Psychedelic Research Recap September 2025
Psychedelic Research Recap September 2025
Welcome back to our monthly update on psychedelic research!
September 2025 saw clear advances in psychedelic research, especially in anxiety, depression, and addiction treatments. A major trial showed that a single dose of lysergide (MM120) significantly reduced anxiety in generalised anxiety disorder without additional psychotherapy. Another study found that combining psilocybin with mindfulness-based therapy improved depressive symptoms among healthcare workers more than mindfulness alone. Early-stage trials also suggested promising outcomes for psilocybin in treating methamphetamine addiction and for ayahuasca-assisted therapy in alleviating severe grief.
Human lab studies further defined MDMA’s unique effects, showing enhanced feelings of community-level trust not observed with methamphetamine, and demonstrating that its close relative, MDA, produces longer-lasting and stronger subjective experiences. Mechanistic research provided fresh insights by linking brain activity changes directly with subjective experiences under DMT, aligning closely with earlier studies of other psychedelics. However, LSD microdosing trials found minimal evidence for pain relief, highlighting questions about dosing thresholds and tolerance.
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.
MDMA and MDA in controlled trials
MDMA and MDA sit in the same family, but do not feel the same. Here we cover two human studies: a within-person lab comparison of MDMA, MDA, and lysine “prodrugs,” and a social study that sets MDMA against methamphetamine.
In a five-arm crossover study with healthy volunteers (n=23), equimolar MDMA (100 mg) and MDA (92 mg) were compared alongside lysine-MDA and lysine-MDMA. MDA produced stronger and longer effects than MDMA (about 6.1 vs 4.1 hours), with more stimulation, more visual changes, and more “bad drug effects.” Lys-MDA behaved like a slow-release MDA, delaying onset and peak but not softening peak intensity. Lys-MDMA failed to release MDMA and was essentially inactive. All active arms raised vital signs as expected; MDMA and MDA also increased oxytocin, a hormone linked to social bonding. Taken together, the signal is clear: MDA has a punchier, more psychedelic-leaning profile and a tighter tolerability window than MDMA.
Two small, placebo-controlled studies tested social attitudes after a structured chat. On 100 mg MDMA (n=15), people reported higher “global trust” in their community and society shortly after the session; the matched placebo session did not show this shift. A separate study with 20 mg methamphetamine (n=20) found no change in trust or other social-well-being scores versus placebo. The contrast supports a distinct prosocial effect with MDMA that does not generalise to a standard stimulant comparator. How long this trust effect lasts beyond the acute window remains to be shown.
Tryptamines and How They May Help
Psilocybin and ayahuasca sit in the same broad family (tryptamines). This section groups two psilocybin trials, one ayahuasca therapy study, and one DMT brain-imaging reanalysis. Together, they touch clinical signals (depression, burnout, substance use, grief) and mechanisms (how the brain changes during a DMT state).
A randomised trial tested psilocybin plus mindfulness-based stress reduction (MBSR) for frontline clinicians with depression and burnout. The combo arm (group psilocybin-assisted therapy with a 25mg dose inside an 8-week MBSR course) beat MBSR alone on depression at two weeks, with no serious adverse events. Gains on burnout, demoralisation, and connectedness also leaned toward the combo, though most secondary effects did not hold after multiple-testing correction.
An open-label pilot in methamphetamine use disorder delivered one 25 mg psilocybin session with brief prep and integration built on motivational enhancement and ACT. It was feasible and safe in an outpatient clinic. Meth use days dropped to zero at day-28 and rose modestly by day-90; craving and distress fell, and well-being rose. With no control group and small N, these are signals, not proof.
A three-arm, non-randomised study of ayahuasca-assisted meaning reconstruction therapy for recent bereavement reported larger drops in severe grief than therapy alone or no treatment. The ayahuasca group also showed gains in post-traumatic growth and quality of life. No serious adverse events were reported. Because allocation was sequential and open-label, expectancy and selection effects are possible. Still, the effect sizes are large enough to justify a randomised trial of early grief care.
A reanalysis of two DMT datasets used connectome harmonic decomposition to map how brain activity plays out over the brain’s wiring. Under DMT, the brain shifted toward higher-frequency “harmonics,” and the diversity of patterns (entropy) rose, in line with prior reports for psilocybin, LSD, and ketamine. Crucially, these metrics tracked the moment-to-moment intensity people reported during the dose. This links subjective experience to measurable changes in brain dynamics and supports a shared signature across classic psychedelics.
Two LSD Studies
Lysergamides (LSD family) act mainly at the 5-HT2A receptor. This final section covers a Phase IIb trial in generalised anxiety disorder (GAD) using MM120 without psychotherapy, and a microdose study in healthy people testing pain tolerance.
In a Phase IIb trial of MM120 for GAD, a single session with 100 µg or 200 µg MM120 reduced anxiety significantly at week 4 compared to placebo, and these benefits persisted through week 8. Lower doses (25 µg and 50 µg) showed no meaningful difference from placebo. Visual changes, nausea, and headache were common but generally brief side effects. Crucially, the trial did not involve any accompanying psychotherapy, meaning the improvements seen were purely from the drug. Based on efficacy and tolerability, 100 µg appears most suitable for further testing in Phase III trials.
A LSD microdosing study for pain found that over four sessions, LSD microdoses (15 µg) failed to improve pain tolerance or reduce pain ratings compared to placebo, as assessed by the Cold Pressor Task. LSD did modestly increase blood pressure, which correlated with better pain tolerance, but subjective experiences of drug effects did not relate to pain outcomes. A secondary analysis excluding individuals who hit the maximum pain-tolerance threshold found marginal improvements after just the first dose, indicating 15 µg may be too low or repeated dosing might lead to rapid tolerance.
