The warrior in the machine: neuroscience goes to war Irene Tracey and Rod Flower

Abstract | Ever since Stone Age men discovered that knapping flint produced sharp stone edges that could be used in combat as well as for cooking and hunting, technological advances of all kinds have been adapted and adopted by the military. The opportunities provided by modern neuroscience are proving no exception, but their application in a military context is accompanied by complex practical and ethical considerations. The US Army general George S. Patton is credited with saying: “The soldier is the Army. No army is better than its soldiers.” Despite the focus on ‘glamorous’ military hardware such as remote-controlled drones and fully autonomous combat vehicles, the fundamental unit of the military is, and will remain for the foreseeable future, the individual soldier, sailor or airman/ woman. It is the expectation that knowledge and techniques gained from advances in neuroscience could enhance their combat effectiveness while degrading that of their opposition that makes neuroscience such an alluring subject to military planners. Here, we review some examples of these applications. We begin with an examination of the military use of pharmacological agents and then consider the use of imaging, neural interface systems and other devices. We conclude with a section that highlights some of the ethical issues raised by the ‘militarization’ of neuroscience. There have been many other studies that address this topic in whole or in part. Among the most recent are the ‘Brain Waves’ studies by the Royal Society 1–4, which deal with several aspects of neuroscience and their impact on policy and society, including one module dealing specifically with the military applications of neuroscience3. A report5 from the Nuffield Council on Bioethics similarly describes the spread of neurotechnologies through society and discusses the ethical implications of their use. Reports from The National Academy of Sciences (in the United States) deal specifically with emerging neuro­science technologies6, survey trends in science and technology of relevance to the Biological Weapons Convention (BWC)7, and explore the potential of neuroscience applications by the US Army 8. An influential book by Moreno9 and subsequent papers by

this author and his colleagues10 analyse and discuss the entire phenomenon of ‘mind wars’. Huang and Kosal11 review the security-related aspects of military neuroscience, and Farah12 and others13 have discussed the ethical issues surrounding the exploitation of neuroscience by the military. The use of biological and chemical weapons in warfare is restricted by international conventions. Dando14 comments on advances in neuroscience from the perspective of the BWC, whereas a seminar organized by the Royal Society in preparation for the Third Review Conference of the Chemical Weapons Convention (CWC)15 addressed concerns that some weapons could ‘fall between the gaps’ of the legislative frameworks encompassed by the BWC and the CWC. Many of the issues discussed were relevant to neuroscience (for example, incapacitating chemical agents, synthetic biology and nanotechnology). The warrior in the machine Military personnel bent on enhancing their physique could opt for a suitable chemical fix from the tarnished pharmacopoeias of the athletics ‘doping’ community — and evidently some troops do16. However, the mind is different: is it possible to fortify the ‘warrior spirit’? Is there, to adapt Ryle’s17 metaphor, a ‘warrior in the machine’ of the mind that can be influenced by stimulant drugs, or that could perhaps be modified by specific training regimes or technologies (such as transcranial magnetic, direct current or deep brain stimulation/modulation, or even brain–computer interface implants)1,3? This has proved an attractive and enduring idea18. Would‑be berserkers from many cultures in the ancient world consumed alcohol, coca leaves, ma huang leaves (which contain ephedrine), cola nuts (which contain caffeine) and marijuana to boost their performance.


‘Trench cocktails’ — a mixture of cocaine and vodka — were used by Russian troops in the Second World War19 and, more recently, the New York Times reported that stressed Iraqi soldiers were self-medicating with high doses of trihexyphenidyl (also known as benzhexol), an anti-parkinsonian drug, in the belief that it made them more courageous and brave20. There were persistent rumours that fighters in Gaddafi’s Libya consumed “sex drugs and hallucinogenic drugs” presumably for the same reason21,22. Even intravenous benzodiazepines are apparently perceived to give criminals “courage and … the alertness to commit crimes” (REF. 23). At the opposite end of the spectrum, the horrors of war force some soldiers to seek solace in the use of recreational drugs24. Contemporary applications of neuro­ pharmacology to military efficiency have been directed to more prosaic objectives. War is adversarial, with one side seeking to promote the effectiveness of its own forces while degrading those of the opposition. It is not surprising, therefore, that the applications of neuroscience knowledge and techniques fall broadly into these two categories, with the former embracing both neuro-enhancement techniques and novel approaches to enhance recovery and rehabilitation post-injury (both physical and mental), so that expensive assets such as highly trained and specialized soldiers can resume their duties as quickly as possible. Stay awake, stay alert. Adequate sleep is essential for optimal military performance25, but for the majority of personnel on deployment this is frequently impossible26. As a consequence, they are at greater personal risk and are potentially a danger to their comrades, and they may also suffer from long-term psychological problems. Sleep disorders themselves can be treated with conventional hypnotics and anxiolytics, but a common8 military application of neuro­ pharmacological know-how has been the use of drugs to promote alertness in situations where sleep is impossible — drugs that can, as Caldwell puts it, “temporarily bridge the gap between widely spaced sleep periods” (REF. 27). Although cocaine is able to improve endurance and stamina and to elevate mood, it is too prone to producing dangerous side effects to be of much use in a disciplined military environment. However, there are many other types of drugs (and dietary supplements) that claim to have similar effects28. Whether these actually work as stated is the subject of an erudite review by Rose29; nevertheless, several have been tested and used by the military (TABLE 1). VOLUME 15 | DECEMBER 2014 | 825

