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European Review for Medical and Pharmacological Sciences 2019; 23: 3-15 Use of cognitive enhancers: 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 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 have been duce the uprising threat, and education efforts sold onto the 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 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 that preferentially target the cate- ders and . More recently, it has been used as a cognitive enhancer and a recreation- cholamines of the 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, and analogs, and )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 -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, , 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 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 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 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 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, , 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 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 , MPH competes dents of the Massachusetts College of Liberal with in the central Arts had tried MPH recreationally24. A larger and blocks (DA) and 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- performance – although it im- males percentages of misuse/abuse were found.

4 Use of cognitive enhancers: methylphenidate and analogs

Figure 1. of methylphenidate and analogs.

In addition, an association between MPH and reported Ritalin as their of choice. 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 that the week. Outside colleges or campus, the poten- use of MPH among young adults and college tiality of abuse of MPH was considered in the students was 2.6% and 3.9%, respectively28. early 1960s in a case report of a patient who According to White et al, 16% students of a was taking 125 tablets of MPH per day30. northeastern US university misused or abused MPH adverse effects include pupil dilation, stimulant medications29. Of this category, 96% loss of hair, depression, , headaches, im-

5 J. Carlier, R. Giorgetti, M.R. Varì, F. Pirani, G. Ricci, F.P. Busardò pairment of , , restlessness, anx- and concentration, increased socialness51,52. EPH iety, and hypersensitivity31-35. In cases of high is marketed as a powder, a pellet, or a crystal and doses, anorexia and tachyarrhythmia are more is mainly taken by (10 to 100 mg), common. Oral MPH abuse included reports of although it can be administrated orally or anally MPH , , delusional disor- in a capsule form, through the inhalation of evap- der, and euphoria36-39. Intravenous abuse of MPH orating fumes, or injected intramuscularly or in- associated with was reported in 1963 travenously51,52. It is associated with a high risk of and the early 1970s36,37,40. Moreover, it has been drug abuse and addiction (redose is frequent)51,52. reported that the consumption of MPH was asso- Onset of action reportedly ranges from 0 to 35 ciated with a 1.8-fold increase in risk of sudden min with nasal insufflation, 5 to 31 min with oral death or ventricular arrhythmia41. In 1986, Levine ingestion, 0 to 2 min with intravenous injection, et al reported the first case of MPH fatal - over and 2 to 10 min with rectal administration52. Du- dose, following intravenous injection of Ritalin; ration of effects reportedly ranges from 15 to 300 post-mortem blood concentration was 2,800 ng/ min52. Adverse effects following EPH intake may mL42. Another fatality following MPH parenteral include , , , administration was subsequently reported43. In endocarditis, , , insomnia, irrita- 1999, Massello and Carpenter reported the first bility, paranoia, , and delusional thoughts. case of MPH fatality by intranasal abuse of Rit- Recovery after acute intoxication is slow, as it can alin44. In 2014, Cantrell reported the first fatality take several days51-56. Several deaths associated resulting from MPH ingestion; post-mortem pe- with EPH were reported (Table I)57-59. Maskell et ripheral blood concentration was 1,100 ng/mL al reported a fatal case of EPH intoxication where and central blood concentration was 980 ng/mL45. EPH was the sole cause of the death. EPH con- (d-MPH) is the active centration in the post-mortem femoral blood was dextrorotatory of racemic MPH (R,R) 2,180 ng/mL – no other drugs were detected59. (Figure 1). It is sold under the trade names Fo- EPH was seemingly directly involved in several calin among others as a causes of death57,58. EPH is a controlled drug in stimulant that is used in the treatment of attention several European countries, in , and in deficit hyperactivity disorder (ADHD) and narco- China60,61. EPH schedule in the United Kingdom lepsy. d-MPH is a stimulant with similar effects, drastically reduced the number of hospital admis- addiction liability, and dependence liability to sions for EPH intoxication in Scotland from 15 to those of amphetamine21,46. 1 per month62,63. EPH is mainly metabolized by human carbox- Ethylphenidate ylesterase 1c and is converted in ritalinic Ethylphenidate (EPH) is the ethyl acetate an- (hydrolysis) and MPH (transesterification)64,65. alog of MPH (ethyl phenyl(2-piperidinyl)acetate, Conversely, EPH is formed after co-ingestion of Figure 1). It is an amphetamine-like stimulant that MPH and via hepatic transesterification, inhibits DA and NE reuptake in the central ner- and EPH can be detected in blood and spec- vous system through DAT and NET inhibition. imens (< 3% MPH concentration in blood)66,67. EPH affinity to DAT and inhibition potency are l-MPH is more extensively converted (to l-EPH) similar to those of MPH, but its affinity to NET than d-MPH (to d-EPH)47,68. and inhibition potency are much lower (7-fold factor)47,48. Like MPH, EPH threo form (d-EPH) Other Methylphenidate Analogs (R,R) binds DAT and NET with a much higher Other MPH analogs are being marketed as affinity (10-fold factor)47. The drug was patent- NPS for their and stimulant effects. ed in 2003 as a potential treatment for attention Most of these substances are substituted with deficit disorders and narcolepsy, with lower abuse a halogen atom at positions 3- or/and 4- of the potential compared to MPH49. It was first notified phenyl ring, for potential increased potency (and as an NPS in the European Union in 201150. addiction liability)69. These substances are taken Soussan and Kjellgren51 and Ho et al52 com- to mimic MPH cognitive effects while circum- piled Internet reports from drug user forums venting the legislation (“legal high”). Due to their on the subjective effects of EPH intake. EPH is recent availability on the drug market, only little mainly used for recreational purposes. It is de- information on MPH analogs is available in the scribed as a potent stimulant with euphoric and scientific literature to date. Other active MPH an- arousing effects, increased (or decreased) focus alogs exist but, to the best of the authors’ knowl-

