Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
Biological Psychiatry
September 15, 2023
Robin J Murphy, Rachael Sumner, William Evans et al.
69 citations
Microdosing LSD (10 μg every three days for six weeks) in healthy adult men produced transient improvements in creativity, connectedness, energy, happiness, irritability, and wellness on dose days compared with nondose days, even after controlling for preintervention expectancy. However, no enduring changes in overall mood or cognition were observed between baseline and six-week assessments. The most notable adverse event was treatment-related anxiety, which led four participants in the LSD group to withdraw. Microdosing appears relatively safe in this population but does not support claims of lasting mood or cognitive benefits.
Journal of psychopharmacology (Oxford, England)
August 1, 2021
Rachael Sumner, Emme Chacko, Rebecca McMillan et al.
68 citations
Ketamine, given at 0.44 mg/kg to 32 volunteers with major depressive disorder in a crossover design with the active-placebo remifentanil, produced psychedelic experiences that correlated with greater antidepressant response at 24 hours. Specifically, higher scores on spirituality, experience of unity, and insight were linked to larger reductions in depression ratings. Qualitative interviews revealed perceptual changes, loss of control, emotional shifts, a psychedelic afterglow, and lasting changes in perspective on life, people, problems, and depression. The findings suggest the psychedelic experience and afterglow contribute to ketamine's antidepressant effects, and that standard questionnaires may not fully capture these properties.
Australian & New Zealand Journal of Psychiatry
March 4, 2022
Suresh Muthukumaraswamy, Anna Forsyth, Rachael Sumner
59 citations
The psychedelic renaissance has generated excitement about potential medical uses, but the field faces significant challenges that must be addressed. This viewpoint identifies three categories of challenges: research study design issues including blinding, expectancy, therapy use, and bias; broader research environment problems such as evidence standards, funding, and scheduling that contradicts risk profiles; and implementation hurdles related to social and economic contexts. The authors offer suggestions for improving research protocols to mitigate these challenges.
Pilot and Feasibility Studies
October 5, 2023
Carina Joy Donegan, Dimitri Daldegan-Bueno, Rachael Sumner et al.
23 citations
An estimated 260 million people worldwide have depression, and many self-treat with microdoses of psychedelics like LSD and psilocybin despite limited clinical evidence. A prior phase 1 study in healthy volunteers found LSD microdosing safe, well tolerated, and feasible with good adherence. This open-label pilot trial (LSDDEP1) will test tolerability and feasibility of an 8-week LSD microdosing regimen in 20 patients with major depressive disorder. Participants receive a sublingual LSD formulation (MB-22001) twice weekly at 5–15 µg. Tolerability is measured by withdrawal due to adverse events; feasibility by clinic visit attendance. Antidepressant response will be assessed with MADRS scores over 8 weeks. Results will inform a future randomized controlled trial.
Trials
April 23, 2021
Robin J Murphy, Rachael Sumner, William Evans et al.
23 citations
A proposed study will test whether regular low doses of LSD, known as microdosing, produce the cognitive and emotional benefits reported anecdotally. Eighty healthy men will receive either a placebo or 10 micrograms of LSD every third day for six weeks. The study will measure personality, creativity, mood, cognition, brain plasticity, and brain imaging at baseline and after the protocol, with additional acute measures after the first dose. Daily functioning will be tracked via questionnaires and a wearable device. The goal is to rigorously evaluate microdosing claims using objective measures, with potential future applications for treating depression, addiction, and other conditions.
BMC Neuroscience
February 5, 2024
Robin J Murphy, Kate Godfrey, Alexander D Shaw et al.
16 citations
Microdosing psychedelics is claimed to improve cognition, but clinical evidence is limited. In a placebo-controlled trial, 80 healthy adult males took 10 µg of LSD or placebo every third day for six weeks. A visual long-term potentiation (LTP) EEG paradigm measured neural plasticity indirectly. Standard event-related potential (ERP) analyses of N1b and P2 components showed no evidence of changes in LTP from LSD, either acutely or after six weeks. However, dynamic causal modeling of the ERP timecourse using a thalamocortical model revealed changes in laminar connectivity in primary visual cortex, including acute changes to self-gain and inhibitory input parameters and differences in excitatory connectivity from layer 2/3 to layer 5 between...
Translational Psychiatry
April 15, 2024
Nathan Allen, Aron Jeremiah, Robin J Murphy et al.
