Daily administration of m-chlorophenylpiperazine to healthy human volunteers rapidly attenuates many of its behavioral, hormonal, cardiovascular and temperature effects

Psychopharmacology (Berl). 1996 Sep;127(2):140-9. doi: 10.1007/BF02805987.


The serotonergic agent meta-chlorophenylpiperazine (m-CPP) increases temperature and plasma ACTH and other hormones and decreases social interaction, locomotor activity and food intake in rats, most likely via stimulation of 5-HT2C receptors. Repeated daily administration of m-CPP to rats induces rapid tolerance to these effects of m-CPP. As m-CPP has been used in challenge tests and in preliminary treatment trials in humans, we evaluated the possible development of tolerance to m-CPP in ten healthy human volunteers using a double-blind, random assignment crossover study of placebo versus daily m-CPP infusions. Psychological and physical symptoms of anxiety, temperature, pupil size, diastolic blood pressure, and plasma ACTH, cortisol, and prolactin concentrations were increased by the first administration of m-CPP (0.08 mg/kg) compared to placebo. All of these responses were attenuated on m-CPP days 2 and 3. Plasma m-CPP levels did not differ across the 3 m-CPP days. Repeated m-CPP administration thus appears to induce rapid tolerance to its behavioral and physiological effects in humans. Further investigations of the mechanisms involved in the development of subsensitivity to m-CPP may contribute to increased understanding of the regulation of serotonin-mediated functions and of anxiety disorders.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adult
  • Anxiety / drug therapy
  • Behavior / drug effects
  • Blood Pressure / drug effects
  • Body Temperature / drug effects*
  • Cardiovascular System / drug effects*
  • Double-Blind Method
  • Drug Tolerance
  • Female
  • Heart Rate / drug effects
  • Humans
  • Hydrocortisone / blood
  • Male
  • Piperazines / administration & dosage
  • Piperazines / blood
  • Piperazines / pharmacology*
  • Prolactin / blood
  • Serotonin Receptor Agonists / administration & dosage
  • Serotonin Receptor Agonists / pharmacology*


  • Piperazines
  • Serotonin Receptor Agonists
  • Adrenocorticotropic Hormone
  • Prolactin
  • 1-(3-chlorophenyl)piperazine
  • Hydrocortisone