It’s possible that I shall make an ass of myself. But in that case one can always get out of it with a little dialectic. I have, of course, so worded my proposition as to be right either way (K.Marx, Letter to F.Engels on the Indian Mutiny)
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.
Journal
JAMA Psychiatry
Thursday, March 19, 2026
The scientist who warned that profit, not science, decides which drugs reach patients
Dr. Gabriella Gobbi, CINP president-elect and McGill neuropsychopharmacologist and psychiatrist, challenges the logic of drug discovery
MONTREAL, Quebec, CANADA, 17 March 2026 – Dr. Gabriella Gobbi, Professor of Psychiatry at McGill University, Canada Research Chair (Tier 1) in Therapeutics for Mental Health, Staff Psychiatrist at the McGill University Health Center (MUHC), and Senior Scientist, Brain Repair and Integrative Neuroscience Programat the Research Institute of the MUHC, and President-Elect of the Collegium Internationale of Neuropsychopharmacology (CINP), has issued an unambiguous challenge to the global drug-development system, warning that promising treatments for mental illness are failing to reach patients not because the science is flawed but because venture capital and profit motive govern which compounds advance through clinical trials. Her warning appears in a new Genomic Press Interview published in Brain Medicine.
"My greatest fear concerns the future of psychopharmacology and drug discovery," Dr. Gobbi states in the interview, "not because the science is failing, but because a greedy system oversees innovation today." She describes a landscape in which public funding can sustain early academic research, but the more expensive steps, from toxicology to first-in-human trials, depend on private investment that is guided by margin expectations rather than medical need. "We may lose good, non-expensive treatments because a greedy, capitalistic system controls which drug will finally be brought to market."
A Career Built on Bedside Questions
Dr. Gobbi grew up in a book-filled house in central Italy, the granddaughter of a man who died under Allied bombing in March 1945 after writing from a German prison to insist that his children receive the education he himself had been denied. That inheritance, part moral conviction and part intellectual hunger, runs as a thread through everything she has since done. At fourteen she put down comic books and picked up Freud. In high school she read about Rita Levi-Montalcini and the discovery of nerve growth factor, and understood that the brain was not fixed but plastic, a revelation that pointed her toward medicine. By twenty, during training in Rome, she had encountered translational research, the practice of moving continuously between laboratory bench and clinical ward, and found that she could not relinquish either world.
The path to independence was neither smooth nor linear. In Italy during the 1990s, academic positions were controlled by senior professors acting as gatekeepers, and Dr. Gobbi spent time working at a private psychiatric hospital in a small central-Italian town, applying to PhD programs and genuinely unsure whether she would ever gain entry to research. The turning point arrived on the evening of January 29, 1996, in the form of a telephone call. She was invited to sit a PhD entrance examination in Cagliari, in Sardinia, the following morning. She boarded a plane at eleven that night. At eight the next morning she sat the exam, and she won. That examination opened the door to work with Professor Gianluigi Gessa, a neuroscientist known for landmark contributions to the neurobiology of dopamine and addiction. Two years later, at a Biological Psychiatry meeting in Nice, a chance conversation with Professor Pierre Blier led to an invitation to join his laboratory at McGill. That single year in Montreal became more than two decades.
From Cannabis and Anhedonia to Melatonin and Psychedelics
The clinical observation that drives her best-known research line is almost painfully simple. In the early 2000s, she kept seeing adolescents and young adults who smoked cannabis and who, in the years that followed, developed depression marked by profound anhedonia. The bedside pattern became a bench question. In 2007 her laboratory reported one of the first links between cannabinoids, serotonin systems, and depression-related phenotypes. In 2010, animal-model studies demonstrated that adolescent cannabis exposure could increase vulnerability to later depressive-like outcomes. By 2019, supporting evidence had emerged in human cohorts. This body of work has now accumulated more than 1,700 citations and contributed directly to public-health decisions in Quebec. Dr. Gobbi also testified as an expert witness before the Canadian Senate and the Ministries of Health and Justice in Quebec on cannabis policy, contributing to legislation raising the legal age for cannabis access and to the regulation of cannabis advertising.