15 citations
Microdosing LSD (10 µg every third day for six weeks) increased sleep duration in healthy adult male volunteers. On nights after dosing, the LSD group slept an extra 24.3 minutes per night compared to placebo, with no change in sleep on dosing days. Sleep stage proportions and physical activity remained unchanged. The findings indicate that microdosing LSD modifies physiological sleep requirements, and the objective changes are unlikely to be a placebo effect.
Psychopharmacology
February 1, 2025
Robin J Murphy, Rachael Sumner, Kate Godfrey et al.
9 citations
A randomized controlled trial gave 80 healthy adult males 10 µg doses of LSD or placebo every third day for six weeks and tested creativity with the Alternate Uses Test, Remote Associates Task, Consensual Assessment Technique, and an Everyday Problem-Solving Questionnaire. No drug effect was found on any creativity measure at the first dose or after six weeks, despite participants reporting feeling more creative on dose days. Baseline vocabulary skill significantly influenced scores on two tests. The null findings may reflect that laboratory testing misses naturalistic creative differences, available tests do not capture the facets of creativity anecdotally affected, or reported enhancements are placebo effects.
Translational Psychiatry
February 24, 2024
Rachael Sumner, Rebecca McMillan, Anna Forsyth et al.
7 citations
Ketamine's antidepressant effects may be driven by acute changes in brain connectivity and GABA receptor dynamics, not primarily by NMDA receptor blockade. In 30 patients with major depressive disorder, resting-state EEG was recorded before and during a 0.44 mg/kg ketamine infusion. Computational modeling revealed a significant increase in parietal-to-frontal AMPA-mediated connectivity and a significant decrease in the frontal GABA time constant. Both changes correlated with antidepressant response. NMDA receptor changes did not survive correction and were not correlated with symptom improvement. The findings suggest that acute fronto-parietal connectivity and GABA-A/AMPA receptor dynamics mediate ketamine's antidepressant properties.
BMC Neurosci
June 30, 2023
Rachael Sumner, Kacper Łukasiewicz
6 citations
The editorial reviews how different neuroscientific fields are studying the effects of psychedelics on neural plasticity. It describes the strengths of various research techniques, identifies major gaps in current knowledge, and highlights the need for future work, especially translating findings from pre-clinical animal studies to human research.
Neuropharmacology
December 1, 2025
Carina Joy Donegan, Dimitri Daldegan-Bueno, Tehseen Noorani et al.
4 citations
Before starting a low-dose LSD regimen, people with major depression held varied expectations shaped largely by media and personal experience. Over half had tried other treatments that failed. Many expected subtle effects or had no specific expectations, while some anticipated changes in consciousness or neural rewiring. Hope served both as a motivator and a buffer against disappointment. The findings underscore how media influences expectations and suggest that current expectancy measures miss important factors specific to psychedelic therapy.
Neuropharmacology
November 5, 2025
Dimitri Daldegan-Bueno, C Donegan, Rachael Sumner et al.
4 citations
In an open-label phase 2A trial, 19 participants with major depressive disorder, most of whom were taking antidepressants, took microdoses of LSD twice weekly for eight weeks. No serious adverse events occurred, and one participant withdrew due to anxiety. Depression scores on the Montgomery-Åsberg Depression Rating Scale dropped by 59.5% at the end of the intervention, with improvements sustained for up to six months. Anxiety, rumination, stress, and quality of life also improved. The results provide preliminary evidence that microdosed LSD is safe and feasible for treating moderate depression, but randomized controlled trials are needed.
Journal of psychopharmacology (Oxford, England)
April 18, 2025
James D Morse, Soo Hee Jeong, Robin J Murphy et al.
3 citations
After a 10 µg sublingual dose of LSD, the drug's concentration in the blood peaks at about 0.20 µg/L after 1.5 hours and has an elimination half-life of roughly 3 hours. A one-compartment model best describes how the body processes the drug. The small increases in heart rate and perceived drug effect (less than 15% above baseline) limited the ability to model those effects. Two participants who withdrew due to anxiety had intermediate-to-weak CYP2D6 enzyme activity, and several CYP genotypes appeared to influence LSD concentration. No evidence of changes in peripheral BDNF levels was found. The findings provide a pharmacokinetic model and assay useful for future clinical studies, but larger samples are needed to assess CYP genotypes as response biomarkers.
bioRxiv Preprint Server
May 5, 2020
Alexander D Shaw, Suresh Muthukumaraswamy, Neeraj K. Saxena et al.
