Discovery of Methylphenidate and its therapeutic effect on Attention Deficit Hyperactivity Disorder  

Methylphenidate (MPH) sold under the trade name Ritalin is classified as a phenylethylamine compound (Axten et al., 1999). Originally when it was synthesized and Patented by CIBA, now Novartis in 1944, it was used as treatment for chronic fatigue and psychosis associated with depression. Today, it is used as a first line of defense to treat individuals with attention deficit hyperactivity disorder (ADHD) (Morton and Stockton, 2000). Studies show that ADHD is characterized by insufficient levels of Dopamine (DA) and Norepinephrine (NE) in many brain areas that need these neurotransmitters. This deficiency may be due to an usual amount of dopamine transporters (DAT) and norepinephrine transmitters (NET) in those brain areas (Farone, 2018). MPH is a racemic mixture of the D-threo and L-threo compound, with the D-threo isomer having the major psychostimulant effect (Axten et al., 1999).  

MPH works by acting as a competitive inhibitor of DAT. When MPH binds DAT, there is an increased level of DA in the extracellular portions of the brain. Imaging studies show that the when given intravenously, there is a large concentration of MPH binding in the striatum (Volkow et al., 2004). Two major postulates stand out as to why MPH blocking DAT activity is of therapeutic relevance for ADHD; amplification of DA in the striatal cells lead to an increase in the signal-to-noise ratio in target neurons which consequently causes greater attention in individuals with ADHD. Secondly, DA is responsible for eliciting saliency (relevance) of an impulse, therefore, increase in DA levels in the brain can lead to better appreciation of tasks (Volkow et al., 2004). In a study by Hannestad and co., they hypothesize that although previously it had been thought the efficacy of MPH was solely due to DAT inhibition, its efficacy may also be due to NET inhibition (Hannestad et al., 2010). Another possible neurotransmitter that may play a role in ADHD is serotonin because the expression of its gene in brain regions associated with memory and attention (Loureiro-Vieira et al., 2017).  

MPH has proven to be generally efficacious as a treatment for ADHD, but many patients with ADHD show no or partial response to MPH. Others report intolerance for its adverse effects like nausea, anorexia, headache, anxiety and insomnia. Another major problem which cannot be overlooked is the tendency for abuse of MPH due to its stimulant effect (Loureiro-Vieira et al., 2017). With the increased diagnosis of ADHD over the years, there has been a rapid surge in the availability of MPH which in turn could lead to illicit use of this therapeutic agent. Reports show that when MPH is taken intravenously, the feeling of euphoria is synonymous to the feeling derived from cocaine intake (Morton and Stockton, 2000). This tendency for abuse is the major problem with MPH use and has consequently led to the invention of non-stimulants like Atomoxetine as an alternative to MPH. However, MPH remains the most efficacious therapeutic for ADHD.  (Loureiro-Vieira et al., 2017). 

Methylphenidate was originally patented by CIBA pharmaceutical companies, now Novartis in 1954. It is mostly marketed by Novartis under the trade name Ritalin (Axten et al., 1999). However, there are other generic formulations like Concerta which is sold by Ortho-McNeil-Janssen Pharmaceuticals. In 2007, Novartis filed a law suit against Barr laboratories for infringement in patent rights after they learned of Barr’s abbreviated new drug application (ANDA) for generic Ritalin (FDA news, 2007). 

The efficacy of Ritalin LA was shown in a clinical pharmacology study where 134 children aged 6-12 with ADHD were subject to a randomized double-blind placebo-controlled procedure. The proof of efficacy was a statistically significant improvement in the CADS-T test of those who took Ritalin LA compared to those that were not given Ritalin LA (Novartis Ritalin prescribing information). However, controversy remains as to how efficacy can really be measured in terms of treating ADHD; although ADHD has been included and described in DSM V, because of its predominance in children, the decision as to when a child is classified as hyperkinetic is a subjective one (Padway, 1978). In a 1995 joint toxicology study by the department of health and human safety (DHHS), National Cancer Institute (NCI) and the Food and Drug Administration (FDA), it was shown that Oral formulations of Methylphenidate (Ritalin) showed no carcinogenic or toxic effects (NTP report 1995). 

