Psychedelic Research Recap November 2025

Welcome back to our monthly update on psychedelic research!

November 2025 was a noticeably busier month for psychedelic research, with new papers landing across microdosing trials, mechanistic work on brain dynamics, and early clinical studies in highly vulnerable populations. In this recap, we start with three studies refining what microdosing can realistically offer for mood, creativity, and lived experience, before turning to a cluster of mechanistic papers on criticality and plasticity in the brain. We then look at emerging macrodose treatments for depression, PTSD, and end-of-life distress, and close with work exploring mystical experiences, 5-MeO-DMT phenomenology, and how ayahuasca use interacts with our deep-seated responses to death.

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

Microdosing Psychedelics Under Close Scrutiny

Microdosing has moved from niche practice to mainstream trend, with many people saying it boosts mood, focus, and creativity without the intense effects of a full psychedelic dose. The three studies in this section test those claims in more controlled ways: a detailed interview study in healthy men, an open-label trial in people with major depression, and a pooled analysis of three psilocybin microdosing trials on creativity. Together with a recent Phase IIb trial of LSD microdosing for depression that failed on all endpoints against an active placebo, they suggest that any real effects are subtle, context-sensitive, and often hard to separate from expectation and placebo.

The qualitative LSD microdosing study followed 40 healthy men who took 10 micrograms of LSD every third day for six weeks in a double-blind, randomised trial. Two days after the final dose, they took part in in-depth video interviews about how the regimen had affected their mood, thinking, social life, and body. Many described feeling a little brighter on dose days, more relaxed, more open in conversations, and more able to enjoy everyday activities such as music or walks. At the same time, others reported spikes in anxiety, restlessness, sleep disruption, and feeling overstimulated. Across themes like mood, social contact, focus and energy, effects ran in both directions: the same person might feel calm and clear at one moment and tense or “wired” at another. The study also shows how much set and setting matter, even at these low doses. Calm surroundings and a stable life situation supported positive effects, while stress at work or at home could tip experiences into agitation.

The open-label Phase IIa LSD microdosing trial in major depressive disorder sits at the centre of current debate about microdosing as a treatment. Nineteen adults with moderate depression, most already on antidepressants, took LSD twice a week for eight weeks, with flexible doses between 6 and 20 micrograms. The regimen was easy to follow, there were no serious side effects, one person stopped due to anxiety, and detailed heart checks found no signs of valve problems, which has been a safety worry for repeated LSD use. On symptom scores, the results looked very strong: average MADRS scores (a standard scale for depression) fell by almost 60%, and many participants met responder and remission criteria, with gains lasting up to six months. On its own, this could be read as a major success. But the larger Phase IIb randomised trial from the same programme, with 89 participants and an active placebo (caffeine), did not show any benefit of LSD over placebo on the same depression scale or any secondary measures. In fact, the placebo arm improved slightly more. Taken together, the Phase IIa and IIb data suggest that while people can do well during an open-label microdosing course, much of that change may come from expectancy, support, and natural swings in symptoms rather than the small LSD doses themselves.

A psilocybin microdosing creativity meta-analysis tackles a different claim: that microdosing makes people more creative. Prochazkova and colleagues pooled data from three double-blind placebo-controlled trials, with 171 participants who microdosed psilocybin truffles on a regular schedule. Creativity was broken down into two parts. Convergent thinking meant finding a single correct link between items; divergent thinking meant coming up with many uses or ideas for a common object. Across the combined data set, microdosing did not change convergent thinking and did not increase the number of ideas people produced. What did change was the quality of those ideas: the originality ratio went up, especially when dose was adjusted for body weight, meaning that people produced fewer but slightly more original responses. These effects were modest and only showed up on some measures, even in a well-powered pooled analysis that controlled for dose guesses and prior psychedelic use. In other words, when microdosing is tested with strong blinding and clear tasks, it may nudge certain aspects of creative output, but far less than many public claims suggest.