6 Table I. Fatalities associated with methylphenidate analogs’ use. F, female; M, male; PM, post-mortem; AM, ante-mortem. MPH analog Victim MPH analog Co-administration Cause of death Ref. involved concentration

EPH M/32 PM femoral blood 110 ng/mL, , EDDP, , , Mitral valve endocarditis in combination 59 180 ng/g, pericardium fluid MPH, and ritalinic acid with a pneumonia; EPH might have contributed 131 ng/mL, urine 987 ng/mL, (2140 ng/mL in blood) to the death stomach content 20.7 ng/mL (200 mL) EPH M/38 PM femoral blood 23 ng/mL , fentanyl, norfentanyl, Aspiration of stomach content; EPH might 59 and ritalinic acid (943 ng/mL in blood) have contributed to the death EPH M/38 PM femoral blood >2,000 ng/mL , paracetamol, morphine and Acute haemorrhage related to an 60 metabolites, 6-monoacetylmorphine, and acetone EPH F/33 PM femoral blood 1,900 ng/mL Methadone, , , Polydrug toxicity and acute pyelonephritis 60 morphine and metabolites, diazepam, temazepam, and metabolites, metabolite, pregabalin, and methylthienylpropamine EPH F/31 PM femoral blood 1,200 ng/mL Alcohol, morphine and metabolites, Polydrug toxicity 60 and diazepam and metabolites EPH M/27 PM femoral blood 760 ng/mL Alcohol, diazepam and metabolite, Unascertained cause 60 and methylthienylpropamine EPH M/37 PM femoral blood 610 ng/mL Diazepam and metabolite Empyema; chronic drug abuse might have 60 and mirtazapine contributed to the cause of death EPH F/31 PM femoral blood 470 ng/mL Lignocaine, methadone, mirtazapine, Bronchopneumonia and chronic drug abuse; 60 and methadone and EPH intoxication might have contributed to the cause of death EPH M/34 PM femoral blood 410 ng/mL Alcohol, methadone, diazepam and Multiple injuries 60 metabolites, and cannabis metabolite EPH M/38 PM femoral blood 350 ng/mL α-Methyltryptamine, etizolam, α-Methyltryptamine and EPH toxicity 60 and EPH M/20 PM femoral blood 320 ng/mL and metabolite, pregabalin, EPH, methoxyphenidine, morphine, pyrazolam, 60 zuclopenthixol, morphine and and etizolam toxicity metabolites, etizolam, pyrazolam, 2-MeO- EPH M/40 PM femoral blood 250 ng/mL Methadone, olanzapine, diazepam and Polydrug toxicity; coronary 60 metabolites, cannabis metabolite atherosclerosis might have contributed to the cause of death EPH M/35 PM femoral blood 140 ng/mL Methadone Unascertained cause 60 EPH F/33 AM blood 460 ng/mL; PM femoral Dihydrocodeine, , morphine, Sepsis/multiple organ failure and 60 blood 130 ng/mL desmethyldiazepam, , bronchopneumonia; Chronic drug abuse morphine, paracetamol, and alfentanil might have contributed to the cause of death Continued