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PERSPECTIVES Table 1 | Military use of drugs to combat fatigue and enhance cognitive functions Drug type


Amphetamine and related drugs

Principal mechanism of action


Military use

Dexamphetamine ADHD and narcolepsy

Increases noradrenaline and dopamine levels by blocking uptake by transporters, displacing intracellular monoamines from stores and promoting their release from neurons

Risk of dependence or anorexia; chronic use may lead to anxiety, restlessness and insomnia; and overdose can lead to psychotic episodes

Maintaining alertness and vigilance; combating fatigue

Methylphenidate (Ritalin)

ADHD and narcolepsy

Increases noradrenaline and dopamine levels by blocking uptake by transporters

Risk of insomnia, irritability and aggression

Modafinil (Provigil)


Inhibits dopamine re‑uptake by blocking transporter

Risk of anxiety, sleep disturbances and dependence



None, but widely consumed in beverages

Inhibits phosphodiesterase; adenosine A1 and A2 receptor agonist

Risk of insomnia

Maintaining alertness and vigilance; combating fatigue

Cholinergic agonists


None, but widely consumed in cigarette smoke, nicotine patches or chewing gum

Agonist targeting nicotinic acetylcholine receptors in several areas of the brain, enhancing neurotransmitter release

May lead to addictive behaviour

Improving cognitive functions

Alzheimer’s disease

Cholinesterase inhibitor

Risk of insomnia, agitation and aggression

Improving cognitive functions

Anticholinesterases Donepezil

Conventional clinical use

ADHD, attention-deficit hyperactivity disorder.

Methylxanthines occur naturally in beverages such tea and coffee. They are consumed by millions of people who appreciate their mild stimulant actions and are not generally regarded as ‘drugs’ (REF. 30). Caffeine itself has been extensively evaluated by the military 31,32. Administration of this compound to military personnel in various formulations (including chewing gum)33 maintained vigilance, reduced fatigue and enhanced some cognitive functions (although not others such as marksmanship)34,35, and these actions were enhanced by prior ‘prophylactic’ sleep36. In practice, however, caffeine has been largely superseded by amphetamines, which exhibit superior effects across a range of physical and cognitive tests37. Originally used as decongestants, the psychostimulant actions of amphetamines were not fully appreciated until the 1930s38 but were thereafter quickly pressed into service by the military during the Second World War39. In Nazi Germany a methamphetamine derivative called Pervetin was widely used by the Luftwaffe and possibly even by the High Command40,41. Benzedrine and other amphetamine formulations (aside from being James Bond’s favoured ‘pick‑me‑up’)42 were used by the US military during the Korean war, as well as the Vietnam and Gulf war campaigns, with useful results and continue to be used by US forces27,43. Amphetamine preparations are used clinically to treat attention-deficit

hyperactivity disorder (ADHD), and apparently there is a brisk secondary market among college students, academics and other groups44–46 hoping to benefit from the increased focus and concentration promised by these drugs. Methylphenidate and modafinil are among other related agents with similar clinical indications, and they also chiefly act by blocking monoamine uptake transporters, although modafinil has a rather puzzling pharmacological profile in this regard47. In a comprehensive review of the literature, Repantis et al.48 suggested that methylphenidate improved some cognitive functions (for example, memory) but not others (for example, mood and vigilance), whereas modafinil was effective in promoting wakefulness, attention, executive function and memory. Importantly, the effects of modafinil were observed in both sleep-deprived individuals and well-rested subjects, which suggests that it would be particularly suitable for military use. Indeed, both drugs have been widely tested as agents to combat fatigue and to promote efficiency during complex military tasks. For example, in a study of its utility as an operational fatigue countermeasure49,50, modafinil was reported to be effective and well tolerated with few side effects. When tested in sleep-deprived helicopter pilots in a flight simulator, it significantly mitigated the effect of sleep deprivation, although less potently than dextroamphetamine27,51.

