Psychedelic Research Recap December 2025

Psychedelic Research Recap December 2025

Welcome back to our (final, at least in this format) monthly update on psychedelic research!

In December 2025, we tracked research on the potential of psilocybin to prevent migraines (in a small cohort with a non-significant result), the effects of ayahuasca on mind-wandering using EEG measures, and the dose-response curve of DMT. These were the three RCTs that were published.

We also tracked four open-label pilots covering 5-MeO-DMT in combination with CBT for alcohol use disorder (showing an increase in abstinent days from 33% to 81%), LSD microdosing for major depression (mapping subjective effects), the effects of inhaled DMT on brain connectivity, and the qualitative data from a trial of psilocybin-assisted therapy for meth use disorder.

Looking at the qualitative aspect of psychedelic therapies, three studies examined the effects of psilocybin-assisted therapy. The first study examined interviews of participants with OCD and their unique challenges. The second study looked at PTSD, a topic that has additional relevance now that Compass has gotten the green light to continue trials for this patient population. The third study examines the predictors of subjective experiences, finding (unsurprisingly) that dose was the strongest predictor (and pretreatment clinical characteristics less so).

Stepping outside the lab, we covered results from psychedelic therapies in Switzerland, and the effect of psychedelics on heart-rate patterns in compassionate use programs. Taking an even broader view, researchers mapped out some parts of what it would take to get psychedelics to be integrated into European healthcare systems.

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

Check out the research link overview (now temporarily available to everyone with an account) for all the studies we didn’t add to the database.

Three Blinded Trials With Placebos

These papers sit in the “most controlled” end of human psychedelic research. They use randomisation (a fair, chance-based group allocation), blinding (so participants do not know which drug they received), and placebo or active placebo (a control pill that also produces some effects) to reduce expectation effects. This matters because psychedelics can produce strong expectancy and strong context effects, so you need tight designs to tell what the drug is doing versus what the setting is doing.

A small, double-blind randomised trial in 18 adults with migraine compared single and repeated doses of psilocybin for prevention. Participants received either diphenhydramine both times (25 mg; active placebo), diphenhydramine followed by psilocybin (10 mg), or psilocybin both times (10 mg each). The main outcome was migraine days per week, tracked with diaries from two weeks before dosing through eight weeks after the second session. In the key two-week window after dosing, the groups did not differ in a statistically significant way, although the psilocybin groups showed large effect sizes relative to the diphenhydramine-only group. Over eight weeks, all groups improved by roughly 50%, which makes it hard to credit the change to psilocybin alone. A key detail is that diphenhydramine partially replicated some of psilocybin’s acute effects, which likely made guessing group assignment more difficult but may also have boosted the control response.

What is the effect of ayahuasca on perception, mind-wandering, and EEG measures? A double-blind, placebo-controlled trial assigned healthy volunteers to ayahuasca or placebo and tracked both felt effects and brainwave changes (EEG, a cap that records electrical rhythms from the scalp). The researchers measured psychedelic effects with standard questionnaires (HRS and MEQ) and mind-wandering with the ARSQ, then recorded EEG at baseline, 2 hours, and 4 hours after dosing. Ayahuasca increased scores for altered perception, emotion, and “mystical-type” effects, and it shifted mind-wandering toward more visual and content-heavy thinking. On EEG, ayahuasca lowered global alpha (a common “resting rhythm”) and increased other bands, including delta, theta, and beta in specific regions. Two results stand out: during the session, lower theta was linked with stronger mystical-type ratings; and baseline EEG patterns before dosing predicted parts of what people later reported (for example, lower baseline theta linked with more body-focused sensations, and lower baseline beta linked with more positive emotion).

