November 2025 brought a reality check for microdosing alongside meaningful progress in macrodose psychedelic therapy. Three controlled studies testing low-dose psilocybin and LSD found that most claimed benefits either disappeared under rigorous conditions or were indistinguishable from placebo effects. At the same time, clinical trials using therapeutic doses of MDMA, psilocybin, and ibogaine showed durable symptom relief in major depression, PTSD with traumatic brain injury, and end-of-life distress in hospice patients. For healthcare providers preparing to offer psychedelic services, this month’s data underscores a clear divide: microdosing remains unproven as a treatment, while carefully supervised macrodose protocols continue to demonstrate clinical value in populations with limited alternatives.
Microdosing Claims Tested and Found Wanting
The strongest signal against microdosing came from a Phase IIb randomized trial of LSD for major depressive disorder. Eighty-nine participants received either LSD microdoses or an active placebo (caffeine) twice weekly for eight weeks. Depression scores improved in both groups, but caffeine produced slightly larger gains than LSD on the primary outcome and all secondary measures.
This followed a smaller Phase IIa open-label trial in which nineteen adults with moderate depression showed substantial symptom drops after eight weeks of flexible LSD dosing between 6 and 20 micrograms. The contrast between the two trials is stark: when expectancy was controlled with an active placebo, the LSD signal vanished entirely. Safety monitoring in the Phase IIa cohort found no cardiac valve issues, and only one participant withdrew due to anxiety.
A qualitative study of forty healthy men who microdosed 10 micrograms of LSD every third day for six weeks added texture to this picture. In-depth interviews revealed divergent experiences even within the same person: moments of calm focus alternating with agitation, restlessness, and sleep disruption. Participants in stable life situations with low ambient stress tended to report positive shifts, while those facing work pressure or interpersonal conflict described feeling wired or overstimulated.
For clinic operators, this variability poses a practical problem. If microdosing produces inconsistent effects that hinge on factors outside clinical control, it becomes difficult to predict who will benefit and nearly impossible to standardize a treatment protocol.
Psilocybin microdosing fared no better on creativity measures. A pooled analysis of three double-blind placebo-controlled trials with 171 participants found no effect on convergent thinking tasks or on the total number of ideas generated during divergent thinking tests. The only statistically significant change was a modest increase in the originality ratio of responses when dose was adjusted for body weight.
Even this effect was small and appeared only on certain scoring dimensions. For employers or wellness programs considering microdosing as a productivity tool, the data offers little support. Claims that regular low doses unlock creative potential are not holding up when tested with proper blinding and clear cognitive endpoints.
Brain Dynamics Shift Under Psychedelics But Cognitive Gains Remain Modest
Mechanistic studies this month showed how psychedelics alter brain activity patterns, but translating those changes into measurable cognitive improvement proved harder. An fMRI study of fifteen healthy adults given 75 micrograms of intravenous LSD found that local brain signal strength and regional synchrony both dropped in visual, sensory, and association networks during the acute effect. The largest changes overlapped with areas rich in dopamine D2 and serotonin 5-HT1A receptors, not just the 5-HT2A sites usually emphasized in psychedelic pharmacology.
An EEG analysis of twenty-seven volunteers receiving intravenous DMT found that theta, alpha, and beta rhythms became less structured over time, moving toward what researchers describe as a more subcritical state with higher randomness and lower complexity. Participants who reported stronger ego dissolution also showed larger drops in these timing patterns, linking a core subjective experience to a specific shift in ongoing brain rhythms.
A computational modeling study then asked whether similar shifts could be induced in digital reconstructions of patients with disorders of consciousness. When virtual brains built from real patient MRI data were perturbed under simulated psychedelic conditions, their dynamics moved closer to the balanced regime associated with conscious awareness, especially in minimally conscious patients. The effect size depended on how much structural white matter damage was present, suggesting future trials in severely injured brains would need careful patient selection based on imaging.
Long-term effects were visible in rat prefrontal cortex neurons three months after a single dose of psilocybin or the 5-HT2A agonist 25CN-NBOH. Recorded cells showed shifts in resting potential, lower firing thresholds, and altered excitatory input, yet dendritic spine counts and synaptic gene expression were unchanged. This pattern implies that enduring functional plasticity can persist without obvious structural remodeling, complicating the search for biomarkers that predict treatment response.
When these ideas were tested in humans, the results were underwhelming. Twenty-six adults with treatment-resistant depression who received open-label psilocybin-assisted therapy improved on processing speed and executive function tests over two weeks. But when researchers calculated reliable change indices to separate true gains from practice effects and measurement noise, only four to twelve percent of participants showed improvements large enough to exceed chance. For reimbursement discussions, this is a problem: payers want clear cognitive endpoints, and the current data suggest psychedelics produce measurable brain changes without consistently translating into robust improvements on standard neuropsychological batteries.