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The cholinergic system of the CNS is crucial for the execution of many cognitive tasks, including attention, learning and memory, and is defective in some neuropathologies such as Alzheimer’s disease52. Nicotine, which itself has a long history of social use to aid concentration, has a beneficial effect on the cognitive deficit observed in patients with Alzheimer’s disease53. Cholinesterase inhibitors that have similar effects on cognitive performance54, such as donepezil, have become standard therapy for this condition. Nicotine, in the form of chewing gum, enhances aspects of pilots’ performance55; conversely, nicotine withdrawal in pilots who smoke can lead to a detectable reduction in their performance56. Anticholinesterase drugs have a similar effect to nicotine, and chronic treatment with donepezil significantly improved the performance of pilots in flight simulators when compared to a placebo55,57. The benefits of improved nutrition on physical performance (for example, increasing endurance) are of course well known, but there is also growing interest and research into the impact of nutrition on the functioning of the brain, with potential beneficial effects such as enhanced cognition and even recovery from stress58,59. Rehabilitation and recuperation. The military use of neuropharmacology is not restricted to the promotion of efficiency on the battlefield; it also has a useful role in the management of

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PERSPECTIVES Table 2 | The neuropharmacology of rehabilitation Drug type


Conventional clinical use

Principal mechanism of action


Military use

Amphetamine derivatives


None as such, but widely used as a ‘lifestyle’ drug

Releases 5‑HT and inhibits monoamine uptake transporters (5‑HT, dopamine and noradrenaline)

‘Empathogenic’: promotes a feeling of intimacy and trust; produces euphoria

As an adjunct to psychotherapy in PTSD



Hypertension, cardiac arrhythmias, anxiety and muscular tremor

Antagonists; target the β‑adrenoceptor system

May enable ‘emotionally charged’ memories to be ‘extinguished’

As an adjunct to psychotherapy in PTSD

5‑HT, 5‑hydroxytryptamine; MDMA, 3,4‑methylenedioxy-N‑methylamphetamine; PTSD, post-traumatic stress disorder.

casualties of war (TABLE 2). We leave aside here the routine use of drugs, for example, to treat depression or to provide analgesia, although it should be noted that a highly coordinated acute‑to‑chronic pharmacological and rehabilitation programme for managing traumainduced pain improves clinical outcomes and facilitates an early return to military duty 60. Here, we focus instead on the treatment of post-traumatic stress disorder (PTSD), a potentially devastating condition that can leave victims with long-lasting anxiety dis­orders that are sometimes linked to increased suicidal ideation. PTSD affects only a proportion of the population and may be partly genetically determined61. It is, of course, not restricted to those serving in the armed forces and is also encountered in routine psychiatric practice. One characteristic of PTSD is the persistent and unwanted recurrence of traumatic memories, and treatment is hindered in sufferers because these recollections are already established and potentially ‘consolidated’. The phenomenon of Pavlovian ‘extinction’ is well known, although the actual details of how the ‘extinction’ memory is coupled with the original conditioned memory are unclear. Unfortunately, classical ‘deconditioning’ programmes designed to eliminate painful memories are only moderately successful (reviewed in REF. 62), and unpleasant memories may therefore be ‘reinstated’ under some circumstances63. An alternative therapeutic approach, which exploits the brain’s phenomenal plasticity, is the use of mental imagery to ‘reshape’ the traumatic image or experience64,65. The discovery that memories become labile when they are recalled66 and may then need to be further ‘re‑consolidated’ (reviewed in REF. 67) suggests other approaches to this problem. Attention has focused on the use of drugs that specifically interfere with the biochemical correlates of memory formation and retention. The administration of protein synthesis inhibitors, for example, can prevent the consolidation of the fear memory trace68

