Psychedelic Research Recap March 2025

Psychedelic Research Recap March 2025

Welcome back to our monthly update on psychedelic research!

This month’s research offers mixed results from clinical trials testing psychedelics for various conditions. LSD microdosing failed to help ADHD symptoms despite high expectations, while psilocybin showed uncertain benefits for alcohol use disorder in a small trial, contradicting a larger study that found positive results. More encouragingly, early research suggests psilocybin might help manage fibromyalgia pain, and a long-term follow-up study indicates that higher doses of psilocybin provide longer-lasting depression relief, though most patients see effects fade within 3-6 months.

Brain scanning studies reveal new details about how psychedelics work. DMT creates a brief but intense “destabilisation” of brain activity, particularly affecting areas rich in serotonin receptors. The largest-ever psychedelic brain imaging study found that psilocybin blurs the line between eyes-open and eyes-closed brain states, creating what researchers call “embeddedness”—a state where the boundaries between self and environment dissolve.

Researchers are also exploring the human experience of psychedelic therapy. A study on therapeutic touch during psilocybin sessions found most participants valued appropriate physical contact during intense moments, though proper consent and boundaries remain crucial. A large review discovered that “insight” experiences—sudden moments of understanding—may be even more important for healing than the mystical experiences that have received more attention. Meanwhile, European regulators highlight methodological challenges that must be addressed as the field advances toward potential approval of these treatments.

This month’s recap is made possible by our supporting members.

Check out the research link overview for all the studies we didn’t add to the database.

Assessing Psychedelic Interventions in Clinical Settings

This month, we got mixed results from the three clinical trials, one secondary analysis, and one long-term follow-up study on the outcomes of psychedelic therapies. Here we take a look at the results of these trials and the effects on ADHD, fibromyalgia, alcoholism (AUD), and depression (TRD).

Microdosing LSD for ADHD symptoms yielded disappointing results in a recent double-blind placebo-controlled trial with 53 adults. Despite administering 20μg twice weekly for 6 weeks, researchers found the treatment offered no advantage over placebo. Both groups showed similar improvements on standardised symptom measures, pointing to strong placebo/expectancy effects—80% of participants believed they were receiving LSD regardless of their actual treatment assignment. Following these underwhelming findings, MindMed, the study sponsor, has discontinued further development of this treatment approach.

The potential of psilocybin for treating alcohol use disorder remains uncertain following a double-blind randomised clinical trial involving 37 participants. A single 25mg dose with brief psychotherapy failed to significantly reduce alcohol relapse rates or consumption compared to placebo at both 4-week and 6-month follow-ups. While the psilocybin group showed a 22% lower likelihood of relapse and additional reductions in craving, these differences weren’t statistically significant. These results contrast with a larger NYU Langone Health study (n=95) that found psilocybin significantly reduced heavy drinking days during a 32-week follow-up period, suggesting that study design, patient population severity, and therapeutic protocols may significantly influence outcomes.

Chronic pain conditions like fibromyalgia may respond to psychedelic intervention, according to an open-label, proof-of-concept trial we previously covered as a preprint in August 2024. The protocol combined two psilocybin doses (15mg and 25mg) delivered two weeks apart with preparatory and integration therapy sessions. Transient blood pressure elevations and headaches were the only notable adverse effects. One month post-treatment, the five participants showed clinically meaningful improvements in pain severity, pain interference, and sleep disturbance. Patient impressions varied, with one reporting symptoms as “very much improved,” two noting “much improved,” and two indicating “minimally improved,” demonstrating potential for psychedelics in managing chronic pain conditions.

Prior antidepressant use doesn’t appear to hinder psilocybin therapy outcomes, according to a secondary analysis of an open-label clinical trial with 27 participants. The study compared treatment-resistant depression patients who discontinued antidepressants before psilocybin-assisted psychotherapy against those who were unmedicated at screening, finding no significant differences in improvements across depression, anxiety, and suicidality symptoms. Both groups experienced clinically significant benefits and reported similar psychedelic experience intensity. These findings add to the complex picture painted by previous research. Some studies suggested discontinuing SSRIs led to reduced therapeutic effects (e.g. Erritzoe et al., 2024; Gukasyan et al., 2022). Whilst another study, which introduced SSRIs in the weeks before LSD treatment (in healthy participants), actually reduced acute negative effects.

Durability of psilocybin’s antidepressant effects was examined in a one-year observational follow-up of 66 patients with treatment-resistant depression who had received single doses (25mg, 10mg, or 1mg) in two previous Compass trials. The highest dose showed the most lasting benefit, with median time to depressive relapse at 92 days for the 25mg group compared to 83 days (10mg) and 62 days (1mg). Most participants relapsed by week 12, but a post-hoc analysis focusing only on those who opted into the follow-up study (n=58) found more dramatic differences—the 25mg group maintained benefits for 189 days versus just 43 days (10mg) and 21 days (1mg). This marked difference likely reflects selection bias, as only about 25% of the original participants joined the follow-up, suggesting patients with better outcomes may have been more likely to continue participation. The overall picture indicates that while psilocybin provides substantial initial benefits, most TRD patients will experience some symptom return within 3-6 months, potentially requiring periodic maintenance sessions for sustained improvement.

Mapping Psychedelic Action in the Brain

Recent brain scanning and cell studies have taught us a lot about how psychedelics work in the brain. We now better understand how these substances change brain activity, attach to certain brain receptors, and create their mind-altering effects. Here are the three studies from this month that shed some light on how psychedelics work.

