Methylphenidate (Ritalin) – does use by ‘healthy’ students matter?

In their report in the Telegraph, @Josiensor and Rosa Silverman discuss implications of a survey from Cambridge which notes that so-called 'smart' drugs continue to be used by students to try to improve their academic performance, with methylphenidate (Ritalin) a common choice.

Why should this be of public interest?

Methylphenidate has been in use since 1960 for treating ADHD, with effects mainly considered to be improvement in attention and concentration. It is used to treat a number of rare syndromes involving abnormalities in chemical transmission in the brain. The drug is also reported to be in widespread use by students in the UK, the US and elsewhere in the hope that it will improve studying, learning and exam performance.
 

1.    Does it work? Studies of possible effects on studying and learning are typically short-term and usually based on artificial tests – ie not usually test possible benefits of the drug what students may be trying to learn, or effects on the types of exams students may be sitting. Evidence compared to placebo of benefits or risks appears limited to studies lasting 4 weeks or less.

The evidence of benefits from methylphenidate in apparently healthy students is disappointing. For example, in a study in health young volunteers there was a reported benefit from the 1^st dose for a spatial (3D) task and for planning, but not for attention or fluency. However even these effects were not sustained: with a second dose, spatial task performance was less good; ie there was little evidence of sustained benefit on repeat use of the drug and possible evidence that performance might be worse. And one of the side effects is insomnia – fatigue could also therefore be an indirect reason why performance might be impaired by the drug. There are also reports by users that with the drug, too much focus on details may make it difficult both to complete an assessment and to consider a broad enough range of issues to give a complete answer.

2.    Is use of methylphenidate any different from using caffeine? Because of the lack of convincing evidence of benefit from methylphenidate and concerns about serious risks, methylphenidate is not approved for use in the absence of specified medical conditions – e.g. ADHD. As for other drugs, the balance between risk and benefit must be considered by prescriber and user. In the event of any benefit for studying from the drug, others not using it are put at a disadvantage. In contrast caffeine is widely available for those who chose to use it. Too much caffeine, or sensitivity to caffeine can cause troublesome symptoms, including anxiety, tremor, sleep disturbance and palpitations. 

3.    Risks of methylphenidate Potential risks may be serious and include serious cardiac and psychiatric disorders. This has lead to important restrictions by regulatory authorities such as the FDA on use of the drug, even when the drug is medically indicated. 

Withdrawal symptoms of methylphenidate can include psychosis, depression and irritability.

Risks of the drug may be greater if there are medical problems, in particular if the user has a medical history of cardiovascular or psychiatric problems. Use without clinical advice may mean that important underlying conditions are not identified, for example high blood pressure, disorders of heart rhythm, and psychiatric risk; and potential important interactions with other drugs (including other stimulants) may not be considered. For example: 

-      alcohol can delay clearance of the drug from the body, increasing risk of adverse effects; 

-      concurrent use of stimulants such as caffeine would be expected to increase risk from methylphenidate of serious disorders of heart rhythm.

4.    What about access to the drug from internet pharmacies? For the above reasons, licensed pharmacies would not supply methylphenidate in the absence of specified medical conditions. Unlicensed internet pharmacies should be avoided. The quality of medicines is not reliable, with serious risk of being supplied poorly active or counterfeit or contaminated medicines. And medical contra-indications need to be identified and discussed to minimize the risk of preventable serious adverse effects.

5.    Fairness and coercion There are also a number of ethical concerns including:

a)    the need to protect students and others from using so-called ‘smart drugs’ in response to pressure to compete, both in exams and in professional life; 

b)    being fair to other students who do not have access to the drug, or do not wish to use what may be a medically harmful pharmacological aid to improving performance in examinations or to meeting challenges at work.

See also
June 2009: Opposing opinions in the British Medical Journal from John Harris and Anjan Chatterjee

September 2011: Methylphenidate and delayed puberty
July 2012: Methylphenidate for Parkinson's disease
November 2012: Commentary in the Guardian by William Leith: Ritalin before an exam fails the test of common sense 
June 2013: Cautionary report in from Canada on methylphenidate use and learning in  ADHD

Painkillers: powerful drugs with important adverse effects

A new report in the Lancet from the Oxford Clinical Trials Unit provides an update on potential risks from newer and traditional painkillers of the non-steroidal anti-inflammatory drug type. The report analysed results of a large number of clinical trials comparing these painkillers against placebo or against a comparator different painkiller. Studies were largely of high doses of the drugs, prescribed for relatively short duration - on average for under a year.

