Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Psychiatry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.959590/full |
| _version_ | 1811170967949410304 |
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| author | Candace R. Lewis Candace R. Lewis Joseph Tafur Sophie Spencer Joseph M. Green Charlotte Harrison Benjamin Kelmendi David M. Rabin Rachel Yehuda Rachel Yehuda Berra Yazar-Klosinski Baruch Rael Cahn Baruch Rael Cahn |
| author_facet | Candace R. Lewis Candace R. Lewis Joseph Tafur Sophie Spencer Joseph M. Green Charlotte Harrison Benjamin Kelmendi David M. Rabin Rachel Yehuda Rachel Yehuda Berra Yazar-Klosinski Baruch Rael Cahn Baruch Rael Cahn |
| author_sort | Candace R. Lewis |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T17:05:37Z |
| format | Article |
| id | doaj.art-ceb6b349a524468186db515c742b80f0 |
| institution | Directory Open Access Journal |
| issn | 1664-0640 |
| language | English |
| last_indexed | 2024-04-10T17:05:37Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Psychiatry |
| spelling | doaj.art-ceb6b349a524468186db515c742b80f02023-02-06T05:37:06ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402023-02-011410.3389/fpsyt.2023.959590959590Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSDCandace R. Lewis0Candace R. Lewis1Joseph Tafur2Sophie Spencer3Joseph M. Green4Charlotte Harrison5Benjamin Kelmendi6David M. Rabin7Rachel Yehuda8Rachel Yehuda9Berra Yazar-Klosinski10Baruch Rael Cahn11Baruch Rael Cahn12School of Life Sciences, Arizona State University, Tempe, AZ, United StatesNeurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, United StatesModern Spirit, Phoenix, AZ, United StatesSchool of Life Sciences, Arizona State University, Tempe, AZ, United StatesSchool of Life Sciences, Arizona State University, Tempe, AZ, United StatesMAPS Public Benefit Corporation, San Jose, CA, United StatesDepartment of Psychiatry, School of Medicine, Yale University, New Haven, CT, United StatesThe Board of Medicine, Pittsburgh, PA, United StatesDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United StatesDepartment of Psychiatry, James J. Peters VA Medical Center, Bronx, NY, United StatesMAPS Public Benefit Corporation, San Jose, CA, United StatesDepartment of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, United States0Brain and Creativity Institute, University of Southern California, Los Angeles, CA, United StatesBackgroundPrevious 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.https://www.frontiersin.org/articles/10.3389/fpsyt.2023.959590/fullPTSDMDMAMDMA-assisted therapyHPANR3C1glucocorticoid receptor |
| spellingShingle | Candace R. Lewis Candace R. Lewis Joseph Tafur Sophie Spencer Joseph M. Green Charlotte Harrison Benjamin Kelmendi David M. Rabin Rachel Yehuda Rachel Yehuda Berra Yazar-Klosinski Baruch Rael Cahn Baruch Rael Cahn Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD Frontiers in Psychiatry PTSD MDMA MDMA-assisted therapy HPA NR3C1 glucocorticoid receptor |
| title | Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD |
| title_full | Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD |
| title_fullStr | Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD |
| title_full_unstemmed | Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD |
| title_short | Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD |
| title_sort | pilot study suggests dna methylation of the glucocorticoid receptor gene nr3c1 is associated with mdma assisted therapy treatment response for severe ptsd |
| topic | PTSD MDMA MDMA-assisted therapy HPA NR3C1 glucocorticoid receptor |
| url | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.959590/full |
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