Circadian alteration in neurobiology during 30 days of abstinence in heroin users

Biol Psychiatry. 2009 May 15;65(10):905-12. doi: 10.1016/j.biopsych.2008.11.025. Epub 2009 Jan 9.


Background: Previous studies have shown that individuals withdrawn from chronic opiate administration undergo substantial elevations of cortisol levels with blunted corticotropin (ACTH) rhythms and that these changes persist beyond the 7-10 days of acute withdrawal symptoms. However, there are no published studies of changes in expression of clock genes or of other neuropeptides related to circadian-rhythm regulation, which may influence relapse susceptibility.

Methods: Blood samples were collected from 8 healthy control subjects and 16 heroin addicts during pharmacologically unassisted withdrawal on the 3rd, 10th, and 30th days of abstinence at 3-hour intervals for 24 hours. Outcome measures were the relative expression of clock gene mRNA (hperiod1, hperiod2, hclock) and the levels of serum cortisol, plasma ACTH, beta-endorphin (beta-EP), leptin, neuropeptide Y, interleukin-2 (IL-2), and tumor necrosis factor (TNF) in these subjects.

Results: Compared with healthy volunteers, abstinent addicts showed disruptions in diurnal rhythms of hPER1 and hPER2 mRNA expression, along with disruptions in diurnal rhythms of cortisol, ACTH, beta-endorphin, leptin, and IL-2 release. Several of these disruptions (hPER1, hPER2, ACTH, beta-endorphin, and IL-2) persisted for the 30-day testing period, as did elevation of 24-hour levels of cortisol and decreases in 24-hour IL-2 and TNF levels.

Conclusions: These prolonged neurobiological changes may play a role in protracted opiate withdrawal symptoms and contribute to relapse vulnerability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adult
  • Animals
  • CLOCK Proteins
  • Case-Control Studies
  • Chronobiology Disorders / metabolism*
  • Drug Users
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
  • Heroin Dependence / metabolism*
  • Humans
  • Hydrocortisone / blood
  • Hypothalamus / metabolism*
  • Interleukin-2 / blood
  • Intracellular Signaling Peptides and Proteins / blood
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Leptin / blood
  • Male
  • Neuropeptide Y / blood
  • Nuclear Proteins / blood
  • Nuclear Proteins / metabolism
  • Period Circadian Proteins
  • RNA / metabolism
  • Rats
  • Substance Withdrawal Syndrome / metabolism*
  • Time Factors
  • Trans-Activators / blood
  • Trans-Activators / metabolism
  • Transcription Factors / blood
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor-alpha / blood
  • beta-Endorphin / blood


  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • Leptin
  • Neuropeptide Y
  • Nuclear Proteins
  • PER1 protein, human
  • PER2 protein, human
  • Per1 protein, rat
  • Period Circadian Proteins
  • Trans-Activators
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • beta-Endorphin
  • RNA
  • Adrenocorticotropic Hormone
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • CLOCK Proteins
  • CLOCK protein, human
  • Clock protein, rat
  • Hydrocortisone