Sigma (σ) receptors as potential therapeutic targets to mitigate psychostimulant effects

Adv Pharmacol. 2014;69:323-86. doi: 10.1016/B978-0-12-420118-7.00009-3.


Many psychostimulants, including cocaine and methamphetamine, interact with sigma (σ) receptors at physiologically relevant concentrations. The potential therapeutic relevance of this interaction is underscored by the ability to selectively target σ receptors to mitigate many behavioral and physiological effects of psychostimulants in animal and cell-based model systems. This chapter begins with an overview of these enigmatic proteins. Provocative preclinical data showing that σ ligands modulate an array of cocaine and methamphetamine effects are summarized, along with emerging areas of research. Together, the literature suggests targeting of σ receptors as an innovative option for combating undesired actions of psychostimulants through both neuronal and glial mechanisms.

Keywords: Addiction; Cocaine; Glia; Methamphetamine; Neurotoxicity; Sigma receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Central Nervous System Stimulants / metabolism*
  • Clinical Trials as Topic / methods
  • Cocaine / metabolism
  • Drug Delivery Systems / methods*
  • Humans
  • Methamphetamine / metabolism
  • Opipramol / administration & dosage
  • Opipramol / metabolism
  • Protein Binding / physiology
  • Receptors, sigma / agonists
  • Receptors, sigma / antagonists & inhibitors
  • Receptors, sigma / metabolism*
  • Substance-Related Disorders / drug therapy
  • Substance-Related Disorders / metabolism


  • Central Nervous System Stimulants
  • Receptors, sigma
  • Methamphetamine
  • Opipramol
  • Cocaine