However, there remains so many controversial issues concerning the commercialization of Ritalin. One of the major issues is the over prescription of the drug in the united states. Between 1990 and 1995, the United States’ production of Ritalin increased by almost 700% and because of its stimulant nature, and potential for abuse, the DEA has labelled Ritalin as a Schedule II drug which is only one rating below illicit drugs (Morton and Stockton, 2000). In a 2017 federal investigation, the department of justice reported that a Michigan doctor had been charged with the fraudulent prescription of Ritalin in amounts excess of the adult drug dosage, and as such was sentenced to 10 months in prison (dea.gov)  

There are various federal statutes that currently regulate the use and distribution of Ritalin in the united states. One of those statutes is the regulation under the controlled substances act. This statute gives the attorney general with advice from certain departments and drug agencies the classify a drug that has a potential for abuse to stymie any illicit drug use. Ritalin was originally classified as a schedule III drug but has been reclassified as a schedule II drug (Padway, 1978).  This tendency for illicit use is the major problem associated with Ritalin and has consequently led to the invention of non-stimulants like Atomoxetine as an alternative. But to this day, Ritalin remains the first line of defense for treating for ADHD.  (Loureiro-Vieira et al., 2017).

References 

Axten, J. M., Ivy, R., Krim, L., & Winkler, J. D. (1999). Enantioselective Synthesis ofd-threo-Methylphenidate. Journal of the American Chemical Society,121(27), 6511-6512. doi:10.1021/ja991466o 
“Barr Sued Over Ritalin LA Patent Challenge.” FDANews, www.fdanews.com/articles/100965-barr-sued-over-ritalin-la-patent-challenge. 

Farone, S. V. (2018). The Pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neuroscience and Biobehavioral Reviews,87, 255-270. doi:10.1016/j.neubiorev.2018.02.001 

Hannestad, J., Gallezot, J., Planeta-Wilson, B., Lin, S., Williams, W. A., Dyck, C. H., Malison, R. T., Carson, R. E., Ding, Y. (2010). Clinically Relevant Doses of Methylphenidate Significantly Occupy Norepinephrine Transporters in Humans In Vivo. Biological Psychiatry,68(9), 854-860. doi:10.1016/j.biopsych.2010.06.017 
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/ritalin_la.pdf

Larry Padway, Federal Regulation of Ritalin in the Treatment of Hyperactive Children, 7 Ecology L. Q. 457 (1978). 

Loureiro-Vieira, S., Costa, V. M., Bastos, M. D., Carvalho, F., & Capela, J. P. (2017). Methylphenidate effects in the young brain: Friend or foe? International Journal of Developmental Neuroscience,60, 34-47. doi:10.1016/j.ijdevneu.2017.04.002 
“Michigan Physician Sentenced To Federal Prison For Writing Fraudulent Prescriptions To Obtain Controlled Substances.” DEA, www.dea.gov/press-releases/2017/11/08/michigan-physician-sentenced-federal-prison-writing-fraudulent.

Morton, W. A., & Stock, G. G. (2000). Methylphenidate Abuse and Psychiatric Side Effects. The Primary Care Companion to The Journal of Clinical Psychiatry,02(05), 159-164. doi:10.4088/pcc.v02n0502 
Toxicology And Carcinogenesis Studies Of Methylphenidate Hydrochloride In F344/N Rats And B6C3Fl Mice. vol. 439, 1995, pp. 7–8, ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr439.pdf 

Volkow, N. D., Wang, G., Fowler, J. S., & Ding, Y. (2005). Imaging the Effects of Methylphenidate on Brain Dopamine: New Model on Its Therapeutic Actions for Attention-Deficit/Hyperactivity Disorder. Biological Psychiatry,57(11), 1410-1415. doi:10.1016/j.biopsych.2004.11.006