Treatment with Psychedelics May Provide a Missing Link Towards Long-Term PTSD Recovery

Post-traumatic stress disorder (PTSD) is not only characterized by strongly encoded traumatic memories, but also by disrupted coordination across brain networks. New research shows that treatment with psychedelic drugs triggers a large-scale reconfiguration of brain network dynamics driven by the remodeling of myelin—the neuronal insulation layer. The findings from the novel study in Biological Psychiatry, published by Elsevier, show enhancing myelination might be a viable strategy to augment or sustain the therapeutic effects of psychedelic-assisted treatments for PTSD and related disorders.

Psilocybin and 3,4-methylenedioxymethamphetamine (MDMA) produce rapid clinical effects in patients with PTSD. However, durable benefits require circuit-level stabilization. As the underlying cellular mechanisms remain incompletely understood, the current study identifies myelin as the missing link bridging the short-lived psychedelic experience and longer-term maintenance of healthier neural network dynamics. The study shows that activity-dependent oligodendrogenesis and myelin remodeling can tune the disrupted timing and persistent response to threat observed in PTSD by synchronizing and harmonizing the rhythm of brain circuits.

John Krystal, MD, Editor of Biological Psychiatry, explains, “The focus of psychedelic and MDMA research has been the effects of these drugs on neurons and neuroplasticity. This work has largely ignored a potentially important role for other cell types in the neurobiology of their therapeutic effects. Oligodendrocytes play a number of roles in the brain, which produce the myelin that insulates neurons. Subgroups of oligodendrocytes take up glutamate and contribute to glutamate homeostasis, protecting the brain from neurotoxicity. Another group of oligodendrocytes is involved in immune and inflammatory functions in the brain.”

Researchers used a rat model of contextual fear conditioning and administered repeated low doses of psilocybin or MDMA. They then quantified anxiety-like and exploration behaviors and assessed spatial learning and memory.

The results showed that anxiety-like behaviors were reduced—a shift accompanied by changes in oligodendrocyte biology and multi-omic (genetic) signatures towards myelin remodeling in the dentate gyrus (part of the hippocampus, the brain’s memory center).

“To test whether myelin integrity was simply associated with behavioral change—or actually required for it—we combined the drug interventions with models that either damaged brain insulation (demyelination) or chemically enhanced it (promyelination) to see how these changes affected recovery,” explains lead investigator Mehmet Bostancıklıoğlu, PhD, Department of Physiology, Gaziantep University Faculty of Medicine, Gaziantep, Turkey.

Using high-powered microscopy and genetic analysis, the researchers confirmed both psilocybin and MDMA trigger physical myelin repair. Furthermore, a serotonin receptor 5-HT_2A blockade prevented both the behavioral and myelin-associated effects. When the team used a different drug (anisomycin) to block the formation of fear memories, anxiety decreased, but the myelin remained unrepaired. This suggests that while memories can be suppressed, biological recovery requires the structural support of myelin.

“Taken together, this moves oligodendrocytes and adaptive myelination from ‘background correlates’ to a mechanistically testable gate on the durability of psychedelic-associated circuit change,” notes Dr. Bostancıklıoğlu.

“The implication of oligodendrocytes in the therapeutic effects of psychedelics and MDMA is important because of their many functions in the brain, including myelin formation, glutamate homeostasis, and neuroinflammation. The dependency of the therapeutic effects of these drugs in animals may suggest that myelin compromise may undermine their efficacy,” adds Dr. Krystal. “Overall, these data suggest that psychedelics and MDMA, like selective serotonin reuptake inhibitors (SSRIs) and ketamine, may promote the recovery from stress-related damage to myelin, contributing to clinical recovery.”

The study also found that psilocybin and MDMA reduce astrocyte reactivity that can cause inflammation.

The investigators point out that enhancing myelination would not be expected to replace psychotherapy; rather, it could support consolidation and maintenance of healthier network communication after the acute psychedelic session, when the brain is transitioning from destabilization back towards reintegration.

Dr. Bostancıklıoğlu concludes, “We often talk about psychedelics as ‘opening a window’ for brain plasticity. Recent work emphasizes that these drugs can acutely loosen entrenched network patterns and then leave a sub-acute period in which experience can reshape circuits. What we show here is that myelin-producing cells may be an underappreciated part of that story—helping translate a transient window into longer-lasting circuit change, at least in a fear-based rat model.”

Notes for editors

The article is "MDMA and Psilocybin Regulate Oligodendrocyte-Lineage Cell Numbers and Anxiety-Like Behaviors in a Rat Model of Fear,” by Mehmet Bostancıklıoğlu, Davut Sinan Kaplan, Ramazan Bal, Elif Yiğit, Hasan Ulusal, and Ebru Temiz (https://doi.org/10.1016/j.biopsych.2026.01.016). It is published online in Biological Psychiatry, published by Elsevier.

The article is openly available for 60 days at https://www.biologicalpsychiatryjournal.com/article/S0006-3223(26)00052-1/fulltext.

Full text of the study and additional information are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected]. Journalists wishing to interview the authors should contact Mehmet Bostancıklıoğlu, PhD, at [email protected].

The work was supported by The Scientific and Technological Research Council of Turkey (TÜBİTAK, grant number 223S425).

The authors’ affiliations and disclosures of financial relationships and conflicts of interest are available in the article.

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial relationships and conflicts of interest are available here.

About Biological Psychiatry

Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms, and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 9^th out of 156 Psychiatry titles and 17^th out of 271 Neurosciences titles in Journal Citation Reports^TM, published by Clarivate. The 2024 Impact Factor score for Biological Psychiatry is 9.0.www.sobp.org/journal

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