2 citations
preprint
Ketamine alters brain oscillations, increasing high-frequency gamma waves and reducing low-frequency alpha and theta waves. A thalamo-cortical model better explained these changes than a cortex-only model. The model showed that ketamine increases specific synaptic connections: from superficial pyramidal cells to inhibitory interneurons via AMPA and NMDA receptors, and within-layer-5 pyramidal cell gain control via GABA-A and NMDA receptors. Receptor time-constants remained unchanged. These findings support using generative models to understand oscillatory data and provide computational evidence that ketamine alters local neural coupling through multiple neurotransmitter systems.
JAMA Psychiatry
June 1, 2026
Ben Deverett, Duan Li, Theresa R. Lii et al.
1 citation
Ketamine produces distinct brain-wave patterns that may be linked to its therapeutic effects. General anesthesia selectively blocks one of these patterns—theta oscillations—while leaving another pattern, beta-gamma oscillations, intact. In 52 participants, ketamine given during anesthesia preserved beta-gamma power increases but eliminated the characteristic theta augmentation seen during awake administration. This suggests that different neurophysiologic effects of ketamine can be separated, offering a way to investigate which brain-wave changes underlie its antidepressant, analgesic, or dissociative properties.
Progress in Neuro-psychopharmacology and Biological Psychiatry
February 18, 2026
Dimitri Henriques Daldegan-Bueno, C Donegan, Rachael Sumner et al.
1 citation
Taking very low doses of LSD (8 micrograms) repeatedly over a short period may temporarily improve mood in people with depression, though the effect needs confirmation in controlled experiments. The drug's behavior in the body was measured in this group, and no evidence of tolerance or increased sensitivity appeared, even when the dose was gradually increased.
Ther Adv Psychopharmacol
December 4, 2025
Carina Joy Donegan, Dimitri Daldegan-Bueno, Rachael Sumner et al.
People with depression who microdosed LSD described their experiences in interviews from an open-label trial. The analysis identified themes such as improved mood, increased energy, and greater emotional openness, though some participants also reported anxiety or discomfort. The findings suggest that microdosing may offer benefits for some individuals, but the open-label design means results should be interpreted cautiously.
Journal of Chromatographic Science
November 15, 2025
Mahima Bansal, Estelle Miller, Rachael Sumner et al.
A new high-performance liquid chromatography method accurately measures LSD and separates it from its degradation product iso-LSD. Validated according to international guidelines, the method works even when LSD is exposed to stress conditions that cause breakdown. Applied to illicit microdosing samples from a New Zealand drug checking service, the analysis found a significant discrepancy between users' estimated doses and actual LSD levels. This highlights risks for people using non-pharmaceutical microdosing preparations and underscores the need for reliable quality control to ensure safety.
Journal of Humanistic Psychology
November 10, 2025
Robin J Murphy, Mia Wardlaw, Thomas A. Smith et al.
After a six-week double-blind placebo-controlled trial of 10 µg of lysergic acid diethylamide taken every third day, healthy male participants reported changes in emotions, mood, social life, mindfulness, cognition, work, creativity, and physiological effects. Openness to experience and bidirectionality of effects were overarching themes. Some reported changes have potential clinical relevance for mood disorders, and reports of changes in anxiety suggest careful patient and dose selection. Participants' experiences with set and setting, uncertainty from placebo control, and perceived bidirectionality of effects inform psychedelic clinical trial design.
medRxiv
August 7, 2025
Ben Deverett, Duan Li, Theresa R. Lii et al.
preprint
Ketamine produces dissociative, analgesic, and antidepressant effects, but it is unclear whether its underlying neurophysiological signatures can be separated. In this observational cohort study, 52 participants (healthy volunteers, elective surgery patients, and patients with depression) received a subanesthetic infusion of ketamine or placebo, with or without general anesthesia. When ketamine was given under general anesthesia, its characteristic low-frequency brain wave augmentation was absent, while high-frequency power modulation was preserved. This selective modulation suggests a method for investigating the distinct roles of high- and low-frequency neural activity in ketamine's behavioral effects.
July 25, 2025
Rachael Sumner, Yuxin Ni, Suresh Muthukumaraswamy
preprint
People with premenstrual dysphoric disorder (PMDD) microdose psilocybin to manage their symptoms, and all 14 interview participants reported benefit, though their regimens and treatment goals varied widely. PMDD is a severe mood disorder with limited treatment options. Participants described how PMDD harmed their quality of life and why they turned to microdosing. The findings suggest clinical trials into microdosing psychedelics for PMDD are warranted, as current information to support people engaging in this practice is lacking.