The Effects of Psychedelics on Brain Function
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Trial Title
Brain-Epigenome Wide Association Study (BEWAS) on the Effects of Two Emerging Psychedelics: Ketamine and MDMA
Collaborating Institutions
Arizona State University; University of Southern California; Modern Spirit; Translational Genomics Research Institute (TGen)
Summary Snapshot
Study Type: Brain-Epigenome Wide Association Study (BEWAS)
Sample Size: Ketamine: 20 participants; MDMA: 16 participants
Duration: 2-3 weeks; MDMA: ~12 weeks (three doses ~4 weeks apart, post-treatment samples 6-8 weeks after last dose)
Primary Endpoint: Changes in DNA methylation at brain-enriched CpG sites from pre- to post-treatment
The DNA Methylation Edge
DNA methylation made it possible to capture lasting, brain-relevant molecular changes following ketamine and MDMA therapy using peripheral samples. This approach uncovered convergent neuroimmune and neuroplasticity pathways that extend beyond short-term symptom relief and point toward shared therapeutic mechanisms.
Objective & Rationale
Study Goal and Scientific Context: The study aimed to evaluate epigenetic changes in brain-enriched genes following ketamine or MDMA treatment using a BEWAS on peripheral samples (blood/saliva), focusing on neuroplasticity, immune, and mental health pathways to uncover molecular mechanisms. It addressed gaps in understanding psychedelics' lasting therapeutic effects for mood/trauma disorders beyond pharmacology, given rising mental health burdens and low treatment rates, which could help elucidate shared/convergent pathways, inform psychedelic-assisted therapies, and advance biomarkers for psychiatric outcomes.
Methodology
Design: Mixed models for repeated measures (MMRMs) on pre/post methylation data; BEWAS restricted to brain-enriched genes; Stouffer-Lipták-Kechris for gene-level aggregation; STRING for functional enrichment
Population: Ketamine: Adults with moderate-severe MDD/PTSD (mean age 40, 75% female); MDMA: Adults with severe PTSD (mean age 43, 56% male)
Intervention: Ketamine: 6 IV subanesthetic infusions (0.5 mg/kg) over 2-3 weeks; MDMA: 3 oral doses (80-180 mg) ~4 weeks apart with psychotherapyDuration: Ketamine: 2-3 weeks; MDMA: ~12 weeks
Epigenetic Measurements: Infinium HumanMethylationEPICv1 BeadChip; Minfi preprocessing (quantile normalization, probe filtering); EpiDISH for epithelial cell proportions; filtered to ~15% of array (brain-enriched genes from Human Protein Atlas); CpG changes
Key Findings
Results:
- Ketamine altered 1,210 CpGs (788 genes), mostly hypermethylated (72.3%), enriching immune (25%) and mental (20.8%) networks
- MDMA altered 2,074 CpGs (1,027 genes), enriching immune (13%) and mental (10.8%) networks
- Both affected ~20% neuroplasticity genes (e.g., PTPRN2, SHANK2) with substantial overlap (e.g., 12 genes with ≥10 CpGs each)
Standard Metrics: % change in biological age, direction of effect, significance.
Academic Significance: Though psychedelics are gaining more interest from clinicians as treatment options, little research yet exists on biomarker indicators for psychedelic efficacy. This study contributes to the research gap and identifies promising convergent mechanisms for further study.
Clinical Significance: This intervention demonstrated a range of epigenetic alterations occurring after therapeutic administration of either MDMA or ketamine – both psychedelics affected immune system functioning, mental health functioning, and neuroplasticity, demonstrating that psychedelics can impact multiple body systems simultaneously while inducing methylation changes across multiple genes.
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