Macrodose Protocols Deliver Durable Symptom Relief Across Conditions
A follow-up study of twelve adults with moderate to severe major depressive disorder who received two MDMA-assisted therapy sessions one month apart found that depression scores dropped from around 30 at baseline to about 10 post-treatment and stayed near that level seven months later. Two-thirds of participants still met response and remission criteria at final follow-up, and functional impairment on work, social, and family scales showed similar sustained gains.
This was an open-label proof-of-principle trial with no control group, but the durability of effect without additional dosing sessions matches what has been seen in MDMA trials for PTSD. The findings strengthen the case for larger randomized studies in major depression that include extended follow-up windows.
A secondary analysis of thirty male combat veterans with traumatic brain injury and PTSD who received ibogaine in a magnesium-supported protocol found that the intensity of mystical-type experience during the session predicted larger drops in PTSD severity both immediately and one month later. Veterans who scored higher on the mystical experience questionnaire also showed bigger reductions in peak alpha frequency on EEG at one month, evidence of lasting changes in brain rhythms.
This was a single-arm study with no placebo control, so it cannot prove that mystical experiences cause symptom relief. But it adds ibogaine to the growing list of psychedelics where depth of meaning-laden experience tracks clinical response. For therapy protocols, this suggests that session preparation should emphasize emotional openness and meaning-making, not just safety monitoring.
A home hospice pilot demonstrated that a single 25 milligram psilocybin session can be delivered safely in terminally ill patients, though patient selection is extremely narrow. Out of more than 4,600 screened hospice enrollees, only ten ultimately received the intervention. Among those ten, demoralisation scores dropped by nearly nine points at week three despite ongoing physical decline, and over half met response criteria.
Qualitative interviews revealed that grief, loss, love, and peace were central themes during sessions. Many patients described a stronger sense of acceptance or inner calm afterward, though the emotional intensity was demanding for some. For hospice and palliative care teams, this work shows that psilocybin can address existential distress in a community setting with appropriate medical oversight, but the logistical and medical complexity means it will remain a highly selective option even as regulatory pathways open.
Emotional Processing Shifts Differ Between Psilocybin and Standard Antidepressants
A randomized trial comparing psilocybin to escitalopram in long-standing moderate to severe depression found that both treatments reduced negative bias in how participants interpreted facial expressions at six weeks. People were less likely to misread neutral or positive faces as negative, and they processed positive expressions more efficiently regardless of which treatment they received.
But when researchers looked at whether these changes in emotional processing predicted later mood outcomes at ten weeks, a clear link emerged only in the escitalopram group. In the psilocybin arm, mood gains were not tightly coupled to shifts in how quickly or accurately participants read emotions. This suggests that while both treatments can soften negative filters, psilocybin’s antidepressant effects may rely more on intensive, meaning-heavy experiences during dosing sessions than on a simple retuning of early emotional processing.
For clinic protocols, this means preparation and integration work should focus on supporting patients through those experiences rather than expecting automatic changes in day-to-day emotional reactivity to carry the therapeutic load.
Clinical and Policy Implications of November’s Psychedelic Research
November’s research points to three clear next steps for psychedelic service rollout. First, microdosing should not be marketed or reimbursed as a treatment for depression or cognitive enhancement until randomized controlled trials show effects that exceed an active placebo. Clinics that offer microdosing outside research contexts risk overpromising on benefits that current evidence does not support. Second, macrodose protocols for MDMA, psilocybin, and ibogaine are producing durable symptom relief in populations with high unmet need, but these interventions require skilled therapists, extended preparation and integration sessions, and careful medical screening. Staffing models will need to account for multiple hours of direct contact per patient per dosing session, not the brief check-ins typical of medication management. Third, the link between mystical-type experiences and symptom change across multiple trials suggests that training programs should teach therapists how to prepare patients for emotionally intense sessions and how to help them construct meaning from those experiences afterward. Safety monitoring must include cardiac screening for ibogaine, psychiatric history review for all psychedelics, and infrastructure for managing acute psychological distress during sessions.
Delphi remains committed to a safe and equitable rollout of psychedelic therapies grounded in evidence rather than expectation. This month’s findings make clear that not all psychedelic interventions are created equal, and that rigorous testing separates treatments that work from those that rely on placebo and hype. As regulatory pathways open and payer negotiations begin, the field must prioritize protocols with demonstrated durability, transparent reporting of adverse events, and training standards that match the intensity and complexity of the clinical work.
