Drug of the Month:
Methylphenidate and its variants

Methylphenidate is an amphetamine


Methylphenidate 3D structure

The most widely used amphetamine agent is methylphenidate. In fact, all prescribed amphetamines are variants of either methylphenidate or dextroamphetamine. In this issue we focus on methylphenidate and its variants; in the next PL issue, the focus will shift to dextroamphetamine and its variants.


Clinical efficacy and inefficacy

Methylphenidate and its variants have been shown to be effective in ADD, as well as in major depressive episodes. They also produce weight loss and increase sexual libido. They have been found to cause mania and/or worsen bipolar illness.  

“Benefit” in ADD for attention is not surprising, since methylphenidate has been shown to be effective in normal individuals to improve attention.  In other words, since some inattention is normal, methylphenidate “works” in everyone, and efficacy is not indicative of presence of an illness.  

Biological mechanism

This agent is a dopamine and norepinephrine reuptake inhibitor and directly stimulates dopamine and norepinephrine receptors. Thus, it increases both dopamine and norepinephrine activity.

For some reason, there is a common misconception that methylphenidate is NOT an amphetamine. It clearly is an amphetamine, based both on its pharmacological structure and its biological effects. As seen in the figure, it has the same basic structure as dextroamphetamine and dopamine. It also has the same basic biological effect of dopamine agonism as is the case with dextroamphetamine. The only difference is that it also has noradrenergic effects. But this additional effect doesn't remove or cancel out its basic dopaminergic effect, which is part and parcel of its basic amphetamine structure.  

Fig 1. Note the structure similarity between norepinephrine, dopamine, methylphenidate and amphetamine. All share the 4-ethylphenyl structure, in orange.

                   Fast facts: Methylphenidate


                         Typical dose: 10-60 mg/d

Variants: Focalin, dex-methylphenidate; Concerta, methylphenidate ER

Biological mechanism: Dopaminergic and noradrenergic agonist

Typical side effects: insomnia, anxiety, jitteriness

Less common but important side effects: mania

Medically important side effects:  ventricular arrhythmia, neurotoxicity

Clinically proven efficacy: Treatment of  ADD and non-bipolar depressive episodes

Side effects and dosing

Besides neurotoxicity in animals, methylphenidate is known to have cardiotoxicity, specifically cardiac arrhythmias.  This risk may be lower in children than in adults. In adults, a recent analysis found that there was almost a doubling of risk of sudden cardiac death due to ventricular arrhythmias with methylphenidate. The authors tried to explain this result away given the observational setting, and the presence of confounding factors should prevent definitive judgments pro or con. Nonetheless, these are the best data we now possess, and they do indicate some risk as far as we can accept those data. The PL editor has analyzed the results to calculate an absolute frequency of risk, which was about 1: 1000.  In other words, if these results are correct, methylphenidate can cause sudden cardiac death in 1 in 1000 adults.  Other studies do not find evidence of such risk, so that at present one cannot be definitive. 

In sum, it is not the case that this medication is proven safe in children and adults, as is commonly repeated by some experts.  


The PL Bottom Line

  • Methylphenidate is an amphetamine.
  • It is effective for attention in everyone, not just persons with ADD. 
  • It is proven neurotoxic in animals, and human studies do not prove or disprove that risk.
  • It is possibly cardiotoxic in adults with 1:1000 risk. 
  • It is not proven safe in children and adults such that one can prescribe it without any concerns.

PL Reflection


On the wish to use medications and the role of pharmaceutical marketing, in Germany circa 1876:

  

“The chemical industry of our days produces various substances for which no market can yet be found….We know that a great number of physicians, without rhyme or reason, go after every new remedy that is recommended to them.  If an industrialist is but shrewd enough to advertise sufficiently, he usually succeeds in increasing the sale of his product – for some time at least – and thus enriching himself.” 

R Buchheim


Buchheim, R. Uber die Aufgaben und die Stellung der Pharmakologie an den deutschen Hoschshulen. Arch Exp Pathol Pharmakol 5: 261, 1876.   

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