7 Table I (Continued). Fatalities associated with methylphenidate analogs’ use. F, female; M, male; PM, post-mortem; AM, ante-mortem. MPH analog Victim MPH analog Co-administration Cause of death Ref. involved concentration

EPH M/54 PM cardiac blood 41 ng/mL Dihydrocodeine Unascertained cause 60 EPH M/45 PM femoral blood 40 ng/mL Diazepam and metabolites, methadone, Methadone and toxicity 60 morphine and metabolites, and 6-monoacetylmorphine EPH M/44 PM femoral blood 28 ng/mL Methadone and diazepam and metabolites Pneumonia and methadone toxicity; cachexia 60 might have contributed to the cause of death EPH M/42 PM femoral blood 15 ng/mL Alcohol, dihydrocodeine, morphine and Head injury 60 metabolites, and diazepam and metabolite

EPH F/46 PM femoral blood 10 ng/mL β-Hydroxybutyrate, mirtazapine, Disseminated Staphylococcus pyogenes 60 , morphine, diazepam and infection and heroin and EPH use metabolite, fluoxetine and metabolite, and paracetamol EPH M/25 PM femoral blood 10 ng/mL Diazepam and metabolite, paracetamol, Heroin and codeine toxicity and acute 60 codeine and metabolites, morphine and liver failure metabolites, 6-monoacetylmorphine, and mirtazapine EPH M/45 AM blood 30 ng/mL, serum 8 ng/mL; Alcohol, morphine and metabolites, Intracerebellar haematoma and EPH toxicity 60 PM femoral blood 8 ng/mL 6-monoacetylmorphine, paracetamol, methadone, and desmethyldiazepam EPH M PM femoral blood 2,180 ng/mL None EPH toxicity 61 EPH M PM femoral blood 1,370 ng/mL Benzoylecgonine, , and Hanging 61 diphenhydramine EPH M PM femoral blood 870 ng/mL Dothiepin, , Hanging 61 and ethanol EPH M PM femoral blood 110 ng/mL Methadone, EDDP, zopiclone, sertraline, Methadone and 2-aminoindane toxicity 61 aripiprazole, dehydroaripiprazole, 2-aminoindane, and ethanol EPH M PM femoral blood 140 ng/mL Morphine, codeine, ketamine, , Heroin toxicity 61 benzoylecgonine, , and O-desmethylvenlafaxine EPH M PM femoral blood 30 ng/mL Methiopropamine and 5-APB/6-APB Polydrug toxicity 61 EPH M PM femoral blood 110 ng/mL Diazepam, nordiazepam, temazepam, Polydrug toxicity 61 oxazepam, morphine, and codeine 4F-TEP - - - 4F-TEP involvement in the cause of death 89 is not documented

