Pharmacological profile of methylphenidate-based designer drugs

Neuropharmacology. 2018 May 15;134(Pt A):133-140. doi: 10.1016/j.neuropharm.2017.08.020. Epub 2017 Aug 18.


Background: Methylphenidate-based designer drugs are new psychoactive substances (NPS) that are used outside medical settings and their pharmacology is largely unexplored. The aim of the present study was to characterize the pharmacology of methylphenidate-based substances in vitro.

Methods: We determined the potencies of the methylphenidate-based NPS N-benzylethylphenidate, 3,4-dichloroethylphenidate, 3,4-dichloromethylphenidate, ethylnaphthidate, ethylphenidate, 4-fluoromethylphenidate, isopropylphenidate, 4-methylmethylphenidate, methylmorphenate, and propylphenidate and the potencies of the related compounds cocaine and modafinil with respect to norepinephrine, dopamine, and serotonin transporter inhibition in transporter-transfected human embryonic kidney 293 cells. We also investigated monoamine efflux and monoamine receptor and transporter binding affinities. Furthermore, we assessed the cell integrity under assay conditions.

Results: All methylphenidate-based substances inhibited the norepinephrine and dopamine transporters 4 to >1000-fold more potently than the serotonin transporter. Similar to methylphenidate and cocaine, methylphenidate-based NPS did not elicit transporter-mediated efflux of monoamines. Besides binding to monoamine transporters, several test drugs had affinity for adrenergic, serotonergic, and rat trace amine-associated receptors but not for dopaminergic or mouse trace amine-associated receptors. No cytotoxicity was observed after drug treatment at assay concentrations.

Conclusion: Methylphenidate-based substances had pharmacological profiles similar to methylphenidate and cocaine. The predominant actions on dopamine transporters vs. serotonin transporters may be relevant when considering abuse liability. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Keywords: Cocaine; Methylphenidate; Monoamine; New psychoactive substances; Receptor; Transporter.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biogenic Amines / metabolism
  • Central Nervous System Stimulants / chemistry
  • Central Nervous System Stimulants / pharmacology*
  • Designer Drugs / chemistry
  • Designer Drugs / pharmacology*
  • HEK293 Cells
  • Humans
  • Methylphenidate / chemistry
  • Methylphenidate / pharmacology*
  • Neurotransmitter Transport Proteins / antagonists & inhibitors
  • Neurotransmitter Transport Proteins / metabolism
  • Protein Binding / drug effects
  • Receptors, Biogenic Amine / metabolism
  • Transfection


  • Biogenic Amines
  • Central Nervous System Stimulants
  • Designer Drugs
  • Neurotransmitter Transport Proteins
  • Receptors, Biogenic Amine
  • Methylphenidate