A second major research program, running in parallel since 2006, has focused on the melatonin MT2 receptor, a target that was poorly understood when her group began. Her laboratory contributed to defining MT2 receptor localization and elucidated its specific role in restorative NREM sleep and neuropathic pain. An MT2-selective partial agonist, a first-in-class candidate, is now moving from early discovery toward clinical development. "I have learned that in science, the projects that take the longest are often those that yield the most meaningful results," she observes in the interview. Her laboratory began investigating psychedelics in 2013, before the contemporary wave of clinical trials brought the field to prominence, characterizing the anxiolytic and prosocial effects of LSD in preclinical models and beginning to identify underlying molecular mechanisms including mTORC1 signaling. That work is now extending to psilocybin, DMT, and 5-MeO-DMT, while new clinical studies aim to identify objective neurophysiological biomarkers of psychedelic action in humans.
The Hidden Tax on Women in Science
Dr. Gobbi does not confine her scrutiny to drug-development economics. She speaks with notable directness about gender inequality in academic science, describing both overt harassment and a quieter structural erosion: unequal access to administrative support, diversion toward low-visibility service work, and a conference-invitation culture that disadvantages researchers who carry disproportionate caregiving burdens. "This is the cause that fires me up the most," she states, "changing the structure of our scientific culture so excellence is recognized without imposing an additional, hidden tax on women." In her current role as President-Elect of the CINP, the organization whose presidency she will hold as its first woman in the organization's 70-year history, she has heard such accounts repeatedly from accomplished women who have been isolated, evaluated inconsistently, or simply not invited to the table.
The Letter and the Paddleboard
There is a letter from Dr. Gobbi's mother, written before her death from glioblastoma in 2000, that she names as her most treasured possession. It is the kind of detail that resists elaboration, so this account will leave it alone. What she says about happiness is perhaps more useful to science journalism: her happiest moments have occurred in those rare instants in research when data suddenly align and something obscure becomes clear, "the feeling that nature has briefly lifted a corner of the veil, and that an experiment is no longer just results on a page but a story that finally makes sense." When she disconnects entirely, in summer, she paddles on the Adriatic Sea. In Quebec she skis in spring, when the light softens. Winter skiing here, she notes in the interview, is simply too cold.
Asked what she would change about herself, Dr. Gobbi does not cite a scientific limitation. She wishes she had sought mentorship and leadership education earlier. She began her career as an assistant professor without a mentor and without foundational training in management, grant-writing, or conflict resolution. The regret is characteristic: it is not personal but structural, a comment about what academic systems fail to provide rather than about what she personally lacks. Her life philosophy, offered at the interview's close, is unadorned: "Do your best, stay true to what matters, and trust what comes."
Dr. Gabriella Gobbi's Genomic Press interview is part of a larger series called Innovators and Ideas that highlights the people behind today's most influential scientific breakthroughs. Each interview in the series offers a blend of cutting-edge research and personal reflections, providing readers with a comprehensive view of the scientists shaping the future. By combining a focus on professional achievements with personal insights, this interview style invites a richer narrative that both engages and educates readers. This format provides an ideal starting point for profiles that explore the scientist's impact on the field, while also touching on broader human themes. More information on the research leaders and rising stars featured in our Innovators and Ideas – Genomic Press Interview series can be found on our interview website: https://interviews.genomicpress.com/.
The Genomic Press Interview in Brain Medicine titled “Gabriella Gobbi: Embracing psychiatry from bench to bedside,” is freely available via Open Access, starting on 17 March 2026 in Brain Medicine at the following hyperlink: https://doi.org/10.61373/bm026k.0015.
About Brain Medicine: Brain Medicine (ISSN: 2997-2639, online and 2997-2647, print) is a peer-reviewed medical research journal published by Genomic Press, New York. Brain Medicine is a new home for the cross-disciplinary pathway from innovation in fundamental neuroscience to translational initiatives in brain medicine. The journal’s scope includes the underlying science, causes, outcomes, treatments, and societal impact of brain disorders, across all clinical disciplines and their interface.
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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The American Chemical Society (ACS) is a nonprofit organization founded in 1876 and chartered by the U.S. Congress. ACS is committed to improving all lives through the transforming power of chemistry. Its mission is to advance scientific knowledge, empower a global community and champion scientific integrity, and its vision is a world built on science. The Society is a global leader in promoting excellence in science education and providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, e-books and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a leader in scientific information solutions, its CAS division partners with global innovators to accelerate breakthroughs by curating, connecting and analyzing the world’s scientific knowledge. ACS’ main offices are in Washington, D.C., and Columbus, Ohio.
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
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.
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.”
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.
