Editorials Smart drugs: implications for general practice

The familiar landscape of substance misuse in the UK is changing. Recently a briefing in the BJGP highlighted two “... so-called ‘smart drugs’ are prescription only newer misuse scenarios: legal highs and medicines; some being class B drugs.” ‘chemsex’.1 Another new misuse scenario generally escapes the attention of professionals and others because it does not fit our concept of the term ‘recreational reactions, and so on; 49% of adverse events The reviewers concluded that since most 5 drugs’, since motivation for use is to relate to off-label prescriptions. In 2011, of the studies were short-term single enhance performance in exams or at work. the European Medicines Agency concluded dose studies, no comment can be made However, so-called ‘smart drugs’ are that the benefits of could only on dependence development and drug 6 prescription-only medicines; some being be considered to outweigh the risks when tolerance. class B drugs. After becoming aware of treating ; and recommended A recent review used a single search this emerging issue the BMA Occupational that other previous indications (obstructive engine and provided a narrative description Medicine Committee published a report.2 sleep apnoea, shift-work sleep disorder of the same and similar, mainly single This editorial aims to distil the evidence and idiopathic hypersomnia) be removed dose studies; without describing critical most relevant for primary care specialists. from the product information.5 appraisal or quality of included studies. The authors stated ‘... modafinil has PRESCRIBED USE OF STUDIES IN HEALTHY INDIVIDUALS been extensively evaluated for cognitive PHARMACOLOGICAL COGNITIVE One robust systematic review and modulation in healthy humans, and ENHANCERS meta-analysis of healthy individuals appears safe for widespread use’.7 This Pharmacological cognitive enhancers used two search engines, discussed the statement was made without reference to are licensed for use in three disorders: methodological quality of included studies, wider and more relevant evidence relating attention deficit hyperactivity disorder and presented an evidence synthesis.6 For to the safety of medicines; including clinical (ADHD), dementia, and narcolepsy. There there was no consistent trials and adverse drug reaction reporting is no evidence of misuse of drugs used evidence for neuroenhancement, although schemes. to treat patients with dementia, such as, there was some evidence for memory A Cochrane Collaboration systematic acetylcholinesterase inhibitors (, enhancement, notably spatial working review reported that both modafinil and galantamine and rivastigmine) and memory in laboratory tests. Modafinil had armodafinil increase alertness and reduce hydrochloride. Those misused moderate enhancing effects on individuals sleepiness to some extent in employees are modafinil, licensed to treat narcolepsy- who were not sleep-deprived, namely suffering from shift-work sleep disorder related excessive daytime sleepiness; on attention. A single dose maintained but are associated with adverse events; and and the class B drug methylphenidate wakefulness, memory, and executive that systematic reviews of adverse effects licensed to treat patients with ADHD. functions in moderately sleep-deprived are needed.8 The class B drugs dexamfetamine and individuals. However, repeated doses mixed amfetamine salts (Adderall®), used did not prevent cognitive decrement for PREVALENCE AND DRIVERS OF MISUSE as second-line treatment for ADHD and prolonged and simply Studies of use among high school and narcolepsy are also misused as smart maintained wakefulness. The effect of university students indicate prevalences drugs. Modafinil3 and methylyphenidate4 modafinil depends partly on the individual of 11–25% in North America and 1–20% are prescribed off-label, for example baseline performance, having greater elsewhere, including the UK.2 A student for refractory depression, narcolepsy, effect on those with a lower IQ. It appeared newspaper survey in The Tab reported that and Parkinson’s disease, and modafinil that modafinil induced overconfidence, 20% of UK university students had tried additionally for multiple sclerosis. interfering with the ability to accurately modafinil; with Oxford students using it self-assess cognitive performance.6 more than any other (26%).9 Lowest use ADVERSE SIDE EFFECTS Indeed, dexamfetamine given to the US was among medical students (12%). Off-label use in patients with comorbid military as ‘go-pills’ have been associated Little is known outside of student conditions and concurrent medications with ‘friendly-fire’ incidents.2 populations. An online poll of 1400 Nature raises concerns about potential for adverse Most research involves small readers reported a prevalence of 20%, events.3 Methylphenidate is associated experimental studies and not large with use driven by desires to improve with, for example, drug dependence, scale clinical trials; and most have no concentration and focus; but also to party overdose, and suicide attempts. In France, standardised method to assess adverse and counter . Methylphenidate was 43% of reported methylphenidate adverse reactions or report dropouts due to the most popular (62%) followed by modafinil drug reactions are attributable to off-label side effects. Some, usually benign, (44%).10 Half of users reported unpleasant prescribing (children 30%; adults 88%).4 side effects were reported leading to a few side effects; some discontinued use for Modafinil is associated with psychiatric drop-outs. Adverse reactions common to that reason. An anonymous questionnaire disorders, cardiovascular symptoms, and both drugs included , dizziness, survey of around 1000 German-speaking serious skin and multiorgan hypersensitivity tachycardia, nervousness and . surgeons revealed lifetime use of 8.9%;