In the third RCT of December, a within-subjects, blinded, counterbalanced study (which we covered earlier as a pre-print) administered 19 participants two sessions of freebase DMT under naturalistic conditions, one at 20 mg and one at 40 mg, with the dose order randomised across participants. The key method point is that they did not just take one end-of-session rating; they paired EEG with time-resolved ratings of what the experience felt like over time (Temporal Experience Tracing). Both doses produced rapid shifts in reported experience, but the 40 mg condition produced more pronounced visual effects and greater emotional intensity. On the EEG side, the measures that best tracked moment-to-moment experience were alpha power changes and permutation entropy (a measure of signal irregularity). A notable negative finding was that Lempel–Ziv complexity, which is often used as a “brain complexity” marker in psychedelic papers, showed the weakest links with the reported experience dimensions here. That matters because it pushes the field away from treating any single “complexity score” as a stand-in for psychedelic intensity, and toward checking which signal features actually map onto what people report in real time.

Four Early Open-label Clinic Pilots

These open-label studies sit closer to “trial-as-care” than classic RCTs. Everyone knows they are getting the drug, and the main goals are usually safety, feasibility (can a clinic run this), and early signals that a bigger controlled trial is worth doing. The trade-off is that expectation and context can push results up or down, so you read outcomes as signals, not proof.

In a Phase IIa open-label proof-of-concept study of 5-MeO-DMT for alcohol use disorder, 12 people with moderate-to-severe AUD received a single intranasal dose of 5-MeO-DMT (10 mg) alongside relapse-prevention psychological support (CBT). The main message was tolerability, with the protocol described as well tolerated, and no major safety concerns were identified in the study. Regarding drinking outcomes, the paper reported a substantial increase in abstinent days, from 33% at baseline to 81% at follow-up, and that half of the participants were continuously abstinent at 12 weeks.

In an open-label LSD microdosing trial for major depressive disorder, researchers focused on participants’ lived experience rather than only symptom scores. Seventeen participants completed an 8-week course with twice-weekly dosing, then participated in semi-structured interviews, which were analysed using thematic analysis (a structured method for identifying shared themes in interview text). The dosing described was LSD microdoses in the 4–20 microgram range across 16 total doses. Many participants reported greater agency (feeling more able to act), greater connection with others, and improved mood, whereas a minority reported negative effects or no benefit.

An open-label within-subject brain imaging study looked at what inhaled DMT does to the brain’s reward network in 11 healthy volunteers who already had experience with psychedelics. Participants self-administered inhaled DMT immediately before an MRI scan, and in a control session, they underwent the same scan without DMT; the listed dose range was 50–70 mg administered once. The main finding was a drop in functional connectivity (how strongly two brain areas’ activity moves together during the scan) between the nucleus accumbens and the ventral tegmental area, two key nodes in dopamine-based reward signalling, alongside higher connectivity between the nucleus accumbens and the anterior cingulate cortex and between the medial prefrontal cortex and the anterior cingulate cortex.

In a qualitative study linked to an open-label pilot of psilocybin-assisted psychotherapy for methamphetamine use disorder, researchers interviewed 12 people in Sydney who received the intervention within an outpatient stimulant treatment service. Participants were interviewed before treatment and again about a month after, covering expectations, the acute session, and perceived changes in drug use, self-view, relationships, and meaning or spirituality. A recurring theme was that difficult moments during the session were often described as contributing to the therapeutic process, provided therapist support was strong.

How Experience Links to Change

These papers focus on the lived side of psychedelic treatment and how the session is experienced and interpreted. Two use interviews embedded in trials to capture the acute experience and how participants described change afterwards. The third uses a larger clinical dataset to test whether baseline clinical features strongly shape the acute psychedelic experience, rather than assuming that “set” is the main driver.

In a qualitative analysis from the first randomised, double-blind, placebo-controlled trial of psilocybin for treatment-refractory obsessive-compulsive disorder, researchers analysed interviews with 12 participants who received a single 17.5 mg psilocybin session with non-directive support. They used interpretative phenomenological analysis (IPA), which seeks shared themes in first-person accounts while maintaining visibility of individual differences. Several participants described the acute effects as less intense than expected, and the authors suggest OCD symptoms may compete with or blunt parts of the psychedelic experience. Even so, many participants described meaningful post-dosing shifts, including changes in how they related to obsessions and compulsions, in ways that resembled targets in standard OCD therapies (for example, learning to sit with discomfort rather than trying to neutralise it).

