Biological psychiatry. Cognitive neuroscience and neuroimaging
May 1, 2024
Balázs Szigeti, Boris D Heifets
62 citations
Clinical trials of psychedelics such as psilocybin, LSD, and DMT have challenged how nondrug factors like participant expectations are measured and controlled in mental health research. Higher doses of these psychoactive substances make it harder to conceal treatment conditions in double-blind, placebo-controlled designs. Growing public enthusiasm for psychedelic therapy raises questions about whether trial results are biased by positive expectancy. This review covers key concepts of expectancy and its measurement, examines expectancy effects reported in modern microdose and macrodose trials, and considers expectancy as a physiological process that can be independent of or interact with drug effects. Expectancy can be harnessed to improve outcomes and managed to enhance trial rigor.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
November 1, 2023
Daniel Ryskamp Rijsketic, Austen B Casey, Daniel A N Barbosa et al.
49 citations
Psilocybin increased neural activity (c-Fos expression) in the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while decreasing it in the hypothalamus, cortical amygdala, striatum, and pallidum of mice, largely regardless of whether the mice were in their home cage or an enriched environment. Network analyses showed that psilocybin disrupted co-activity between highly correlated brain regions, reduced modularity, and attenuated communication between modules. Context and psilocybin each had widespread effects on brain activity and network architecture, but interactions between the two were surprisingly sparse.
bioRxiv (Cold Spring Harbor Laboratory)
April 9, 2025
Odilia D Lu, Katrina White, Kendall Raymond et al.
18 citations
preprint
Psilocybin, the active compound in magic mushrooms, had several clear and repeatable immediate effects on mouse behavior, including increased anxiety and avoidance and reduced fear expression. However, its effects one day later were not consistent across five different laboratories, and no reliable changes were seen in depression-like behavior, fear extinction learning, social preference, or social reward learning. Using about 200 mice per experiment across five independent labs, the findings show that psilocybin's lasting behavioral effects in mice are more modest and less reliable than previously claimed. This coordinated multi-lab approach highlights the importance of replication for producing trustworthy results.
Biological psychiatry
May 5, 2025
Matthew B Pomrenze, Sam Vaillancourt, Pierre Llorach et al.
11 citations
Ketamine produces a rapid increase in movement (locomotor activation) in mice by acting on mu opioid receptors (MORs) in the central amygdala (CeA). This effect is blocked by the opioid receptor antagonist naltrexone, and the same blockade occurs with a MOR-selective antagonist. Whole-brain imaging showed that naltrexone most strongly altered ketamine-induced cFos expression in the CeA, particularly in neurons that co-express MOR and PKCδ. Interrupting MOR function specifically in the CeA, either with a drug or genetic manipulation, prevented ketamine's locomotor effects. This indicates that ketamine's acute behavioral effects involve opioid signaling in the CeA, which may relate to its antidepressant mechanism in humans.
JAMA network open
April 1, 2025
Xue Zhang, Laura M Hack, Claire Bertrand et al.
10 citations
In a double-blind, placebo-controlled trial, 16 adults with subthreshold PTSD symptoms and early life trauma but no current psychiatric disorders were given 120 mg of MDMA or placebo. Participants were split into two groups based on baseline brain activity in the amygdala in response to nonconscious threat cues: those with high amygdala reactivity (NTNA+) and those with low reactivity (NTNA-). MDMA, compared with placebo, reduced activity in the amygdala and subgenual anterior cingulate cortex (sgACC), increased connectivity between the sgACC and amygdala, and increased liking of threatening facial expressions, but only in the NTNA+ subgroup. These findings suggest that baseline neural circuit profiles can identify who may benefit most from MDMA therapy and point to possible biomarkers for personalized treatment.
The American journal of psychiatry
June 1, 2026
Jason M Tucciarone, Igor D Bandeira, Christine Blasey et al.
5 citations
Ketamine rapidly reduces suicidal thoughts in major depressive disorder, but the effect is short-lived. In this trial, adults with major depression and active suicidal ideation received a single ketamine infusion, then were randomly assigned to take either low-dose buprenorphine or a placebo daily for four weeks. Suicidal thoughts dropped significantly more in the buprenorphine group (average decrease of 11.6 points on the Scale for Suicide Ideation) than in the placebo group (average decrease of 6.3 points). Depression scores did not differ between groups. No serious side effects occurred. Buprenorphine appears to sustain and boost ketamine's antisuicidal effects, offering a potentially safe, scalable option for suicide prevention.