8 Use of cognitive enhancers: methylphenidate and analogs edge, they are not reported by NPS users (e.g., 3,4-Dichloroethylphenidate 3-bromomethylphenidate, 4-bromomethylpheni- 3,4-dichloroethylphenidate (3,4-CTEP) is a date, 3-chloromethylphenidate, 4-hydroxymeth- chlorinated analog of EPH threo form (R,R), ylphenidate)69,70. and the ethyl acetate of 3,4-CTMP (eth- yl(3,4-dichlorophenyl)(2-piperidinyl)acetate, Fig- 3,4-Dichloromethylphenidate ure 1). 3,4-CTEP is a DAT and NET inhibitor 3,4-Dichloromethylphenidate (3,4-CTMP) is a with a lower potency than MPH and cocaine, halogenated analog of MPH threo form (R,R) as shown in human embryonic kidney cells48. (methyl(3,4-dichlorophenyl)(2-piperidinyl)ace- Like 3,4-CTMP, it also binds SERT with a high tate, Figure 1) that was first synthesized in 1996 affinity48. 3,4-CTEP products were seized by the as a potential treatment for cocaine addiction69. It German authorities in 201787. The drug is banned was first marketed as an NPS in the United King- in the United Kingdom82. 3,4-CTEP NMR, GC- dom in 2013 and is sold as a powder or a tablet EI-MS, and ESI-HRMS/MS characterization was to be taken orally or snorted (up to 10 mg)71,72. It reported85. was first detected in illegal products in Japan in 201373,74. 3,4-CTMP subjective effects are report- 4-Fluoromethylphenidate ed by consumers on drug forums71. 4-Fluoromethylphenidate (4F-TMP) is another 3,4-CTMP was shown to increase electrical- halogenated derivative of MPH threo form (R,R) ly evoked DA efflux in the in the position 4- of the phenyl ring (methyl(4-flu- (NAc) of rat brain slices75, as observed with orophenyl)(2-piperidinyl)acetate, Figure 1). Like MPH75,76 and drugs of abuse with rewarding 3,4-CTMP, 4-fluoromethylphenidate (4F-TMP) properties77. Interestingly, potency was much was first synthesized in 1996 as a potential treat- higher than that of MPH75 (as previously sug- ment for cocaine addiction69. 4F-TMP is taken oral- gested by Deutsch et al with in vitro experi- ly or snorted and its effects are described on drug ments69 and Wayment et al in rat striatal tis- user forums71. In vitro studies and ex vivo studies sues78 (more than 15 times as potent as MPH)) in rats suggest that MPH potency is twice as low and cocaine79. Moreover, the threo form (R,R) as that of MPH and cocaine as a DAT inhibitor69,80. displays higher affinity for DAT than itserythro Luethi et al recently showed that 4-TMP DAT diastereoisomer (R,S), as demonstrated in vitro and NET inhibition potency is similar to that of and ex vivo in rats’ brain slices80,81. 3,4-CTMP MPH in human embryonic kidney cells48. 4-TMP was also shown to increase electrically evoked threo diastereoisomer (R,R) is a much more potent NE efflux in the bed nucleus of the stria termi- inhibitor of DAT and NET than its erythro form nalis of rat brain slices75. Taken together, these (R,S) in rat synaptosomes, yet 4-TMP is marketed results suggest that 3,4-CTMP may induce a both in its threo form (R,R) and as a threo/erythro tolerance and a cocaine-like abuse liability. mixture88. 4F-TMP is currently scheduled in Unit- Luethi et al48 confirmed 3,4-CTMP DAT and ed Kingdom as a class B drug82. NMR, GC-MS, NET inhibition in human embryonic kidney liquid chromatography-MS (LC-MS), X-ray crys- cells, with a 2- and 10-fold higher potency than tallography, and infrared spectroscopy characteri- MPH (18- and 48-fold higher than cocaine), zation of 4F-TMP and its erythro form (R,S) were respectively. It also shows a high affinity for reported88. (5-HT) transporters (SERT), respon- sible for 5-HT reuptake from the synaptic cleft 4-Fluoroethylphenidate in the central nervous system, which suggests 4-Fluoroethylphenidate (4F-TEP) is the eth- that 3,4-CTMP may modulate depression48. yl acetate analog of 4F-TMP, but it is not clear 3,4-CTMP is subject to a whether the threo (R,R), the erythro form (R,S), order, along with MPH and several analogs (class or a threo/erythro mixture is used (ethyl(4-flu- B drugs), under the in orophenyl)(2-piperidinyl)acetate, Figure 1). No the United Kingdom82. It is also scheduled in Swe- information about the drug was found in the den, China, and Canada61,83,84. Nuclear magnetic scientific literature, although it is available on the resonance (NMR), gas chromatography–electron drug market since 201571. The National Records ionization-mass spectrometry (GC-EI-MS), and of Scotland reported a fatality involving 4F-TEP, electrospray ionization-high resolution tandem which occurred in 2016, but no more data were mass spectrometry (ESI-HRMS/MS) spectra provided (Table I)87. The drug is now controlled were reported for analytical determination73,74,85. in the United Kingdom and Canada61,82.