Below is a summary of my comments on the Lancet article provided to the Science Media Centre.

"In this pooled assessment (meta-analysis) of a large number of clinical trials against placebo or other pain-killer options, the Oxford Clinical Trials Service Unit confirm previous reports that the newer pain-killer drugs – coxibs - are associated with a clinically important increase in risk of coronary disease.

"Their major new finding is that among traditional non-steroidal anti-inflammatory painkiller drugs [tNSAIDs] – diclofenac, and possibly ibuprofen, but not naproxen appear associated with a similar increase fatal and non-fatal coronary heart events to the coxibs. However all naproxen, like all coxibs and tNSAIDs they studied, was associated with increased risk of heart failure and gastro-intestinal complications such as bleeding.

"The type of vascular risk with these painkillers appeared selective as none of these treatments were associated with an increase in stroke risk.

“Cautions include that we are not told about details of adjustments across treatment groups for degree of different cardiovascular risk factors e.g. from smoking as a source of bias. And the authors themselves acknowledge that their findings are largely for high dose tNSAIDs and for treatment on average for under a year. They note that they therefore cannot be sure whether the reported coronary and other risks would persist in patients on longer term treatment or on lower doses of these medicines.

“The paper underscores a key point for patients and prescribers: powerful drugs may have serious harmful effects. It is therefore important to be cautious when considering use of these medicines and to take into account cardiovascular risk, and risk of stomach or intestinal adverse effects, when tNSAIDs are prescribed or obtained over the counter, and when coxibs are considered.”

Many patients taking these tablets rely on them for relief of symptoms from arthritis and other long-term painful conditions. Patients who are concerned should consult their medical or pharmacist adviser.

See also articles by reporters on BBC Health, Reuters, Agence France Presse, CBS News ...

Quarryman's headache: clues to drug discovery

Chemist Ascanio Sobrero

@HealthMed Glyceryl trinitrate - GTN (discovered by Italian chemist Ascanio Sobrero in 1846-1847) - is widely used to prevent or reduce angina, a key warning symptom of coronary heart disease. 

An early clue that GTN might have medicinal properties came from the observation that handling the chemical could result in severe headache. GTN is also known as nitroglycerine, an important component in early explosives.  Workers in early munitions factories developed vascular headaches. And quarrymen handling nitroglycerine-based explosives were also at risk of such severe headaches that resignation may have been preferrable to recurrent onset of these severe symptoms. 

This lead to trials of GTN in angina by Dr William Murrell, with publication of results in 1879 in the UK medical journal The Lancet, followed by increasing popularity in use of GTN as treatment. 

The major beneficial effects of GTN are due to relaxation of veins, so reducing the filling pressure in the heart. This in turn, through Starling's Law of the Heart, reduces the work of the main pumps of the heart, the ventricles. Nitric oxide is a vasodilator made in the body by the cells that line blood vessels, endothelial cells: work on this pathway resulted in the award of the Nobel Prize in Physiology or Medicine for 1998 to Robert F Furchgott, Louis J Ignarro and Ferid Murad for their discoveries concerning "the nitric oxide as a signalling molecule in the cardiovascular system". 

Anti-anginal effects of GTN result from the dilator response of veins to the additional nitric oxide generated from the GTN by vascular enzymes (including mitochondrial aldehyde dehydrogenase). And this effect on veins occurs at a lower concentration of the drug than needed to relax arteries. Headache as an unwanted side effect of the drug is due to an increase in blood flow in arteries in the head.  The chance of arterial headache developing can thus be minimised by spitting out any remaining GTN once angina has settled.

Footnote

There had been an earlier report in The Lancet in 1867 by Dr T. Lauder Brunton from Edinburgh on use of an organic nitrite, amyl nitrite, to treat angina. There is now evidence that nitrite may act as a chemical signal, independent of its vasodilator and other effects through conversion to nitric oxide.

William Murrell's 1879 Lancet paper.

Murrell W. Nitro-glycerine as a remedy for angina pectoris. Lancet 1879; i: 80-81.

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