100 British Journal of General Practice, March 2017 amfetamine (2.6%) methylphenidate ability to communicate effectively about ADDRESS FOR CORRESPONDENCE (2.5%), and modafinil (2.2%).11 Prevalence their health with their own doctors;13 Paul J Nicholson was considerably higher (19.9%) using a • advise healthcare students not to take E-mail: [email protected] randomised response technique which cognitive enhancers off-prescription and guarantees a higher degree of anonymity to declare health impairments arising 11 and confidentiality. from these substances since these Subjective effects motivate people to impair fitness to train; and take a drug, not the objective results.6 • advise patients of risk-free methods of Pressure to achieve, word of mouth, and enhancing performance, for example a media reports help drive increasing use; healthy lifestyle including exercise, diet, whereas ready availability facilitates use. In and the avoidance of excessive amounts the US most students obtain prescription of alcohol. from a peer with a prescription, usually methylphenidate for ADHD.2 In the Nature survey one-third of drugs were CONCLUSION REFERENCES purchased over the internet.10 Generally less robust studies are more 1. Jones R. Matters of substance. Br J Gen Newspapers and websites reacted to the positive, whereas high-quality reviews are Pract, 2016; DOI: https://doi.org/10.3399/ review that stated that modafinil appeared much more cautious about the effects bjgp16X683017. ‘safe for widespread use’7 with headlines for of cognitive enhancers in healthy test 2. Nicholson PJ, Mayho G, Sharp C.Cognitive enhancing drugs and the workplace. BMA, example, in The Guardian ‘Drug developed subjects. Overall, expectations regarding London, 2015. the effectiveness of these drugs in healthy to treat narcolepsy may be the world’s first 3. Peñaloza RA, Sarkar U, Claman DM, et al. safe smart drug’.12 These headlines persist individuals exceed their actual effects. Trends in on-label and off-label modafinil use in and websites quoting the review often Together with safety concerns and a possible a nationally representative sample. JAMA Intern advise how to buy modafinil; providing web effect of overconfidence in one’s cognitive Med 2013; 173(8): 704–706. addresses for overseas suppliers. These performance, it is questionable whether 4. Trenque T, Herlem E, Abou Taam M,et al. repeated use could be of any practical Methylphenidate off-label use and safety. suppliers operate outside of The Human SpringerPlus 2014; 3(286): 286. Medicines Regulations 2012 governing the benefit in healthy individuals. 5. European Medicines Agency. Assessment control, manufacture, and supply of human Faced with websites and articles report for modafinil containing medicinal medicines. advocating smart drugs and a ready products. EMA/4038/2011. London: EMA, 2011. supply, vigilance to the growing misuse 6. Repantis D, Schlattmann P, Laisney O, A ROLE FOR PRIMARY CARE of pharmacological cognitive enhancers, Heuser I. Modafinil and methylphenidate for GPs are the first medical point of contact especially by students, is important. GPs neuroenhancement in healthy individuals: a systematic review. Pharmacol Res 2010; 62: for most patients, therefore occupy an have an opportunity to advise patients 187–120. not to misuse cognitive enhancers and to unrivalled position to detect misuse and 7. Battleday RM, Brem AK. Modafinil for cognitive to provide evidence-based advice. GPs target healthcare students for particular neuroenhancement in healthy non-sleep- have a unique opportunity to influence advice in this context, related to fitness deprived subjects: a systematic review. Eur the expectations and health of students in to train and fitness to practise. It will be Neuropsychopharmacol 2015; 25(11): 1865– 1881. secondary and higher education, as well as helpful if GPs are aware of mandatory shift workers, in this context. The following fitness standards for healthcare students, 8. Liira J, Verbeek JH, Costa G,et al. Pharmacological interventions for sleepiness pointers could be useful when consulting set by statutory regulatory bodies to ensure and sleep disturbances caused by shift students: patient safety.13 These standards include work. Cochrane Database Syst Rev 2014; 8: two gold health standards, namely a full CD009776. • be aware of the prescription-only awareness of their own mental health and 9. Fitsimons S, McDonald M. One in five students medicines used by healthy people as the ability to communicate effectively about have used modafinil: study drug survey results. The Tab 2014; 5 Aug: http://thetab. ‘smart drugs’; their own health. The capability to achieve com/2014/05/08/1-in-5-students-have-used- • be alert to the adverse effects of and maintain these standards is essential modafinil-study-drug-survey-results-14102 ‘smart drugs’ being a potential cause for healthcare students to ensure patient (accessed 1 Feb 2017). of unexplained symptoms for example, safety. The misuse of cognitive enhancers is 10. Maher B. Poll results: look who’s doping. Nature 2008; 452(7188): 674–675. insomnia, especially in students and incompatible with these standards. 11. Franke AG, Bagusat C, Dietz P,et al. Use of young graduates; Paul J Nicholson, illicit and prescription drugs for cognitive or • be able to advise patients who use Accredited specialist occupational physician, mood enhancement among surgeons. BMC ‘smart drugs’ of the risk of side effects; retired, London. Medicine 2013; 11: 102. concerns about the quality of drugs 11. Thomson. H. Narcolepsy medication modafinil is world’s first safe ‘smart drug’.The Guardian Nigel Wilson, purchased through the internet from 2015; 20 Aug: https://www.theguardian.com/ overseas; that the modest benefits are Chair, Higher Educational Occupational Physicians, science/2015/aug/20/narcolepsy-medication- not necessarily long-lasting; and that Liverpool. modafinil-worlds-first-safe-smart-drug they may negatively affect self-control to (accessed 8 Feb 2017). induce overconfidence; Provenance 13. Higher Educational Occupational Physicians/ Prractitioners. HEOPS Guidance, Fitness Commissioned; externally peer reviewed. • be aware of the fitness standards for Standards and Surveys. http://www.heops.org. healthcare students, which include a full uk/guide.php (accessed 8 Feb 2017). awareness of their own health and the https://www.doi.org/10.3399/bjgp17X689437

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