Brain dynamics undergo significant reorganisation during the DMT experience, as a computational fMRI study involving 15 participants revealed. The research team identified a distinct pattern of neural activity following intravenous DMT administration (20mg), characterised by peak destabilisation around 5 minutes post-administration. This destabilisation primarily affected fronto-parietal and visual regions, areas with high serotonin (5HT) 2A receptor density. During this period, the brain enters a state of heightened reactivity where even small perturbations can produce magnified effects, potentially explaining the profound perceptual and cognitive changes experienced during psychedelic states. The temporal (over time) evolution of these brain dynamics closely follows DMT’s pharmacokinetic profile, helping explain how even brief psychedelic experiences can have lasting psychological effects.

The contextual nature of psychedelic experiences has been demonstrated in what researchers describe as the largest psychedelic neuroimaging dataset to date. Sixty-two adults underwent fMRI and EEG scanning during various conditions (rest, meditation, music listening, and visual stimulation) before and after receiving 19mg of psilocybin. Under psilocybin, brain activity during eyes-closed states became more similar to eyes-open states—a neural signature of the reported dissolution of boundaries between self and environment. This alignment manifested as increased connectivity in brain regions involved in associative thinking coupled with decreased connectivity in sensory processing areas. The researchers introduce the concept of “embeddedness” to describe this state, where brain networks that typically separate internal and external processing become more integrated, allowing context to shape neural dynamics more directly. Machine learning analysis revealed that stronger self- and boundary-dissolution experiences produced more structured and distinct neural representations, with half of the participants ranking their experience among the five most meaningful of their lives.

At the molecular level, researchers have mapped how different psychedelic compounds interact with the 5-HT2A receptor—the primary target for classical psychedelics’ effects. Using cryo-electron microscopy, the study presented seven distinct structures showing how various psychedelic and non-psychedelic compounds bind to this receptor. While classical serotonergic psychedelics like LSD and psilocybin shared similar binding patterns, other compounds engaged with the receptor in notably different ways. These molecular interactions explain why different psychedelics produce varied subjective effects and therapeutic outcomes. The findings reveal that psychedelics don’t all work through a single uniform mechanism but rather engage multiple conformations of the receptor, leading to distinct signaling pathways. This diversity opens possibilities for developing new compounds with tailored therapeutic properties while minimising unwanted side effects—a crucial advancement for clinical applications.

These studies show how psychedelics work at different levels in the brain—from tiny molecules to whole-brain networks to what people actually feel. Psychedelics don’t just turn brain activity up or down; they change how the brain handles information and connects inner thoughts with outside experiences.

Examining the Human Experience of Psychedelic Therapy

Current psychedelic research extends beyond measuring clinical outcomes to understanding the qualitative aspects of the experience and reviewing methodological considerations. Three studies provide insights into the therapeutic mechanisms at work, patient perspectives, and research challenges that must be addressed as the field matures.

The sensitive topic of therapeutic touch during psychedelic experiences has received much-needed attention in a recent qualitative study exploring participant perspectives in psilocybin therapy for Generalised Anxiety Disorder (GAD). Most of the 18 participants valued touch during psilocybin sessions, reporting it provided connection during emotionally intense moments and helped manage overwhelming experiences. Some even attributed direct therapeutic benefits to appropriate physical contact. However, the study highlights important considerations around the inherent power imbalance between therapist and patient, already present in conventional therapy but potentially magnified in psychedelic sessions where patients may experience heightened vulnerability. The researchers emphasise that touch should be individualised, embedded within comprehensive consent processes, and provided only within the context of a strong therapeutic relationship.

Insight experiences appear to be a central therapeutic mechanism in psychedelic treatment, according to a systematic review analysing 98 studies. The review found that 86% of studies linked insight—defined as a sudden change in understanding accompanied by a feeling of certainty—to therapeutic improvement. These insight experiences proved dose-dependent and were significantly higher than placebo in 93% of comparative studies. Interestingly, when directly compared with mystical experiences (which have received more research attention), insight more frequently emerged as the stronger predictor of positive therapeutic outcomes in 55% of comparisons versus 23% for mystical experiences. The content of these insights varies widely, from psychological realisations to existential understandings, but they typically produce profound emotional shifts and remain meaningful to participants even years later. While generally beneficial, the authors note that insights can occasionally be misleading or maladaptive, warranting careful integration into the therapeutic process and better measurement tools for this important but complex phenomenon.

European regulatory perspectives on psychedelic research reveal important methodological considerations for future trials, according to a systematic review of eight completed controlled studies of psychedelics for depression. The review analysed trials testing psilocybin, LSD, ayahuasca, and DMT—all currently in Phase I/II or Phase II development—against the European Medicines Agency’s draft guideline revisions for depression treatments. Several methodological challenges emerged, including inadequate blinding strategies (none of the studies formally assessed blinding effectiveness), variable control conditions, and inconsistent reporting of adverse events in relation to subjective effects. The review highlights the difficulty of disentangling drug effects from psychological support components and notes that no classic psychedelic has yet received marketing authorisation as a depression treatment. The authors (as is also a recommendation in our report on psychedelics and reimbursement) recommend early dialogue with regulatory bodies to navigate these challenges as the field progresses toward potential approval of psychedelic-assisted therapies.