Expert Review of Clinical Pharmacology
May 26, 2021
Suresh Muthukumaraswamy, Anna Forsyth, Thomas Lumley
312 citations
Psychedelic drugs like psilocybin, LSD, and ketamine show promise for treating mental health disorders, but their effectiveness in randomized controlled trials may be overstated. Previous research indicates that participants in psychedelic trials often become unblinded—they can tell whether they received the drug or a placebo—and may have strong expectations of improvement. A systematic review of trials from 1990 to 2020 found that most did not measure pre-trial expectancy or check whether blinding was successful. The authors argue that reported treatment effect sizes are likely overestimated due to these confounds. They recommend routine measurement of de-blinding and expectancy, careful trial design, and caution when interpreting existing effect size estimates.
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.
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.
March 8, 2021
Suresh Muthukumaraswamy, Anna Forsyth, Thomas Lumley
16 citations
preprint
Effect sizes reported in randomized controlled trials of psychedelic drugs such as psilocybin, LSD, and ketamine for mental health disorders are likely overestimated because participants often become unblinded and develop strong expectations of improvement. Systematic reviews of these trials show that researchers have not measured or reported expectancy or de-blinding. To obtain accurate estimates, future trials should routinely measure these confounds and adjust effect sizes accordingly. Caution is urged when interpreting existing results.
Translational psychiatry
April 15, 2024
Nathan Allen, Aron Jeremiah, Robin 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.
Trials
August 24, 2024
Dimitri Daldegan-Bueno, Carina Joy Donegan, Anna Forsyth et al.
14 citations
A phase 2b randomized controlled trial will test whether repeated low doses of LSD (4 to 20 micrograms, taken twice weekly for 8 weeks at home) reduce depressive symptoms in people with major depressive disorder, compared to an active placebo. The trial is triple-blind and includes measures of mood, personality, sleep, brain activity, blood biomarkers, and safety. This is the first controlled trial to test microdosed LSD in patients' natural environment. Results will help determine whether psychedelic microdosing is a viable additional treatment for depression and guide future research.
Translational psychiatry
February 24, 2024
Rachael L Sumner, Rebecca L 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.
Journal of Psychedelic Studies
May 16, 2025
Anna-Leigh Hodge, Anna Forsyth, Tehseen Noorani et al.
6 citations
A Māori-led project called Tū Wairua aims to integrate traditional Māori healing practices (rongoā Māori) with psychedelic-assisted therapy to address problematic methamphetamine use in Māori communities. Based at Rangiwaho Marae in Te Tairāwhiti (Gisborne), the project will use Kaupapa Māori methodology and biomedical psychedelic science to develop a decolonized, culturally appropriate approach to psilocybin treatment. It seeks to challenge colonial dynamics in current Western psychedelic therapy models, build a skilled Māori workforce, and challenge legislation restricting Indigenous psychedelic medicines, creating sustainable pathways for collective healing.
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 L. 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.
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 L. 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.
medRxiv : the preprint server for health sciences
October 21, 2024
Pascal Grumbach, Jan Kasper, Joerg F Hipp et al.
1 citation
preprint
Autism spectrum disorder involves altered resting-state brain function, and an imbalance between excitation and inhibition is a proposed mechanism. In two large independent cohorts, individuals with autism consistently showed reduced local brain activity in default mode network nodes and increased activity in temporal regions, cerebellum, and brainstem. These activity changes spatially overlapped with multiple neurotransmitter systems, including dopamine, glutamate, GABA, and acetylcholine. The NMDA-antagonist ketamine, but not the GABA-potentiator midazolam, induced activity changes resembling those seen in autism, suggesting that pharmacologically shifting the excitation-inhibition balance can mimic autism-related brain alterations.
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.
February 27, 2025
Anna-Leigh Hodge, Anna Forsyth, Tehseen Noorani et al.
preprint
A Māori-led research project, Tū Wairua, will integrate traditional Māori healing practices (rongoā Māori) with psilocybin-assisted therapy to address problematic methamphetamine use in Māori communities. Based at Rangiwaho Marae in Te Tairāwhiti, the project is driven by kaupapa Māori methodology and biomedical psychedelic science. It aims to develop a culturally-appropriate treatment, build a skilled Māori workforce, and challenge legislation restricting Indigenous psychedelics. The work represents a shift toward health interventions that respect Indigenous wisdom and address the unique needs of Māori communities.