9 J. Carlier, R. Giorgetti, M.R. Varì, F. Pirani, G. Ricci, F.P. Busardò

Methylnaphthidate (HDMP-28) and intestinal miscrosomes showed that IPH is Methylnaphthidate (HDMP-28) is an analog predominantly metabolized by carboxylesterases of the threo form (R,R) of MPH, with a naphthyl 1, although it seems to be a poor substrate for the group substituting the phenyl ring, that appeared . Finally, the authors showed that racemic on the drug market in 2014 (methyl 2-naphth- IPH significantly increased the locomotor activ- yl(2-piperidinyl)acetate, Figure 1). Reported dos- ity of rats over the entire 120 min study period es range from 10 to 50 mg when taken orally or following a 10 mg/kg intraperitoneal administra- snorted. Subjective effects are reported on user tion91. IPH is a in the United forums71. Like other MPH analogs, HDMP-28 Kingdom and Canada61,82. displays high affinity to the DAT in vitro, the threo form (R,R) being more effective81. Interest- Propylphenidate ingly, both diastereoisomers also display similar Propylphenidate (PPH) is the propyl analog of high affinity to SERT, suggesting that HDMP-28 MPH (propyl phenyl(2-piperidinyl)acetate, Fig- may modulate depression81. HDMP-28 affinity ure 1). Luethi et al48 showed that IPH threo isomer for DAT and SERT was also shown ex vivo in (R,R) binding affinity to NET is similar to that of rats’ striatum and cerebellum, with a higher IPH and EPH in human embryonic kidney cells. affinity than that of cocaine89. The same study However binding affinity to DAT is 4-fold lower, showed that HDMP-28 has reinforcing effects in making it one of the MPH analogs with the lowest vivo in rhesus monkeys, MPH and cocaine pro- affinity to DAT (with N-benzylethylphenidate). ducing similar effects89. HDMP-28 is currently Subjective effects are described as very mild on scheduled in the United Kingdom, , drug user forums71. However, it is a scheduled and Canada61,82,90. substance in the United Kingdom, Switzerland, Canada, and Sweden61,82,90,92. Ethylnaphthidate Ethylnaphthidate (HDEP-28) is the ethyl 4-Methylmethylphenidate acetate analog of HDMP-28 (ethyl 2-naphth- 4-methylmethylphenidate (4-MeTMP) is a de- yl(2-piperidinyl)acetate, Figure 1), with similar rivative of MPH threo isomer (R,R), with a DAT and NET inhibition potency to that of methyl in position 4- of the phenyl ring (meth- MPH48. Although no study was conducted on yl(4-methyl)(2-piperidinyl)acetate, Figure 1). Its HDEP-28 affinity to SERT, its structural analogy use as a psychostimulant was first described in with HDMP-28 suggest that HDEP-28 also inter- 2015 on drug user forums, where its effects are act with the transporter81,89. It was first marketed reported71. 4-MeTMP DAT and NET binding af- in 2015 and its effects are described on drug finity and inhibition potency are similar to those user forums71. Klare et al reported HDEP-28 of 4F-TMP48,80,81. 4-MeTMP NMR, GC-EI-MS, analytical characterization with NMR, GC-EI- and ESI-HRMS/MS spectra were described in MS, and ESI-HRMS/MS spectra85. HDEP-28 the literature85. The substance is controlled in the is banned in the United Kingdom, Switzerland, United Kingdom, Switzerland, and Canada61,82,90. and Canada61,82,90. N-benzylethylphenidate Isopropylphenidate N-benzylmethylphenidate (N-benzylTEP) is the Isopropylphenidate (IPH) is the isopropyl ac- N-benzyl analog of EPH threo form (R,R) (ethyl etate analog of MPH (isopropyl phenyl(2-piper- phenyl(2-piperidinyl-N-benzyl)acetate, Figure 1). idinyl)acetate, Figure 1). It appeared on the drug N-benzylTEP acts as a DAT and NET inhibitor market in 2013 and users describe the effects as with a lower potency than MPH and cocaine, as similar to those of EPH, with a fast onset of ac- shown in human embryonic kidney cells48 and tion71. IPH threo form (R,R) binds DAT and NET rat striatal tissue78. The threo form (R,R) shows with an affinity similar to that of EPH in human higher affinity to DAT than the erythro form embryonic kidney cells89. Markowitz et al showed (R,S) in vitro and ex vivo in rats80. N-benzylTEP that a 10 µM racemic IPH mixture inhibits 96% also binds SERT with a high affinity48. Illegal and 62% the reuptake of DA and NE, respective- products containing N-benzylTEP were recently ly, in in vitro experiments with human DAT and seized by the German authorities, attesting its NET (NE inhibition was stronger with racemic presence on the drug market87. Consequently, MPH and racemic EPH). In the same study, in although no intoxication cases were reported vitro metabolic experiments with human liver to date, the drug is scheduled in the United