in rodents, although such treatment is obviously impractical in humans. The discovery that NMDA receptors are involved in ‘extinction’ learning prompted the finding that this was facilitated by the allosteric NMDA receptor modulator d‑cycloserine69, which also promotes a more generalized extinction of other fear memories. Again, whether these findings will be applicable to humans is yet to be established. Another approach arose from the discovery 70 that the acquisition of emotionally charged memories, such as those experienced by PTSD sufferers, required activation of the β‑adrenergic system and that this could be antagonized by concurrent treatment with the CNS-penetrating β‑blocker propranolol. Subsequent studies have yielded mixed results71–73, but it remains a potentially valuable approach. Other treatments for PTSD, derived from a contemporary understanding of psycho­ pharmacology, include selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, anticonvulsants, α1-adrenoceptor antagonists and others (reviewed in REF. 74), but another unlikely drug that has found a potential use here is MDMA (3,4‑methylenedioxy-N‑methylamphetamine; also known as ecstasy). Building upon earlier reports of its efficacy, Oehen et al.75 reported the results of a small randomized trial in which MDMA was used as an adjunct to psychotherapy, demonstrating that the use of the drug strengthened the ‘therapeutic alliance’ and enhanced treatment outcome. Drugs as weapons As the name implies, ‘incapacitants’ are drugs that can degrade the performance of enemy troops. Although the actual definition of the term is imprecise, the implication is that the effect of these drugs is transient. This group includes ‘pepper’, CS (2‑chlorobenzalmalononitrile) and similar sprays that produce an incapacitating effect secondary to the irritation of mucosal membranes. As they target the peripheral nervous system (PNS) rather


than the CNS, these agents are not discussed here (but are reviewed in REF. 76); more germane to our theme are the hallucinogenic deliriants LSD (lysergic acid diethylamide) and BZ (3‑quinuclidinyl benzilate; an anticholinergic glycolate compound). These are among other chemicals that have, in the past, been considered as general incapacitants but that have been largely abandoned on grounds of unreliability 9,76. It is worth noting that a ‘loophole’ in the formulation of the CWC exempts any substances classed as civilian ‘riot control agents’ from the otherwise comprehensive ban of chemical weapons mandated by the convention. The development of anaesthesia is arguably one of the crowning achievements of modern medicine, but the ability to rapidly and reversibly render one or more people unconscious with no long-term adverse effects has unsurprisingly attracted interest as an alternative approach to handling tactical situations where minimizing casualties is a priority. Drugs with this potential, which comprise a subset of ‘incapacitant’ drugs, are often referred to as ‘calmatives’ on the basis that they induce a calm or tranquil state. On 26 October 2002, Russian Special Forces pumped an aerosolized anaesthetic mixture into a crowded theatre in Moscow, where around 850 hostages were being held by a group of about 45 Chechen separatists. The siege was lifted and all the Chechens were killed, but the ensuing military victory was marred by the fact that 129 hostages also died or suffered long-term health problems. The agent used in this case apparently comprised carfentanyl and remifentanil (potent opiates used as analgesics and sedatives) that were possibly mixed with the volatile anaesthetic halothane76–78. Most of the hostage deaths were probably attributable to positional asphyxia (see below) and could have been averted had the identity of the agent been made known to the emergency services, so that naloxone and other appropriate medical attention could have been be administered. VOLUME 15 | DECEMBER 2014 | 827

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PERSPECTIVES Table 3 | The neuropharmacology of potential incapacitants and calmatives Drug type


Conventional clinical use

Principal mechanism of action



Fentanyl and remifentanil

Analgesia and anaesthesia

Agonists; target the peripheral and central μ-opioid and other receptors

Respiratory depression and Incapacitating and possibly positional asphyxia anti-riot agents in an inappropriate setting


Lorezepam, temazepam and diazepam

Sedation, anxiolytic Agonists; target effects and regulatory site on anaesthesia GABA‑A receptors

Cardiovascular and respiratory depression

Not deployed so far

α2-adrenoceptor agonists



Agonists; target pre-junctional α2A‑adrenoceptors in locus coeruleus neurons

No respiratory depression

Not deployed so far

Neuroleptic anaesthetics


Analgesia and anaesthesia

Antagonists; target NMDA-type glutamate receptors

Potentially less prone to depress respiratory and other reflexes, but may lead to sensory distortion; risk of psychiatric problems

Not deployed so far

Lakoski et al.79 defined an ‘ideal calmative’ as one that is easily administered by several routes; that has a rapid, short-lived and reversible action, few side effects and an effective antidote; and that produces the same effect in all individuals regardless of age and body mass index. The candidates identified in their review included sedatives, hypnotics, anxiolytics, neuroleptic and other anaesthetic agents — drugs that are already used clinically to treat anxious, agitated, disruptive or aggressive patients. The group of drugs classed as sedatives comprises mainly of opioids, benzodiazepines, α2‑adrenoceptor agonists and neuroleptic agents (TABLE 3). Opioids, which act on the μ-opiate receptor, have the general property of inducing respiratory depression and sedation, and this makes their use problematic in a confined and uncontrolled environment such as the Moscow theatre siege77. Benzodiazepines act differently, and their effect on the GABA receptor produces anxiolytic and sedating effects. There is less depression of the respiratory and cardiovascular systems, although this still remains a problem80. From a tactical point of view, short-acting benzodiazepines (such as the experimental drug CNS7056), which have a rapid onset and a very short duration of action81, would be very appealing candidates for inclusion into any calmative arsenal. Central arousal and wakefulness are regulated by the release of noradrenaline from locus coeruleus neurons82. Pre-junctional α2-adrenoceptors reduce this release, leading to a reduction in alertness and a sedative effect. At least one α2A-adrenoceptor agonist, dexmedetomidine83, has attracted the interest of the US military as a potential ‘calmative’ agent.

