Less trippy, more therapeutic ‘magic mushrooms’
Psilocybin — the psychoactive compound in “magic mushrooms” — is gaining scientific attention for its potential in treating neuropsychiatric conditions including depression, anxiety, substance use disorders and certain neurodegenerative diseases. However, its hallucinogenic effects may limit broader therapeutic applications. Researchers publishing in ACS’ Journal of Medicinal Chemistry synthesized modified versions of psilocin, the active form of psilocybin, that retained their activity while producing fewer hallucinogenic-like effects than pharmaceutical-grade psilocybin in a preliminary study in mice.
“Our findings are consistent with a growing scientific perspective suggesting that psychedelic effects and serotonergic activity may be dissociated,” says Andrea Mattarei, a corresponding author of the study. “This opens the possibility of designing new therapeutics that retain beneficial biological activity while reducing hallucinogenic responses, potentially enabling safer and more practical treatment strategies.”
Mood disorders and some neurodegenerative diseases, such as Alzheimer’s disease, involve imbalances of the neurotransmitter molecule serotonin, which helps regulate mood and other brain functions. For decades, scientists have been investigating the therapeutic use of psychedelics such as psilocybin on serotonin-signaling pathways. However, the hallucinations that can accompany these drugs may make people wary of taking them, even if there is a medical benefit.
So, a team led by Sara De Martin, Mattarei and Paolo Manfredi chemically engineered five psilocin derivatives for slower, sustained and potentially non-hallucinogenic release into the brain. They first tested these five compounds using human plasma samples and laboratory conditions mimicking gastrointestinal absorption. These experiments allowed the team to identify a compound they named 4e as the most promising candidate because it displayed favorable stability for absorption and enabled a gradual release of psilocin — a feature that could potentially mitigate hallucinogenic effects. Importantly, 4e retained activity at key serotonin receptors at levels comparable to psilocin.
Next, the researchers compared the effects of equivalent doses of 4e with pharmaceutical-grade psilocybin in mice. The team administered the compounds orally to mice and measured how much psilocin reached the bloodstream and brain over a 48-hour period. In mice dosed with 4e, the compound was able to cross the blood–brain barrier effectively and exhibited a lower but more sustained presence of psilocin in their brains compared to those treated with psilocybin. When the researchers looked at mouse behavior, they observed that 4e-treated animals exhibited significantly fewer head twitches — a well-established marker of psychedelic-like activity in rodents — than those receiving psilocybin, despite the strong serotonin receptor activity of 4e. This behavioral difference appeared to be associated primarily with the amount and timing of psilocin released in the brain.
The researchers say their findings demonstrate the feasibility of developing stable brain-penetrating psilocin derivatives that retain serotonin receptor activity while reducing acute mind-altering effects. Further studies will be needed to clarify their mechanism of action and fully characterize their biological effects before assessing their therapeutic potential and safety in humans.
The authors acknowledge funding from MGGM Therapeutics, LLC, in collaboration with NeuroArbor Therapeutics Inc. Several authors declare they are inventors on patents related to psilocin.
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Journal
Journal of Medicinal Chemistry
Article Title
Design, Synthesis, and Pharmacokinetic Profiling of Fluorinated Reversible N-Alkyl Carbamate Derivatives of Psilocin for Sub-Hallucinogenic Brain Exposure
Treatment with psychedelics may provide a missing link towards long-term PTSD recovery
A study in Biological Psychiatry shows that myelin remodeling after treatment with psilocybin or MDMA can tune disrupted brain circuits, bridging the gap between the short-lived psychedelic experience and long-term neural health
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A novel study in Biological Psychiatry identifies myelin plasticity after treatment with psychedelics as the missing link towards long-term PTSD recovery, triggering a large-scale reconfiguration of brain network dynamics.
view moreCredit: Biological Psychiatry / Bostancıklıoğlu et al.
March 4, 2026 – 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-HT2A 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.”
Journal
Biological Psychiatry
Method of Research
Experimental study
Subject of Research
Animals
Article Title
MDMA and Psilocybin Regulate Oligodendrocyte-Lineage Cell Numbers and Anxiety-Like Behaviors in a Rat Model of Fear
COI Statement
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 at https://www.biologicalpsychiatryjournal.com/content/bps-editorial-disclosures.
