Synergistic interactions between fenfluramine and phentermine

Int J Obes Relat Metab Disord. 1999 Jul;23(7):723-32. doi: 10.1038/sj.ijo.0800920.


'Fen-phen' refers to the off-label combination of the appetite suppressants fenfluramine and phentermine. The rationale for the fen-phen combination was that the two drugs exerted independent actions on brain satiety mechanisms so that it was possible to use lower doses of each drug and yet retain a common action on suppressing appetite while minimizing adverse drug effects. The focus of the present review is to consider whether fenfluramine and phentermine exert actions that are additive in nature or whether these two drugs exhibit drug-drug synergism. The fen-phen combination results in synergism for the suppression of appetite and body weight, the reduction of brain serotonin levels, pulmonary vasoconstriction and valve disease. Fen-phen synergism may reflect changes in the pharmacokinetics of drug distribution, common actions on membrane ion currents, or interactions between neuronal release and reuptake mechanisms with MAO-mediated transmitter degradation. The synergism between fenfluramine and phentermine highlights the need to more completely understand the pharmacology and neurochemistry of appetite suppressants prior to use in combination pharmacotherapy for the treatment of obesity.

Publication types

  • Review

MeSH terms

  • Animals
  • Appetite / drug effects
  • Appetite Depressants / adverse effects
  • Appetite Depressants / pharmacology*
  • Body Weight / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Drug Synergism
  • Drug Therapy, Combination
  • Energy Intake / drug effects
  • Fenfluramine / adverse effects
  • Fenfluramine / pharmacology*
  • Humans
  • Monoamine Oxidase Inhibitors / pharmacology
  • Phentermine / adverse effects
  • Phentermine / pharmacology*
  • Selective Serotonin Reuptake Inhibitors / pharmacology


  • Appetite Depressants
  • Monoamine Oxidase Inhibitors
  • Serotonin Uptake Inhibitors
  • Fenfluramine
  • Phentermine