Science Translational Medicine
December 11, 2019
Boris D. Heifets, Juliana S Salgado, Madison Taylor et al.
119 citations
MDMA's prosocial effects can be separated from its addictive properties by using fenfluramine, a selective serotonin-releasing compound. This finding reveals a conserved neuronal pathway that could be targeted to develop new therapeutics with limited abuse liability, offering a potential strategy for creating safer treatments that promote social connection without the risks of addiction.
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.
Cell
July 1, 2016
Boris D. Heifets, Robert C. Malenka
41 citations
MDMA (ecstasy) is known for inducing feelings of closeness and empathy. Examining how it works may lead to new treatments for psychiatric disorders involving social behavior deficits.
Science Advances
April 26, 2024
Ben Rein, Kendall Raymond, Cali Boustani et al.
37 citations
MDMA, a psychoactive drug known for its prosocial effects, enhances empathy-like behaviors in mice by increasing serotonin signaling in the nucleus accumbens. The drug, whether given systemically or infused directly into this brain region, strengthens the social transfer of pain and analgesia, a behavioral test of empathy. Optogenetically stimulating serotonin release in the nucleus accumbens mimics MDMA's effects, confirming serotonin's role. MDMA also restores deficits in empathy-like behaviors in a mouse model of autism lacking the Shank3 gene. The findings indicate that serotonin signaling in the nucleus accumbens is a core mechanism underlying MDMA's empathogenic effects.
JAMA Psychiatry
June 26, 2019
Boris D. Heifets, Robert C. Malenka
28 citations
Methylenedioxy-methamphetamine (MDMA) and psilocybin may offer therapeutic benefits for mental health conditions, but their approval for treatment would require establishing appropriate mental health care infrastructures. This includes trained therapists, treatment protocols, and regulatory frameworks to ensure safe and effective use. The authors outline the necessary preparations for integrating these substances into clinical practice.
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.
bioRxiv (Cold Spring Harbor Laboratory)
February 21, 2023
Daniel Ryskamp Rijsketic, Austen B Casey, Daniel A. N. Barbosa et al.
10 citations
preprint
Psilocybin, given to mice in either their home cage or an enriched environment, increased neural activity in brain regions including the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while decreasing activity in the hypothalamus, cortical amygdala, striatum, and pallidum. The effects of both the drug and the environment were strong and widespread but largely independent, with very few interactions between context and psilocybin treatment. This suggests that the brain's response to psilocybin is not strongly modulated by environmental setting at the level of immediate early gene expression.
bioRxiv (Cold Spring Harbor Laboratory)
July 7, 2025
Akila Ram, Austen B Casey, Robert C. Malenka et al.
2 citations
preprint
Psilocybin does not produce direct analgesic effects in mice, despite suggestions from clinical and preclinical data that it might help chronic pain. Across multiple pain assays and models of acute and chronic inflammatory, neuropathic, and musculoskeletal pain, no dose of psilocybin was analgesic. The finding indicates that any therapeutic benefits for chronic pain syndromes are unlikely to come from direct pain relief.
Journal of Pain
April 1, 2025
Nicholas Gregory, Tyler E. Girard, Akila Ram et al.
1 citation
No Summary
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.
Neuro-Oncology
November 1, 2025
Richard Drexler, Belgin Yalçın, Rebecca Mancusi et al.
High-grade gliomas integrate into serotonergic circuits via dorsal and median raphe projections, which drive calcium-mediated proliferation. Psilocybin, a serotonergic psychedelic selective for 5-HT2A with activity at TrkB, significantly increased proliferation in glioblastoma and DMG xenografts after a single dose, with effects persisting for at least two weeks. Calcium transients in glioma cells appeared within 30 minutes and remained detectable for two weeks. Genetic knockout of 5-HT2A nearly abolished psilocybin-induced proliferation, while TrkB knockout partially reduced it. These findings indicate that psilocybin promotes sustained glioma growth primarily through 5-HT2A activation, with a modulatory role for TrkB, suggesting caution for clinical use in brain tumor patients.