How Psychedelics Reshape Brain Dynamics

Psychedelics are often described as “shaking up” brain activity, but that can mean different things at different scales. The studies in this section look at local brain activity and connectivity under LSD, the timing patterns of EEG signals under DMT, and computer models of psychedelic effects in patients with disorders of consciousness. They then link this to long-lasting changes in rat prefrontal neurons and to modest cognitive shifts in people with treatment-resistant depression. Together, they suggest that psychedelics nudge the brain’s dynamics away from their usual groove and can leave a long tail of functional change, even when clear cognitive benefits are hard to show in small clinical samples.

The LSD fMRI analysis focuses on simple resting-state measures: how strong slow brain signals are (ALFF) and how tightly nearby voxels move together (regional homogeneity). In 15 healthy adults given 75 micrograms of intravenous LSD, both measures dropped in visual and sensory cortices, and ALFF also dropped in association networks like the default mode and fronto-parietal networks that support self-related thought and control. Local synchrony (ReHo) fell in subcortical hubs. When the authors overlaid these maps with receptor density atlases, the strongest changes sat in regions rich in dopamine D2 and serotonin 5-HT1A receptors. That fits with LSD’s broad pharmacology and hints that its acute effects on local activity are not only about 5-HT2A, but about a wider set of receptor systems that tune how stable or “locally coherent” brain activity is.

The DMT EEG paper zooms in on how brain rhythms behave over time, using the idea of “criticality” – the sweet spot between rigid order and random noise. In 27 volunteers from two placebo-controlled studies, intravenous DMT pushed theta, alpha and beta bands away from this balanced state. A standard timing metric (DFA) went down, meaning the signals became less structured over long timescales and more like random noise, which the authors describe as higher entropy and lower complexity. A model-based index of excitation-inhibition balance suggested that these bands moved towards a more “subcritical” regime, where inhibition dominates. Crucially, people who reported stronger self-dissolution also showed larger drops in DFA in theta and alpha. That links a core psychedelic experience – losing the usual sense of self – to a specific pattern in ongoing brain rhythms, and sets up the next study that asks what happens when you push damaged brains closer to criticality instead.

The virtual disorders of consciousness trial uses whole-brain models as “digital twins” of patients with unresponsive wakefulness syndrome and minimally conscious state. The team built personalised models from each patient’s structural and functional MRI, then tuned them so that the simulated networks matched real resting-state connectivity. They then applied parameter shifts derived from real LSD and psilocybin data and probed the models with brief perturbations. A metric called PILI, which tracks how long the network takes to settle after a push, was lower in anaesthesia and DoC and higher under psychedelics, matching the idea that rich conscious states sit closer to criticality. When simulated psychedelics were applied to patient models, brain dynamics moved closer to this balanced regime, especially in minimally conscious patients. In unresponsive wakefulness syndrome, the size of this effect depended on how intact the structural wiring was; in minimally conscious state it depended more on baseline functional connectivity. This work does not show that psychedelics “wake up” patients, but it offers a mechanistic bridge between criticality models and potential future trials in severely injured brains.

The rat study on psilocybin and the 5-HT2A agonist 25CN-NBOH tackles a different level of brain change: long-term plasticity. A single dose of either drug reduced immobility in the forced-swim test – a standard proxy for antidepressant-like behaviour – and this effect was still present three months later. When the authors recorded from layer 5 pyramidal neurons in the infralimbic medial prefrontal cortex around 100 days after dosing, they found lasting changes in how these cells functioned: resting membrane potentials were shifted, firing thresholds were lower, and excitatory synaptic input was altered. Yet when they counted dendritic spines and looked at gene expression for synaptic markers, they saw no differences from controls. The message is that enduring behavioural effects can be carried by long-term tuning of excitability and synaptic strength, without obvious, stable changes in spine number. That fits well with human data suggesting that functional metrics – like criticality or local activity patterns – may be more sensitive long-term readouts than gross structural measures.

