Elevated Methylation and Decreased Serum Concentrations of BDNF in Patients in Levomethadone Compared to Diamorphine Maintenance Treatment

Eur Arch Psychiatry Clin Neurosci. 2017 Feb;267(1):33-40. doi: 10.1007/s00406-016-0668-7. Epub 2016 Jan 22.


Brain-derived neurotrophic factor (BDNF) appears to play a crucial role in the reward response to drugs such as heroin. The primary objective of the present study was to examine epigenetic changes and serum levels of BDNF in patients undergoing different opiate-based maintenance treatments. We compared patients receiving treatment with either levomethadone (n = 55) or diamorphine (n = 28) with a healthy control group (n = 51). When comparing all subjects (patients and controls), BDNF serum levels showed a negative correlation with the BDNF IV promoter methylation rate (r = -0.177, p = 0.048). Furthermore, BDNF serum levels negatively correlated with Beck's Depression Inventory measurements (r = -0.177, p < 0.001). Patients receiving diamorphine maintenance treatment showed slightly decreased BDNF serum levels compared to healthy controls, whereas patients on levomethadone maintenance treatment with or without heroine co-use showed a pronounced decrease (analysis of covariance: control vs. levomethadone with and without heroine co-use: p < 0.0001, diamorphine vs. levomethadone with heroine co-use: p = 0.043, diamorphine vs. levomethadone without heroine co-use: p < 0.0001). According to these findings, methylation of the BDNF IV promoter showed the highest level in patients receiving levomethadone without heroine co-use (linear mixed model: control vs. levomethadone group without heroine co-use: p = 0.008, with heroin co-use: p = 0.050, diamorphine vs. levomethadone group with heroine co-use: p = 0.077 and without heroine co-use: p = 0.015.). For the first time, we show an epigenetic mechanism that may provide an explanation for mood destabilization in levomethadone maintenance treatment.

Keywords: BDNF; Brain-derived neurotrophic factor; DNA methylation; Epigenetic regulation; Opiate dependence; Opiate maintenance.

MeSH terms

  • Adult
  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use*
  • Brain-Derived Neurotrophic Factor / blood*
  • Brain-Derived Neurotrophic Factor / genetics
  • Case-Control Studies
  • Depression / etiology
  • Epigenesis, Genetic / drug effects
  • Female
  • Heroin / pharmacology
  • Heroin / therapeutic use*
  • Humans
  • Male
  • Methadone / pharmacology
  • Methadone / therapeutic use*
  • Methylation / drug effects
  • Middle Aged
  • Opioid-Related Disorders / blood*
  • Opioid-Related Disorders / drug therapy*
  • Opioid-Related Disorders / psychology
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • Prospective Studies
  • Psychiatric Status Rating Scales
  • Statistics, Nonparametric
  • Surveys and Questionnaires
  • Visual Analog Scale


  • Analgesics, Opioid
  • Brain-Derived Neurotrophic Factor
  • Heroin
  • Methadone