Journal of psychoactive drugs
November 22, 2024
Wesley C Ryan, Boris D Heifets
2 citations
In an addiction psychiatry practice offering intramuscular ketamine with psychotherapy for depression, 70 patients received 1,114 sessions over nearly seven years. Induction produced an 82% response, and improvement remained above 80% after six months of maintenance sessions given every 21 days at a mean dose of 1.13 mg/kg. Many patients (38%) stayed in treatment for at least a year. Dropouts were mostly due to logistical reasons (50%); side effects accounted for only 9.7%. One case of ketamine use disorder required residential treatment. Nausea was the main side effect managed with medication. Maintenance ketamine-assisted psychotherapy extended benefits for mood, anxiety, and substance use and was generally well tolerated.
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.
Journal of affective disorders
July 15, 2025
Theresa R Lii, Josephine R Flohr, Robin L Okada et al.
1 citation
The endogenous opioid system may influence the placebo antidepressant response. A post hoc analysis of a randomized, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery tested whether baseline opioid use affected antidepressant responses. The analysis found that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, pain intensity, and ethnicity. The findings, based on a small sample, require confirmation by prospective controlled studies. Opioid use at baseline attenuated the placebo antidepressant response independently of pain, while the antidepressant response was preserved in opioid users who received ketamine.
bioRxiv : the preprint server for biology
October 22, 2024
Matthew B Pomrenze, Sam Vaillancourt, Juliana S Salgado et al.
1 citation
preprint
MDMA releases both dopamine and serotonin in the brain's reward center, the nucleus accumbens, but its strong serotonin release limits dopamine release and abuse potential. Using conditional knockout mice and direct brain infusions, the authors show that MDMA's serotonin release, acting through the serotonin transporter and 5-HT2C receptors, reduces the drug's reinforcing effects and conditioned place preference, while its prosocial effects are mediated by separate mechanisms. This platform predicts that (R)-MDMA, a novel entactogen, will have prosocial effects and low abuse potential.
bioRxiv : the preprint server for biology
March 6, 2024
Matthew B Pomrenze, Sam Vaillancourt, Pierre Llorach et al.
1 citation
preprint
Ketamine's effects on movement in mice are blocked by the opioid receptor antagonist naltrexone, but its analgesic and antidepressant-like effects are not. Whole-brain imaging identified the central amygdala as the region most affected by naltrexone, where neurons expressing mu-opioid receptors and PKCδ were strongly activated by naltrexone but not by ketamine. Disrupting mu-opioid receptor function in the central amygdala, either with drugs or genetic techniques, blocked ketamine's locomotor effects. These results indicate that mu-opioid receptors in the central amygdala gate certain behavioral effects of ketamine without being direct targets of the drug.
ACS chemical neuroscience
May 6, 2026
Maxemiliano V Vargas, Cassandra J Hatzipantelis, Lee E Dunlap et al.
A safer analogue of MDMA, called R-MDDMA, shows promise for treating PTSD and depression without the abuse potential of MDMA. Unlike MDMA, R-MDDMA does not activate 5-HT2B receptors, induce serotonin release, cause head-twitch responses, affect body temperature, or increase locomotion at therapeutic doses. However, it still promotes structural neuroplasticity in cortical neurons, facilitates fear extinction learning, and produces sustained antidepressant-like effects. These results suggest that R-MDDMA might be a safer MDMA analogue with similar therapeutic properties.
medRxiv : the preprint server for health sciences
November 2, 2024
Theresa R Lii, Josephine R Flohr, Robin L Okada et al.
preprint
The placebo antidepressant response was weaker in depressed patients who were already taking opioid medications, independent of their pain levels. In a re-analysis of a randomized trial, patients on chronic opioid therapy who received a placebo showed depression scores 10 points higher on the Montgomery-Åsberg Depression Rating Scale (MADRS) across 1 to 14 days after treatment, indicating less improvement. When measured as percent change, opioid users experienced 38.4% less improvement than non-users. For patients who received ketamine, baseline opioid use did not significantly affect depression scores. Pain intensity did not predict depression outcomes, and the link between depression and pain was negligible. These results come from a small, unregistered post hoc analysis and require confirmation.