The post-hoc psilocybin cognition analysis in treatment-resistant depression brings these brain-level ideas back to clinical reality. In 26 adults with long-standing TRD or bipolar depression, an open-label psilocybin-assisted therapy protocol led to clear symptom relief and small but statistically significant gains on tests of processing speed and executive function over two weeks. When the authors adjusted for changes in depression severity, improvements on Trail Making Tests A and B – especially the extra “cost” of the harder task – stayed significant, suggesting some mood-independent effect, whereas gains on the Digit Symbol test largely washed out. But when they looked at reliable change indices, only around 4–12% of participants showed cognitive improvements large enough to exceed what you would expect from practice and noise, and that rate was not above chance. In other words, even though imaging and animal studies show that psychedelics reshape brain dynamics and produce long-lasting functional plasticity, robust cognitive benefits in small TRD cohorts remain modest and uncertain, at least with the brief battery and short follow-up used here.

Therapeutic Macrodosing and Clinical Outcomes

High-dose psychedelic sessions are where clinical hopes are highest, and the ethical stakes are sharpest. The four studies in this group span MDMA-assisted therapy for major depressive disorder, ibogaine for combat veterans with PTSD and traumatic brain injury, psilocybin for terminally ill hospice patients facing the end of life, and psilocybin versus escitalopram for depression, focusing on how people read emotional cues. Together they highlight two recurring themes in this field: first, that the quality of the acute experience (mystical, emotional, relational) often tracks clinical change; second, that even when outcomes look similar on depression scales, the underlying psychological shifts and durability of effect can differ.

The MDMA-assisted therapy follow-up study adds an important (first) long-term signal for major depressive disorder. Twelve adults with moderate-to-severe MDD received two day-long MDMA sessions one month apart, embedded in nine preparatory and integration sessions. On clinician-rated depression (MADRS), mean scores fell from around 30 at baseline to about 10 post-treatment and stayed near that level seven months after baseline; two-thirds of the sample still met response and remission criteria at follow-up. Functional impairment on the Sheehan Disability Scale showed a similar pattern, with marked gains that were maintained without further structured therapy. Self-report measures of depression, anxiety, PTSD symptoms, and insomnia all improved and stayed better at follow-up, and suicidal ideation did not rise above pre-study levels. As an open-label proof-of-principle trial with only 12 participants and no control group, this is far from definitive, but it mirrors the sustained benefits seen in MDMA trials for PTSD and strengthens the case for larger, controlled MDD studies that include long-term follow-up and, likely, more than two dosing sessions.

The magnesium-ibogaine study looks at 30 male veterans with traumatic brain injury and PTSD who received ibogaine in a protocol designed to reduce cardiac risk. This secondary analysis zooms in on how the intensity of mystical-type experience, measured by the MEQ30, related to symptom change. Veterans who scored higher on mystical experience showed larger drops in PTSD severity both right after treatment and one month later, even after adjusting for other factors in mixed models. The same group also showed bigger reductions in peak alpha frequency on EEG at one month, a sign that ibogaine leaves a lasting mark on brain rhythms. As an open-label, single-arm study, it cannot prove that mystical experiences cause symptom relief, but it adds ibogaine to the growing list of psychedelics where depth of “mystical” or meaning-laden experience seems to track clinical response, setting up clear questions for future controlled trials.

The hospice pilot moves this focus on meaning and emotion into one of the hardest treatment settings: home hospice. Out of more than 4,600 screened patients, only ten ultimately received a single 25 mg psilocybin session embedded in a brief course of home-based preparation and integration. That low yield underlines how frail, complex and medically constrained this group is. Among those who did receive psilocybin, demoralisation scores dropped by almost nine points at week three despite ongoing physical decline, and over half met response criteria, with no serious adverse events linked to the drug. Qualitative data show that themes of grief, loss, love and peace were central during sessions; many patients described a stronger sense of acceptance or inner calm afterwards, though some found the emotional intensity demanding. Where the ibogaine study links mystical scores to PTSD change, this hospice work shows that a single psilocybin day can be practically delivered in a community hospice and can shift existential distress, at least for a carefully selected subgroup.

