionally, a further example of a biological in-tervention that affects more than one target is an ex-periment on genetically modified mice Tang et al.[17].The authors found that genetically modified miceshowed improved capacities for learning and memory.The smart mice had increased performance comparedto controls on a variety of standard learning tests, suchas novelty object recognition, but also extinction offear. These mice contained a transgene encoding theNR2B subunit of the NMDR receptor. Compared toNR2A subunits NR2B contribute to more persistentexcitatory post-synaptic potentials, and thus enhancelong term potentiating. However, since the specificsubunit of the NMDA receptor is also involved innumerous different processes in addition to memoryfor example pain processing; “smart mice” were alsohypersensitive to pain. Cooke and Bliss [18] speculatethat enhanced cognitive performance, such as 100 %memory function, might not have evolved – eventhough it would have evolutionary benefit – becauseit would be necessarily coupled with disadvantageouseffects. In conclusion, due to the molecular and ana-tomical arrangements of brain structures, it is likely tobe physically impossible to pharmacologically targetonly one specific function, and thus to ever have a drugwith no or negligible side effects.

Decisions about enhancement could thus be under-stood as a pragmatic choice between the benefits ofpossibly minor effects (e.g., as described in the meta-analysis of antidepressant use for enhancing purposes;Repantis et al. [4]) and adverse side effects (such asnausea, and anxiety]. Additionally, the risk of drugaddiction should be taken into account. Since the de-sired effect and the severity of any side effects will bedependent on individual variation it would be difficultto determine a general rule as to when the desired effectof a particular drug would outweigh consequences ofany side effects. Therefore pragmatic decisions wouldhave to be made on an individual basis.

Arguments Reviewed

First, the evidence indicates that the administration of anydrug that would be capable of cognitive and emotionalenhancement would almost invariably be accompaniedby significant side effects. This could result in “… a

world in which people have greater intellectual skills,have sharper memories, and can control their moodsand a world in which people are more productive andhappier.” ([6], p 346), but potentially also a world inwhich people suffered from sexual dysfunction, nervous-ness, and insomnia. So the consequentialist claim for theoverall benefit of neuroenhancement is only valid if thedrug has no other than the desired effect. Since this is notthe case, enhancement might not have ultimate overallbenefits. And even worse, one might want to consider thepossible negative accumulation of side effects, which insome instances might even lead to overall negative con-sequences. At first glance, it might seem beneficial toincrease – if this was possible - intelligence. Advances inmodern technology might create future existential treats,such as natural disasters, that might be resolved if themean intelligence of the population was enhanced. How-ever, if this effect was necessarily coupled with negativeside effects other threats might have been created at thesame time. Additionally,, the side effects of many phar-maceuticals, specifically the long term side effectsremainspoorly understood, so that further research isneeded before any informed decision can be made. Inaddition side effects might persist even if the drug is nolonger being consumed, which might be caused by struc-tural changes in the neurotransmitter system. . It thusseems impossible to propose that pharmacological en-hancement would necessarily have any overall benefit.Following consequentialist argumentation if higher over-all intelligence is created at the expenses of taking a drug,this would seem morally appropriate only if higher intel-ligence is the only effect. If higher overall intelligencewas the consequence of taking a particular drug but thiswas also accompanied by higher overall would this bemorally acceptable? More generally; if ‘something’ pos-itive is created at the expenses of creating somethingequally negative the case of deciding the overall ‘good’becomes more complicated, and as previously stated thedecision to employ any particular enhancement techniquecan only be a pragmatic decision on an individual basis.

Secondly, Dees [7] argued that it should be an indi-vidual’s free choice to enhance themselves or not. Afterall, smoking and alcohol cause widely known side ef-fects, and still people seem to judge those drugs asmorally acceptable. We will demonstrate that the auton-omy claim does not hold for enhancement – at leastperformance enhancement – and that this is particularlythe case when considering a drug that has side effects.Other than alcohol or cigarettes, as Dees [7] argued,

S. Terbeck, L.P. Chesterman

increased use of enhancing drugs in the workplacemight pressure others to enhance themselves pharmaco-logically as well. Taking the case of a drug with sideeffects, individuals might thus be pressured intoaccepting these side effects as well. In competitivesports the pharmacologically “unenhanced” might haveno chance of winning. Thus, if increased use pressuredothers into taking the drug as well, andthis was associ-ated with side effects, increased use of pharmacologicalenhancement would harm others, and thus might beunethical. One counter argument might be that otherthings – such as going to school – can have side effectsas well, and that individuals who want to work in certainjobs are pressured to go to certain schools, and thusgoing to school would be as equally morally inappro-priate as pharmacological enhancement. Even thoughone might want to ask if the side effects of other activ-ities, such as going to school, are not obviously lessharmful than associated with taking a drug, we willdemonstrate that even if this was not the case, and theside effects would be the same, that the argument stillcannot hold, when considering pharmacological en-hancement with side effects; The key point is that po-tential side effects of social interventions may be avoid-able but one could not decide not to have physiologicalmolecular responses. For example it may be possible toameliorate feelings of anger associated with being com-pelled to attend a particular instance school but it wouldbe possible to avoid a physiologicaly automatic re-sponse. Thus the natures of the side effects are different.

Concluding Remarks

When one considers artificial intelligence, or brain-computer interfaces – which might improve in the nearfuture following technical advances - this is then verydifferent to pharmacological enhancement of cognitiveor emotional function with no or negligible side ef-fects, since this is something that, based on our under-standing of brain function, appears to be physicallyimpossible to achieve, even with technological andscientific advances. Thus if neuroethical debates aboutneuroenhancement are aiming to influence politicaldiscourses they need to recognise the likelihood ofsignificant side effects. There should be further inter-disciplinary work involving ethicists and scientists.Indeed the decision to utilise pharmacological ‘en-hancement’ might ultimately be considered to a

pragmatic decision rather than an ethical issue. AsSahakian & Morein-Zamir [9] suggest, there are alter-native ways to achieve cognitive or emotional en-hancement, such as sports, education, or sleep. Thus,if “… reading a book is in a way like deep brainstimulation because they are both forms of enhance-ment that alter the brain”, why not just read a book.

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