The neuroleptic anaesthetic agents — such as ketamine, which acts predominately at NMDA receptors — produce ‘dissociative’ states of anaesthesia. A potential advantage of these agents is that they are less prone to depress muscle tone, respiratory and other reflexes84; hence, their widespread use in developing countries where administration of other anaesthetics may be challenging. However, it should be noted that psychiatric problems have been associated with the use of these agents85. Alongside, and apparently contrary to this observation, is the potential utility of the drug as a treatment for PTSD86. The prospect of calmative ‘combinations’ comprising, for example, neuroleptics with potent opioids would clearly be very attractive. Although many of these drugs have properties that are superficially suitable as incapacitants, their use has been dogged by several complications. The drug delivery problem. To exert a pharmacological effect, a drug has to reach its site of action in adequate concentrations, and this entails absorption and distribution in the body. This is particularly problematic for neuroactive drugs, as their target is within the CNS so they must also penetrate the blood– brain barrier — a substantial problem that is often encountered by pharmaceutical companies when translating from preclinical studies to humans. Peptide drugs are poor candidates for this reason, although advances in delivery systems may eventually change this situation (for example, see REF. 87), and this is another area of interest for the military 8. Anaesthetic gases are volatile, so they can be inhaled and are consequently fairly straightforward to administer. Other agents, such as the mixture of fentanyl derivatives

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Military use

used in the Moscow theatre siege, must be aerosolized before use. Clearly, such an approach may not be suitable for other drugs, especially high-molecular-weight compounds such as peptides, although future advances in aerosol technology may surmount such problems. The ‘dose–response’ problem. The Moscow incident focused attention on another issue: the so‑called ‘dose–response problem’. The British Medical Association published a report88 condemning the whole concept of ‘tactical pharmacology’. One of their chief objections is that although the therapeutic margin of drugs such as carfentanyl (which depress the respiratory centre) may be large in a clinical setting (>10,000)76 where artificial ventilation and emergency support is available, the same does not apply when these drugs are used in a situation where unconsciousness may lead to positional asphyxia. It is a powerful counter-argument to the use of such agents as ‘non-lethal weapons’, and another confounding issue is the choice of appropriate dose, given that the target population may include children, the pregnant and the elderly or infirm, as well as nominally healthy people of different ages and varying body weight (FIG. 1). Although, as Blain76 observes, the fentanyls “come nearest to fulfilling the criteria for an effective incapacitating agent”, most commentators agree that the “ideal calmative” as defined by Lakoski and colleagues has yet to be discovered (see REF. 89 for a full discussion of these and related issues). Truth and morality in bottles? There are other ways in which neuropharmacology could be used to modify the behaviour of enemy combatants. The use, as an aid to interrogation, of ‘truth drugs’ such as scopolamine,

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PERSPECTIVES Desirable effect Undesirable effect 100

Population suffering adverse effects (%)

Population affected (%)




Therapeutic ratio



75 50 25 0




Therapeutic ratio 0










Log concentration (M)

Figure 1 | The ‘dose–response’ problem.  The effect of a drug on a biological system is convention‑ | Neuroscience ally described by a dose–response or concentration–response Nature curve, inReviews which the magnitude of the effect is plotted against the logarithm of the drug dose or concentration. The diagram above illus‑ trates the action of a hypothetical gaseous ‘calmative’ agent that produces both sedating actions and unwanted side effects. As the concentration increases, the drug produces a sedating effect on an increasing proportion of the target population (blue curve). However, the unwanted effects also increase in magnitude according to the concentration (red curve). At the minimum concentration at which this calmative affects 100% of the population, it produces no detectable undesirable effects (indicated by the short black arrows). The therapeutic ratio (or index) — also known as the safety margin — is the difference in doses or concentrations between the desirable and undesirable effects, and is usually measured at the mid-point on each curve. In the hypothetical example above, this is approximately 100. Real drugs that act on the CNS have widely different therapeutic ratios (heroin, alcohol and cocaine are

The warrior in the machine: neuroscience goes to war.

Ever since Stone Age men discovered that knapping flint produced sharp stone edges that could be used in combat as well as for cooking and hunting, te...
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