European Review for Medical and Pharmacological Sciences 2019; 23: 3-15 Use of cognitive enhancers: methylphenidate and analogs J. CARLIER1, R. GIORGETTI2, M.R. VARÌ3, F. PIRANI2, G. RICCI4, F.P. BUSARDÒ2 1Unit of Forensic Toxicology, Sapienza University of Rome, Rome, Italy 2Section of Legal Medicine, Universita Politecnica delle Marche, Ancona, Italy 3National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy 4School of Law, University of Camerino, Camerino, Italy Abstract. – OBJECTIVE: In the last decades, phenidate analogs should be undertaken to re- several cognitive-enhancing drugs have been duce the uprising threat, and education efforts sold onto the drug market. Methylphenidate and should be made among high-risk populations. analogs represent a sub-class of these new psy- choactive substances (NPS). We aimed to re- Key Words: view the use and misuse of methylphenidate and Cognitive enhancers, Methylphenidate, Ritalin, Eth- analogs, and the risk associated. Moreover, we ylphenidate, Methylphenidate analogs, New psycho- exhaustively reviewed the scientific data on the active substances. most recent methylphenidate analogs (methyl- phenidate and ethylphenidate excluded). MATERIALS AND METHODS: Literature Introduction search was performed on methylphenidate and analogs, using specialized search engines ac- cessing scientific databases. Additional reports Consumption of various pharmaceutical drugs were retrieved from international agencies, in- by healthy individuals in an attempt to improve stitutional websites, and drug user forums. cognitive faculties is on the rise, whether for aca- RESULTS: Methylphenidate/Ritalin has been demic or recreational purposes1. These substances used for decades to treat attention deficit disor- are stimulants that preferentially target the cate- ders and narcolepsy. More recently, it has been used as a cognitive enhancer and a recreation- cholamines of the prefrontal cortex of the brain to al drug. Acute intoxications and fatalities involv- induce their effects (e.g., methylphenidate and an- ing methylphenidate were reported. Methylphe- alogs, modafinil and analogs, and amphetamine)2,3. nidate was scheduled as an illegal drug in ma- However, scientific studies supported only small ny countries, but NPS circumventing the ban benefits from cognition-enhancing drugs4 while the and mimicking the psychostimulant effects of risks to health are serious and include dependence, methylphenidate started being available: ethyl- phenidate, 3,4-dichloromethylphenidate, 3,4-di- tolerance, and cardiovascular, neurologic, and psy- chloroethylphenidate, 4-fluoromethylphenidate, chological disorders, with a risk of overdose leading 5 4-fluoroethylphenidate, methylnaphthidate, eth- to death . As a consequence, many of these sub- ylnaphthidate, isopropylphenidate, propylphe- stances are controlled internationally6. Like other nidate, 4-methylmethylphenidate, and N-benzy- new psychoactive substances (NPS), new molecules lethylphenidate have been available in the past mimicking the psychoactive effects of the scheduled few years. Only little data is currently available drugs are being synthesized to evade the legislation. for these substances. Many intoxications involv- ing methylphenidate analogs were reported. To Little information on the pharmacology and the date, ethylphenidate was involved in 28 fatali- toxicology of the new substances is known when ties, although it was reportedly directly related they first emerge. Methylphenidate (MPH) is one of to the cause of death in only 7 cases; 3,4-dichlo- the most popular cognitive enhancers4 and several roethylphenidate was involved in 1 death. analogs appeared on the drug market during the last CONCLUSIONS: The rapid expansion of meth- years. However, little or no scientific data on these ylphenidate analogs onto the drug market in the past few years makes likely the occurrence of in- new analogs is available. toxications and fatalities in the next years. Care- In this mini-review, we aimed to report the cur- ful monitoring and systematic control of methyl- rent trends in the use and misuse of cognitive en- Corresponding Authors: Francesco Paolo Busardò MD, MSc, DipFMS, Ph.D; e-mail: [email protected] 3 J. Carlier, R. Giorgetti, M.R. Varì, F. Pirani, G. Ricci, F.P. Busardò hancers within the sub-class of methylphenidate pairs previously established performance – and (MPH) and analogs. We performed an exhaustive reduced regional blood flow in different parts of review of the scientific data on MPH analogs that the brain3,11. MPH administration increases atten- first appeared on the drug market in the last five tion and cognition in healthy subjects through DA years, i.e. all MPH analogs with the exception of and NE increase in