Issue #39June 1, 20267 studies

Psilocybin's antidepressant effects lasted 12 months in 126 treatment-resistant patients

This week brought the largest and longest follow-up study of any psychedelic trial to date, plus new insights into how these compounds affect everything from personality to pain processing.

🍄 Psilocybin's Depression Benefits Lasted a Full Year

126 patients with treatment-resistant depression showed sustained improvement 12 months after receiving one or two 25mg psilocybin doses with psychotherapy
Depression scores dropped by an average of 7.74 points from baseline at the 12-month mark—a clinically meaningful improvement that held steady from the 6-month assessment
Patients who restarted traditional antidepressants during follow-up had depression scores that were 3.79 points higher, suggesting psilocybin's effects may reduce the need for ongoing medication

Why it matters: This represents the most complete long-term data on any psychedelic therapy, showing that brief psilocybin treatment can produce lasting benefits that persist well beyond the drug's immediate effects.

🥇 Top 1% journal 🔗 Psychotherapy and psychosomatics Journal Article 🗓️ May 27

Key Findings

🧠 Psilocybin Changes DNA Methylation in Alcohol Patients

The first genome-wide study of psilocybin's epigenetic effects found significant DNA methylation changes in 37 patients with alcohol use disorder
One gene (TLE4) showed particularly strong methylation changes (p = 1.1e-7), while network analysis revealed modules linked to neuroplasticity and immune function
Changes in depression and hopelessness scores correlated with specific methylation patterns, suggesting epigenetic mechanisms may underlie psilocybin's therapeutic effects

💡 These DNA-level changes may help explain how a single psilocybin dose produces lasting therapeutic benefits.

🥉 Top 5% journal 🔗 Translational psychiatry Randomized Controlled Trial 🗓️ May 26

⚠️ Psychedelics Trigger Mania in 5.8% to 30% of Users

A meta-analysis of 23 studies found psychedelic-induced mania rates varied dramatically—from 5.8% in controlled clinical trials to 30% in people with existing bipolar disorder
Registry data from 7,478 people showed only 4% transitioned to bipolar disorder after psychedelic use, with no clear evidence that psychedelics specifically caused the transition
Higher risks appeared in people with bipolar I disorder, family history of mood disorders, and unsupervised psychedelic use

💡 While generally safe in clinical settings, psychedelics pose meaningful risks for people with bipolar vulnerability.

🥈 Top 2% journal 🔗 Molecular psychiatry Review 🗓️ May 29

🐭 Psilocybin's Social Effects Differ Dramatically by Sex in Mice

Female mice showed immediate increases in huddling and hypothermia after 1.5 mg/kg psilocybin, while males showed no comparable acute effects
At 24 hours, males became more social toward cage-mates and showed blunted dopamine responses that lasted 7 days
By day 7, females preferred familiar over novel companions and showed prolonged dopamine release during familiar social interactions

💡 Sex differences in psychedelic responses may be crucial for understanding therapeutic effects and optimizing treatment protocols.

🥉 Top 5% journal 🔗 Neuropsychopharmacology Journal Article 🗓️ May 25

💊 Study Challenges the Idea That Psychedelics Always Boost Flexibility

A comprehensive review found mixed evidence for psychedelics enhancing cognitive flexibility, with several cases showing impairment rather than improvement
Researchers propose that psychedelics may initially enhance learning from rewards (leading to perseveration) but later improve learning from negative outcomes
The timing of these effects may explain why insights reached during psychedelic experiences are often held so strongly

💡 The relationship between psychedelics and mental flexibility may be more complex and time-dependent than previously thought.

🥉 Top 5% journal 🔗 Neuroscience and biobehavioral reviews Review 🗓️ May 31

🩺 Swiss Doctors Report Real-World Psychedelic Therapy Practices

41 Swiss physicians providing legal psychedelic therapy primarily treat depression, anxiety, PTSD, and chronic pain using psilocybin (85%), MDMA (71%), and LSD (66%)
90% always play music during sessions, and emergency medication is used in only 2.4% of sessions on average
42% provide both individual and group therapy sessions, with only 9% reporting they never use co-sitters for support

💡 This rare glimpse into legal psychedelic practice reveals considerable variation in clinical methods and generally low rates of serious complications.

Top 20% journal 🔗 Therapeutic advances in psychopharmacology Journal Article 🗓️ May 25

🔬 Blinding Integrity Fails in Psychedelic Studies

In a study of 120 healthy volunteers, participants correctly identified psilocybin, MDMA, or methylphenidate (active placebo) at rates well above chance
Psilocybin showed the highest rates of functional unblinding, MDMA moderate levels, and methylphenidate the lowest
Methylphenidate worked better as an active placebo for MDMA studies than for psilocybin studies, but overall blinding remained insufficient

💡 The inability to maintain proper blinding in psychedelic trials may compromise the reliability of clinical research findings.

🥉 Top 5% journal 🔗 Eur Neuropsychopharmacol Journal Article 🗓️ May 28

Implications

This week's research reveals both the promise and complexity of psychedelic medicine. While long-term benefits appear robust, the field faces challenges around sex differences, timing of effects, patient selection, and research methodology that will need addressing as these therapies move toward broader clinical use.

Studies in this issue

Primary sources used for this newsletter.

Long-Term Effects of Psilocybin with Therapy in Hard-to-Treat Major Depression After 6 and 12 Months
main storyPsychotherapy and psychosomatics2026-05-27PMID 42201843
Mild and full mania linked to psychedelic use: a review and combined analysis
key findingMolecular psychiatry2026-05-29PMID 42215638
How well people stay unaware of treatment type in studies comparing psilocybin, MDMA, and methylphenidate in healthy volunteers
key findingEuropean neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology2026-05-28PMID 42208423
Survey of Swiss doctors’ clinical use of psychedelic-assisted therapy
key findingTherapeutic advances in psychopharmacology2026-05-25PMID 42179908
Psychedelics may not always improve mental flexibility because their changing effects influence how we learn from rewards
key findingNeuroscience and biobehavioral reviews2026-05-31PMID 42219133
Widespread DNA methylation changes linked to psilocybin use in alcohol addiction
key findingTranslational psychiatry2026-05-26PMID 42192100
Psilocybin changes social behavior differently over time in male and female mice
key findingNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2026-05-25PMID 42185639