Are psychedelics better than antidepressants? New study says no

With an innovative approach, scientists try to get around the problem of participant expectation in tests of psychedelics.

University of California - San Francisco

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Psychedelic-assisted therapy may be no more effective than traditional antidepressants when patients know what drugs they are actually taking, according to a first-of-its kind analysis that compared how well each type of drug worked for major depression.

Psychedelic-assisted therapy has resisted placebo-controlled testing methods — the gold standard in clinical trial design. Due to their powerful subjective effects, nearly everyone in the trial knows whether they received a psychedelic or the placebo even if they are not told.

But in trials of antidepressants, participants may not figure out whether they have received the drug or a placebo, which makes it hard to compare them with psychedelics.

To get around this problem, researchers from UC San Francisco, UCLA, and Imperial College, London tried a different approach. They compared the results from psychedelic therapy trials to the results from so-called open-label trials of traditional antidepressants, in which the participants all knew they were getting an antidepressant. That way, both treatments benefitted equally from the positive effect of patients knowing that they were being given a drug instead of a placebo. 

The findings both surprised and disappointed them: there was virtually no difference.

“Unblinding is the defining methodological problem of psychedelic trials. What I wanted to show is that even if you compare psychedelics to open-label antidepressants, psychedelics are still much better,” said Balázs Szigeti, PhD, a clinical data scientist at UCSF’s Translational Psychedelic Research Program, who led the study. “Unfortunately, what we got is the opposite result — that they are the same, which is very surprising given the enthusiasm around psychedelics and mental health.” 

Szigeti is the co-first author of the paper with Zachary J. Williams, MD, PhD, of UCLA; Hannah Barnett, MSc, of Imperial College, London is also an author. The study appeared March 18 in JAMA Psychiatry.

A sobering view

The hype around the use of psychedelics like psilocybin, or “magic mushrooms,” and LSD, to treat such conditions as depression and addiction has grown in recent years as an increasing number of studies have shown promising results, particularly for people who haven’t responded to traditional antidepressants.

The new findings don’t mean that psychedelic therapy does not work — just that it does not work better than traditional antidepressants. Patients improved substantially from both types of treatments, reducing depression scores by about 12 points on a standard scale.

Part of what has made psychedelics seem impressive in trials than antidepressants is how much more those who received the psilocybin or LSD improved than those who did not get it.

But the researchers concluded that this was the result of the lack of blinding in psychedelic trials: those who got the drug improved more because they knew they had gotten it, while those who received a placebo did worse because they knew they did not. Whereas in trials of traditional antidepressants, the difference between the groups was much smaller, making it seem like the drugs weren’t that effective.

When this ‘knowing the treatment’ factor leveled out, the seeming advantage of psychedelics disappeared. 

“Psychedelics may still be a valuable treatment option,” Szigeti said. “But if we want to understand their true benefits, we have to compare them fairly — and when we do that, the advantage over standard antidepressants is much smaller than many people, including myself, expected.”

Funding: None. 

Disclosures: Williams received consulting fees from Roche. The other authors did not declare any conflicts.

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Journal

JAMA Psychiatry

 

Less trippy, more therapeutic ‘magic mushrooms’

American Chemical Society

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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

DOI

10.1021/acs.jmedchem.5c01797 

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

Elsevier

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image: 

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.

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Credit: 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.”

 

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Journal

Biological Psychiatry

DOI

10.1016/j.biopsych.2026.01.016 

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.

 

Single-dose of ayahuasca’s active compound could help ease depression, research finds

Copyright Copyright 2016 The Associated Press. All rights reserved.

By Marta Iraola Iribarren

Published on 17/02/2026 - EURONEWS

One dose of the active compound in ayahuasca significantly improves depressive symptoms in early stages of a clinical trial, according to a new study.

Dimethyltryptamine (DMT), a potent natural psychedelic and a primary psychoactive component of ayahuasca, could work as an antidepressant, a study published in Nature has found.

Researchers at Imperial College London conducted a trial that demonstrated DMT’s potential to ease symptoms of depression.

Intravenous DMT has a short half-life – the time it takes for the concentration of a drug in your bloodstream to drop by half after administration – of around five minutes due to rapid metabolism.

This allows for shorter therapeutic sessions, potentially improving patient convenience and reducing costs, the research noted.

The trial is a phase 2a clinical trial, meaning a pilot study designed to provide preliminary evidence of a drug’s efficacy and to determine the most effective dose for future trials.

The number of participants is typically small, between 30 and 50, to minimise exposure to potentially ineffective treatment and to focus on a targeted patient group.

The research team in London included 34 participants who had lived with depression for an average of 10.5 years. They were randomised so that 17 received the placebo, and 17 received the active substance.

Participants received a single 21.5 milligram dose of DMT or placebo infused over 10 minutes, alongside psychotherapeutic support.

After a two-week follow-up period, those treated with DMT showed a significantly greater reduction in depressive symptoms than those who received the placebo. The effects persisted up to three months after the start of the trial.

The researchers found that DMT was well-tolerated, with no serious adverse events. Most side effects were mild or moderate, the most common being pain where the patients received the injection.

Related

• Psychedelic medicine is promising but not ready to be rolled out to patients, say UK doctors

Independent experts cautioned that, while the findings are promising, further research is needed to assess the treatment’s efficacy.

“In terms of safety concerns, there may be a risk of negative experiences during the psychedelic experience that could be frightening or traumatising,” said James Stone, professor of psychiatry, Brighton and Sussex Medical School.

He added that certain groups of people may be more susceptible to these types of effects, and further studies are required to identify how often they occur.

Need for new depression drugs?

Approximately 332 million people in the world have depression, according to the World Health Organization. In Europe, more than 25 million people are estimated to live with depressive disorders.

The most common treatments include antidepressant medications and psychotherapy. However, the study authors noted that many patients experience insufficient improvement or unacceptable side effects from selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed class of antidepressants.

Previous research has shown that antidepressants achieve response rates of between 40 and 60 percent. Around 20 to 30 percent of patients with major depressive disorder (MDD) develop treatment-resistant depression, meaning they don’t respond to at least two different antidepressant medications.

The study authors argued that there is an urgent need for innovative and more effective treatments and suggested that psychedelics have emerged as a promising candidate.

Related

• Psychedelic therapies are coming to Europe, but face barriers before reaching patients

The future of psychedelic treatments

No psychedelic treatments like DMT and lysergic acid diethylamide (LSD) currently hold full marketing authorisation from the European Medicines Agency for clinical use in Europe.

In most countries, psychedelic treatments are limited to research trials, compassionate use programmes, which allow patients with serious or life-threatening conditions to access investigational drugs outside clinical trials when no approved treatments exist, and they can't join a trial.

The Czech Republic became the first European Union country to legalise medical psilocybin – commonly known as “magic mushrooms” – for psychotherapy from 1 January 2026.

Under the new framework, the treatment is offered to people resistant to traditional depression treatments, suffering from cancer-related, severe non-psychotic, or life-threatening mental deterioration.

It can only be administered by certified psychiatrists and clinical psychotherapists with specialised psychedelic training, and in approved facilities.