Papers Published in September 2025
11 studies from the Blossom database published this month.
Meditation, psychedelics, and brain connectivity: A randomized controlled resting-state fMRI study of N,N-dimethyltryptamine and harmine in a meditation retreat
In a double-blind, placebo-controlled resting-state fMRI study of 40 meditation practitioners, buccal DMT–harmine increased functional connectivity within the visual network and between visual and attention/salience networks, whereas meditation with placebo produced greater network segregation. No prolonged disruption of cortical gradients was observed, indicating a return to typical brain organisation shortly after the experience and pointing to distinct neural mechanisms — and potential clinical complementarities — between meditation and psychedelic-augmented meditation.
Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA in a randomized, double-blind, placebo-controlled, crossover trial in healthy participants
In a randomized, double-blind, placebo-controlled crossover in 23 healthy volunteers, MDA produced longer‑lasting, stronger and more psychedelic‑like subjective and autonomic effects and more adverse reactions than equimolar MDMA. Lys‑MDA acted as a functional slow‑release prodrug that delayed onset and peak effects, whereas Lys‑MDMA did not release MDMA and produced no measurable effects, showing lysine conjugation can alter timing but not necessarily improve tolerability.
Psilocybin-assisted psychotherapy for methamphetamine use disorder: A pilot open-label safety and feasibility study
In a single‑arm, open‑label pilot of 15 people with methamphetamine use disorder, outpatient psilocybin‑assisted psychotherapy (single 25 mg oral dose with preparatory and integration sessions) was feasible and well tolerated with no serious adverse events, and was associated with reductions in self‑reported methamphetamine use and craving at 28 and 90 days; a larger randomised trial is required to confirm efficacy and safety.
The empathogen 3,4-methylenedioxymethamphetamine, but not methamphetamine, increases feelings of global trust
In two placebo-controlled studies, a single dose of MDMA (100 mg) increased participants’ feelings of global trust and marginally raised self-worth 90 minutes after a conversation, whereas methamphetamine (20 mg) produced no change. These results indicate MDMA uniquely enhances generalized social trust beyond lab-specific partners, supporting its potential social‑psychological clinical value.
N,N-dimethyltryptamine effects on connectome harmonics, subjective experience and comparative psychedelic experiences
This neuroscience secondary (n=25) of two earlier studies used connectome harmonic decomposition to analyse how DMT affects brain function across the structural connectome (white matter pathways), finding that DMT reshapes the connectome harmonic repertoire and increases repertoire entropy similarly to other psychedelics (psilocybin, LSD, ketamine), and importantly demonstrating for the first time that energy spectrum differences and repertoire entropy measures correlate with subjective experience intensity in a time-resolved manner, revealing close coupling between connectome harmonics and conscious experience under psychedelics.
A randomised placebo-controlled study of the effects of lysergic acid diethylamide microdosing (15 μg) on pain perception in healthy volunteers
In a randomised placebo‑controlled trial in healthy volunteers, repeated 15 µg LSD microdoses produced no overall analgesic effects on cold‑pressor pain tolerance or subjective pain ratings, despite increasing blood pressure and subjective drug effects. Post‑hoc analyses in participants without baseline ceiling effects suggested a transient increase in pain tolerance and reduced unpleasantness after the first dose, implying the dose may be below the threshold for consistent analgesia and that larger studies with higher doses are needed.
Ayahuasca-assisted meaning reconstruction therapy as an early resource for bereavement: a non-randomized clinical trial
In this non-randomised, three-arm clinical trial of 84 adults bereaved within 12 months, ayahuasca-assisted meaning reconstruction therapy (A-MR) was well tolerated and produced significantly larger reductions in grief severity and greater improvements in prolonged grief symptoms, post‑traumatic growth and quality of life than meaning reconstruction alone or no treatment. These preliminary findings support A-MR as a potentially effective early intervention for severe grief but require replication in larger randomised trials.
Cross-Species Evidence for Psilocin-Induced Visual Distortions: Apparent Motion Is Perceived by Both Humans and Rats
This cross-species experimental study (n=21 humans; n=10 rats) finds that psilocin (18.2mg/70kg for humans; 0.3mg/kg for rats) impairs the ability to distinguish between static and moving images in both humans and rats. In humans, the impairment aligns with psilocin plasma levels and self-reported hallucination intensity. In rats, the effect is specific to motion perception, providing the first evidence of psilocin-induced visual distortions across species.
Efficacy and safety of low- versus high-dose-LSD-assisted therapy in patients with major depression: A randomized trial
This double-blind controlled trial (n=61) found that high-dose LSD-assisted therapy (100μg + 200μg) reduced depression symptoms more than low-dose LSD (25μg + 25μg) in patients with moderate-to-severe major depressive disorder (MDD), with benefits lasting up to 12 weeks and similar side effects between groups.
Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial
In a phase 4, multicentre, double-blind randomised trial in adults with treatment‑resistant depression, intranasal esketamine monotherapy (56 mg and 84 mg) produced significant reductions in MADRS score versus placebo at day 28 (LS mean differences −5.1 and −6.8; effect sizes 0.48 and 0.63) and demonstrated rapid benefit at 24 hours. The tolerability profile was consistent with prior reports, most commonly nausea, dissociation, dizziness and headache.
Psilocybin-assisted psychotherapy for depression and anxiety associated with life threatening illness: A phase 2b randomized controlled trial
This double-blind placebo-controlled trial (n=35) found that psilocybin-assisted psychotherapy (25mg) significantly reduced depression and anxiety symptoms in adults with life-threatening illnesses compared to an active placebo (100mg niacin), with benefits sustained at 26 weeks and improvements in spiritual well-being, quality of life, demoralisation, and death anxiety.