The psilocybin versus escitalopram analysis comes from a randomised trial in long-standing moderate-to-severe depression, and asks a more mechanistic question: how do these treatments change “affective bias” in reading facial expressions? Both groups improved on depression scores in the main trial, and here both also showed a reduction in negative bias on a facial emotion recognition task at six weeks. People were less likely to misread neutral or positive faces as negative, and they processed positive expressions more efficiently after treatment, whether they had received two high-dose psilocybin sessions plus placebo capsules or daily escitalopram plus very low psilocybin. That suggests some shared shift in how emotional information is processed. But when the team looked at whether changes in bias predicted later mood outcomes at ten weeks, a clear link emerged only in the escitalopram group: fewer misclassified positive faces went along with bigger later drops in depression. In the psilocybin arm, mood gains did not line up neatly with bias change, hinting that while both treatments can soften negative filters, psilocybin’s antidepressant effects may rely more on other processes – such as the kind of intensive, meaning-heavy experiences captured in the ibogaine and hospice studies – than on a simple retuning of early emotional processing.

Death, Meaning, and Altered States

Psychedelic science often returns to what people actually feel and remember during and after a session. These three studies stay close to that core. One tests a strong standardised DMT–harmala capsule in healthy volunteers. One maps the fast profile of intranasal 5-MeO-DMT in psychedelic-naïve participants. The last examines how long-term ayahuasca users respond to death-related cues, both consciously and in automatic brain responses. Together they show that powerful psychedelic states can be shaped precisely, that very short sessions may still touch deep emotional themes, and that feeling more at peace with death does not necessarily rewrite the brain’s basic defences.

The pharmahuasca Phase I study tested an encapsulated mix of DMT and three harmala alkaloids in nine experienced healthy volunteers, using purified plant extracts and weight-based dosing. Across 17 sessions, higher doses produced higher mystical experience scores, with the most purified formulation yielding scores among the highest in modern psychedelic literature. One week later, those with stronger mystical experiences reported more personal insight, positive mood shifts, and rated the session as one of the most meaningful events in their lives. Compared with a large ayahuasca survey, high-dose pharmahuasca sat at the upper end of what people typically report in ceremonial settings—suggesting a standardised oral capsule can reliably induce “ayahuasca-level” experiences under clinical control.

The intranasal 5-MeO-DMT trial takes the opposite approach: a short-acting compound, delivered nasally, in psychedelic-naïve participants, with close qualitative tracking minute by minute. In this Phase I study, 32 healthy adults received escalating doses or placebo in a double-blind design, then completed microphenomenology interviews. Reports showed onset within one to two minutes, peak between 8 and 15 minutes, and return to baseline by 45–60 minutes. Visual effects were limited; the centre of gravity was bodily and emotional, with waves of joy, fear, relief, or grief, shifts in self-sense, and frequent descriptions of letting go or resisting. Higher doses brought more intense but well-tolerated experiences, with many describing emotional release once they had “stopped fighting.” This profile suits clinical work: short sessions, strong but narrow-window effects, and clear need for preparation around surrender and trust.

The ayahuasca MEG study asks whether years of ceremonies actually change how the brain automatically responds to death-related information. Using a visual mismatch paradigm in a magnetoencephalography scanner, the authors compared long-term ayahuasca users with meditators and non-meditating controls. Consciously, ayahuasca users reported less fear of death and showed less implicit fear on reaction-time tasks. But when brain responses to “death + self” cues were measured without any behavioural response required, their pattern resembled the general population: a marker of death denial remained, unlike in meditators where this marker was reduced. Stronger neural death denial was linked to lower death acceptance but also higher life satisfaction, suggesting this defence may be adaptive. The emerging picture is layered: ayahuasca may soften fear and change how people consciously relate to death, while leaving deeper unconscious protective processes largely intact.

What you can find on Blossom

Last month, we added 15 studies to the database of over 2250 research publications. Our link overview provides links to 150 psychedelic studies published in November 2025.

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