Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD
Candace R. Lewis, Joseph Tafur, Sophie Spencer, Joseph M. Green, Charlotte Harrison, Benjamin Kelmendi, David M. Rabin, Rachel Yehuda, Berra Yazar-Klosinski, Baruch Rael Cahn
Frontiers in Psychiatry February 6, 2023 DOI: 10.3389/fpsyt.2023.959590 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pilot sub-study of a Phase 3 randomized controlled trial Pilot study Peer reviewed |
|---|---|
| Sample size | 23 |
| Population | Patients with severe PTSD |
| Interventions | MDMA-assisted therapy placebo with therapy |
| Topics | MDMA PTSD |
| Citations | 29 |
| Registration | NCT03537014 |
| Key findings | Methylation changes in HPA axis genes predicted PTSD symptom reduction, with greater change on one NR3C1 site in the MDMA-assisted therapy group compared to placebo. |
Abstract
BackgroundPrevious research has demonstrated that epigenetic changes in specific hypothalamic-pituitary-adrenal (HPA) genes may predict successful psychotherapy in post-traumatic stress disorder (PTSD). A recent Phase 3 clinical trial reported high efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for treating patients with severe PTSD compared to a therapy with placebo group (NCT03537014). This raises important questions regarding potential mechanisms of MDMA-assisted therapy. In the present study, we examined epigenetic changes in three key HPA axis genes before and after MDMA and placebo with therapy. As a pilot sub-study to the parent clinical trial, we assessed potential HPA epigenetic predictors for treatment response with genomic DNA derived from saliva (MDMA, n = 16; placebo, n = 7). Methylation levels at all 259 CpG sites annotated to three HPA genes (CRHR1, FKBP5, and NR3C1) were assessed in relation to treatment response as measured by the Clinician-Administered PTSD Scale (CAPS-5; Total Severity Score). Second, group (MDMA vs. placebo) differences in methylation change were assessed for sites that predicted treatment response.ResultsMethylation change across groups significantly predicted symptom reduction on 37 of 259 CpG sites tested, with two sites surviving false discovery rate (FDR) correction. Further, the MDMA-treatment group showed more methylation change compared to placebo on one site of the NR3C1 gene.ConclusionThe findings of this study suggest that therapy-related PTSD symptom improvements may be related to DNA methylation changes in HPA genes and such changes may be greater in those receiving MDMA-assisted therapy. These findings can be used to generate hypothesis driven analyses for future studies with larger cohorts.
Comparable studies
Other randomized controlled trials on MDMA for PTSD, most cited first.
Citations in the library
Cited by 15
- The Psychedelic Future of Post-Traumatic Stress Disorder Treatment Current Neuropharmacology January 5, 2024
- Transient Elevation of Plasma Glucocorticoids Supports Psilocybin-Induced Anxiolysis in Mice ACS Pharmacology & Translational Science August 2, 2023
- Epigenetic mechanisms of rapid-acting antidepressants Translational Psychiatry September 4, 2024
- Bedside to bench: the outlook for psychedelic research Frontiers in Pharmacology October 2, 2023
- Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents Neuroscience & Biobehavioral Reviews September 20, 2024
and 10 more in the library
Cites 9
- MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine June 1, 2021
- MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology September 1, 2019
- Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies Human Psychopharmacology: Clinical and Experimental December 1, 2001
- Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration Social Neuroscience June 25, 2009
- Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology August 1, 2020
and 4 more in the library