10 Use of cognitive enhancers: methylphenidate and analogs

Kingdom82. The analytical characterization of the which has widely expanded during the last stimulant was described in the literature (NMR, decade. Although originally produced to treat GC-EI-MS, and ESI-HRMS/MS)85. depression and ADHD, MPH has been used as a nootropic drug for the past 20 years to increase Social and ethical issues alertness and cognition or as a doping substance Psychostimulants” or “cognitive enhancers” in sport. Consequently, it was scheduled as an are pharmaceutical drugs developed to treat spe- illicit drug in many countries and new “legal cific pathologies that impair the highs” were synthesized. Only little or no da- systems, such as ADHD and narcolepsy13,93. They ta on the pharmacology and toxicology of the target the catecholamines of the central nervous most recent MPH analogs is available, and few system, namely dopamine, norepinephrine, and analogs, such as EPH and 3,4-CTMP, are cur- serotonin, to induce their effects. As such, they rently controlled in few countries. Moreover, also stimulate alertness, sociability, and libido many cases of intoxication might go unnoticed, and have been abused by healthy individuals for considering that there is only little data on the recreational purposes for many years. Despite the analytical detection of these compounds. Like enforcement of laws banning psychostimulants, other psychostimulants, many intoxication cas- their consumption is on the rise. They are widely es and several fatalities associated with MPH used by students to “improve intelligence”, under analogs were reported. Cardiac effects seem to the illusion that these drugs will improve their play an important role in MPH analogs’ toxicity. grades. However, scientific studies showed only The development and the production of new and little to no benefits for cognitive enhancement. more potent and addictive cognitive-enhancing Worse yet, the consumption of such drugs can be substances suggest that more cases of intoxica- highly addictive and proved hazardous to health tion and death will occur in the future. To limit with risks of psychological, neurologic and car- the consequences, education and communica- diovascular disorders that can be fatal13,94. tion efforts on the side effects and the dangerous Generally speaking, the use of pharmaceutical nature of psychostimulants and MPH analogs drugs in healthy subject to enhance physical and should be made among high-risk populations, psychic performance have changed the concept of i.e. students and regular drug addicts. From a corporeity up to the possibility, for each individ- legal point of view, new MPH analogs should ual, to design his/her own corporeity as desired. be systematically controlled, and new analyti- The concept of self-determination in medicine cal methods should be developed to detect the brought to excess could lead to dangerous choices, newest drugs in biological specimens and seized as in case of misuse of these substances. Even the products in forensic toxicology. doctor-patient relationship, which have consider- ably changed to the detriment of reputation and consideration of the doctor, left wide possibility Conflict of Interest to the patient/individual, until almost imagining The Authors declare that they have no conflict of interests. that to overlap the figure of the doctor through in- correct information and immediate transposition. In the new generations, the concept of personal Funding improvement, immediate, with little effort and lit- The work was partly supported by Presidency of the Min- tle perceived risk would make everything lawful. isters Council, Department of Antidrug Policy, Rome, Ita- Consequently, the lack of perception of the dan- ly, and partly by School of Law, University of Camerino, Camerino, Italy. gerousness of these substances in question, makes them absolutely usable and lawful, exponentially increasing the social danger13,95. Acknowledgements The authors thank Simonetta di Carlo, Antonella Bacosi, and Laura Martucci for technical assistance in manuscript Conclusions preparation.

Like other NPS classes, psychostimulants use is spreading and new legal potent are Authors’ Contribution being synthesized and marketed rapidly. This JC, RG, FPB, and GR conceived the design of the manu- is the case for the sub-class of MPH analogs, script. JC, MRV, and FP performed the literature search,

11 J. Carlier, R. Giorgetti, M.R. Varì, F. Pirani, G. Ricci, F.P. Busardò and RG and FPB revised it. All the authors have been in- date on spatial working memory and planning volved in drafting the manuscript and revising it critically in healthy young adults. Psychopharmacology for important intellectual content, and all of them have giv- (Berl) 1997; 131: 196-206. en final approval to the version to be published. 12) Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and , in medically ill older adults and ter- References minally ill adults. Am J Geriatr Pharmacother 2009; 7: 34-59. 1) Janssen E, Spilka S, Le Nézet O, Shah J. On the 13) Busardò FP, Kyriakou C, Cipolloni L, Zaami S, Frati P. question of non-medical cognitive enhancers From Clinical Application to Cognitive Enhance- among in-school adolescents: Prevalence, ment: The Example of Methylphenidate. Curr predictors and potential health-related harms. Neuropharmacol 2016; 14: 17-27. 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