the striatum of the subcortical MPH and ethylphenidate. Finally, we compiled basal ganglia, the dorsolateral prefrontal cortex, the fatalities associated with the consumption of and the posterior parietal cortex of the brain3. MPH analogs reported in the literature. It was initially used for the treatment of depres- sion, chronic fatigue syndrome, and narcolepsy because of its stimulating and exciting effect, Materials and Methods tiredness and inhibitions elimination, physical efficiency increase for a short time12-15. The sale A literature search was performed on MED- of MPH is approved in some European countries, LINE, EMBASE, and CENTRAL (Cochrane such as the United Kingdom and Germany, but Central Register of Controlled Trials) using the the number of prescriptions is significantly lower keywords methylphenidate intoxication, methyl- than the US and it is commonly prescribed under phenidate fatality, methylphenidate death, meth- the brand name Ritalin16, which is used in the ylphenidate analog, ethylphenidate, nopaine, di- treatment of attention deficit hyperactivity disor- chloromethylphenidate, 3,4-CTMP, 3,4-DMPH, der (ADHD), with limited effectiveness17. dichloroethylphenidate, fluoromethylphenidate, MPH is also a substance under international 4F-TMP, fluoroethylphenidate, methylnaphthi- control, in accordance with the Convention date, HDMP-28, ethylnaphthidate, HDEP-28, on Psychotropic Substances of 19716. MPH isopropylphenidate, IPH, propylphenidate, PPH, is among the substances the most commonly methylmethylphenidate, and benzylethylpheni- misused by individuals seeking to extend their date, with the aim of identifying relevant articles capacities for alertness and cognition18,19. A published in English, up to December 2018. Fur- recent systematic review assessed MPH effect ther research manuscripts were retrieved through on cognitive performances in healthy subjects reference lists of selected articles. Additional including 46 trials and several meta-analyses of reports were found on international agencies or studies that tested the effects of MPH20. It was institutional websites including the European found that a single dose of MPH (5 to 40 mg monitoring centre for drugs and drug addiction or 0.25 to 0.5 mg/kg) had a significant effect (EMCDDA) and drug user forums. on memory but no effect on attention and ex- ecutive functions. When taken for a prolonged period, MPH presents a risk of addiction, and Results possibly physical dependence21. In sport, the substance is considered a doping substance and Methylphenidate is therefore prohibited. Within the last decade, Methylphenidate (MPH) (methyl phenyl Ritalin’s production almost increased tenfold (2-piperidinyl)acetate) is a sympathomimetic due to its misuse as brain doping substance and drug that was first synthesized in 1944 and estab- party drug. Indeed, the drug is one of the most lished as a psychostimulant in 1954. Its 2-benzyl misused cognitive enhancer, especially in US piperidine structure resembles that of catechol- college campuses, with a prevalence from 7 to amines and phenylethylamines, with a piperidine 25%22,23. Several studies investigated MPH mis- group substituting the amine (Figure 1). As such, use in college and University Students starting MPH’s structure is closely related to that of am- from the first years of new century24-26. In 2000, phetamines7. a study showed that more than 16% of 283 stu- Similarly to amphetamines, MPH competes dents of the Massachusetts College of Liberal with catecholamines in the central nervous system Arts had tried MPH recreationally24. A larger and blocks dopamine (DA) and norepinephrine study carried out at the University of Michigan (NE) transporters (DAT and NET, respectively), found that approximately 3% students (out of resulting in elevated synaptic extracellular DA 2250 students who completed the survey) had and NE levels8-10. MPH was shown to modulate declared past year illicit use of the drug. No cognition: e.g., improved planning and spatial significant differences between males and fe- working memory performance – although it im- males percentages of misuse/abuse were found. 4 Use of cognitive enhancers: methylphenidate and analogs Figure 1. Structural formula of methylphenidate and analogs. In addition, an association between MPH and reported Ritalin as their stimulant of choice. alcohol and drugs’ use was found25. A national More than 50% of the students using Ritalin US survey reported that 2.3% high school se- reported 2 or 3 administrations per year, 34% niors declared past-year use of Ritalin in 2003, reported 1 or 2 administrations per month, while 1.9% used methamphetamine27. The same and 15.5% reported 2 or 3 administrations per survey, carried out in 2006, showed