In a qualitative sub-study of psilocybin treatment for PTSD, researchers interviewed 21 participants who received a single 25 mg dose of COMP360 psilocybin as part of a Phase II programme focused on safety and tolerability. The interviews explored how people engaged with trauma material during and after dosing, and how this differed from standard PTSD care. Many participants described engaging trauma both directly (clear memories or images) and indirectly (through body sensations, emotions, or broader themes about self), rather than needing a single explicit retelling of events. They also described processing that differed from typical exposure-based work, including shifts in meaning, self-compassion, and how threat responses manifested in the body.

In a secondary analysisof COMP360 psilocybin in treatment-resistant depression, researchers tested what predicts the “quality” of the acute psychedelic experience using data from 233 participants who received a single dose of 1 mg, 10 mg, or 25 mg. They assessed acute experience using the 5D-ASC (a questionnaire that breaks altered states into several dimensions) and the Emotional Breakthrough Inventory, which focuses on catharsis and emotional release. Using regression models (a method for estimating which factors explain differences in outcomes), they found that dose was by far the strongest and most consistent predictor of the acute experience. Baseline features such as affect, anxiety symptoms, and executive functioning showed only small and inconsistent links with parts of the experience.

Real-world Outcomes and Safety Checks

The final group of papers use retrospective data, meaning the researchers look back at medical records from routine care or compassionate-use treatment, rather than running a planned randomised trial. That makes them highly useful for clinics, because the patients and workflows resemble day-to-day practice. The main limit is also clear: without randomisation and a control group, you cannot separate drug effects from selection effects (who gets offered treatment), added support around the dosing, and normal symptom swings over time.

In a Swiss retrospective study of real-world psilocybin therapy for treatment-resistant depression, researchers reviewed records from 19 patients treated at the Psychiatric University Hospital Zurich. Psilocybin doses ranged from 20 to 35 mg, and patients received between 1 and 4 sessions. Depression was measured with MADRS (a clinician-rated depression scale) and BDI-II (a self-report scale). Symptoms declined in a clinically meaningful way, but response and remission rates were lower than those typically reported in tightly controlled clinical trials. In this small sample, the paper also did not find a clear benefit of additional dosing sessions.

In a retrospective compassionate-use dataset comparing LSD and psilocybin, researchers analysed heart-rate patterns in 30 patients treated for depressive or anxiety disorders. Doses were 100–200 micrograms for LSD and 15–30 mg for psilocybin. The key finding was the time course: LSD showed a delayed but sustained heart-rate rise that peaked around 3–4 hours, while psilocybin showed an earlier pattern that tended to fall rather than rise later in the session. The statistical analysis supported a time-by-drug interaction, indicating that heart-rate curves differed across the session, even when averages were not always substantially different at each time point. No serious cardiovascular adverse events were reported.

Finally, a review by Gründer and colleagues argues that obtaining approval of a psychedelic therapy by the European Medicines Agency is only the first step, and that real patient access in Europe will largely be determined by national health technology assessment (HTA) bodies that control reimbursement. The authors explain that HTA agencies assess “added value” relative to current standard care and consider cost-effectiveness and broader system impact, not just whether a treatment outperforms placebo. That creates a specific problem for psychedelic-assisted therapy: most trials are placebo-controlled, while HTA bodies often want active-comparator data against existing treatments, and there are very few such head-to-head studies. The paper also points out that these treatments combine a drug with structured psychological support, which makes it hard to price, measure, and compare the full package using current HTA methods, and it notes that different country agencies (for example in the UK, Germany, and France) can reach different decisions even with the same evidence, leading to uneven access across Europe.

See our report on psychedelics and reimbursement for much more on this topic.