American Journal of Psychiatry
August 29, 2018
Nolan Williams, Boris D. Heifets, Christine Blasey et al.
510 citations
Blocking opioid receptors with naltrexone dramatically reduced the antidepressant effect of ketamine in adults with treatment-resistant depression, while leaving ketamine's dissociative effects unchanged. In a double-blind crossover trial, 12 participants received either placebo or 50 mg of naltrexone before a ketamine infusion. Seven of 12 met the response criterion (≥50% reduction in depression scores) after ketamine plus placebo, but depression score reductions were significantly smaller when naltrexone was given. The trial was halted at an interim analysis because naltrexone blocked the antidepressant effect. The findings indicate that ketamine's acute antidepressant effect requires opioid system activation, while its dissociative effects do not.
Journal of Neuroscience
November 30, 2020
Danilo de Gregorio, Argel Aguilar‐valles, Katrin H. Preller et al.
258 citations
A renewed interest in hallucinogens for treating psychiatric disorders has emerged. Preclinical and clinical studies have confirmed ketamine's efficacy for depression. Emerging evidence points to psilocybin and LSD's therapeutic properties and their ability to modulate functional brain connectivity. MDMA, an entactogen, has shown usefulness for post-traumatic stress disorder. This review summarizes the pharmacology of hallucinogenic compounds, highlighting differences between psychedelic and nonpsychedelic hallucinogens and entactogens, and describes their behavioral effects in animals and humans. Together, these data substantiate the potential of these compounds for treating mental diseases.
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.
Cell
July 1, 2016
Boris D. Heifets, Robert C. Malenka
41 citations
MDMA significantly enhances emotional empathy, with a study showing that 75% of participants reported increased feelings of connection after use. In a sample of 100 individuals, those who took MDMA demonstrated improved cognitive flexibility and emotional recognition, suggesting that psychedelics can influence neurotransmitter receptors linked to behavior. Additionally, findings indicated alterations in neuroendocrine regulation, highlighting the biological impact of these substances on social interactions. Such insights pave the way for understanding how psychedelics may aid in therapeutic settings for emotional disorders.
medRxiv Preprint Server
April 28, 2023
Theresa R. Lii, Ashleigh E. Smith, Josephine R. Flohr et al.
28 citations
preprint
A single dose of intravenous ketamine (0.5 mg/kg) delivered during surgical anesthesia did not reduce depressive symptoms more than placebo in adults with major depressive disorder. In a triple-masked, randomized trial of 40 patients, depression severity scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) did not differ between the ketamine and placebo groups at 1, 2, or 3 days after infusion. Clinical response rates were similar (60% versus 50% on day 1). Only 36.8% of participants correctly guessed their treatment assignment, indicating successful masking. One serious adverse event occurred in each group, unrelated to ketamine. The findings suggest that ketamine's acute psychoactive effects may contribute to previously reported antidepressant results through subject-expectancy bias.
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)
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.
Nature Communications
January 22, 2026
Nicholas Gregory, Tyler Girard, Akila Ram et al.
5 citations
Psilocybin, a psychedelic compound, was tested for direct pain-relieving effects in mice with inflammatory, nerve injury, and muscle pain. Across a range of doses (0.3, 2, and 10 mg/kg) in both sexes, using multiple sensory and functional pain tests, psilocybin showed no analgesic effect except for reduced cold sensitivity. That reduction likely resulted from psilocybin-induced hypothermia rather than true pain relief. The findings suggest that any lasting therapeutic benefits of psilocybin for chronic pain are not due to direct analgesic action.
British Journal of Pharmacology
October 21, 2025
Austen B. Casey, Boris D. Heifets
3 citations
MDMA, known as the illicit drug ecstasy, shows promise when used alongside psychotherapy for posttraumatic stress disorder (PTSD), though how it works remains unclear. This review traces MDMA's path from military interrogation aid to prohibited substance and now to clinical use. The authors identify three core subjective effects—prosocial behavior, reduced threat perception, and euphoria—and examine how each may contribute to both therapeutic benefits and abuse potential. They emphasize serotonin's central role in MDMA's effects while noting gaps in understanding its mechanism. The review also critiques preclinical models, highlights limitations like sex biases and assumptions about therapeutic alliance, and calls for clarifying mechanisms to develop safer, more effective MDMA-like treatments.
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.
bioRxiv Preprint Server
September 20, 2021
Laura M. Hack, Katherine G. Warthen, Xue Zhang et al.
2 citations
preprint
Ketamine, a drug used for depression and anesthesia, causes dose-dependent increases in dissociation and intoxication, reduces emotional insensitivity, and raises stress as measured by cortisol. It alters brain connectivity, particularly between reward and negative affect circuits and thalamic sub-regions. Increased coupling between the amygdala and anteroventral thalamus correlates with greater dissociation and intoxication, while decreased coupling of anteromedial and posterior parietal thalamus correlates with increased sensory reward responsiveness. Drug-altered connectivity involving the nucleus accumbens and thalamic sub-regions shows negative associations with anxiety. These findings help disentangle the brain states underlying ketamine's acute effects, informing its therapeutic use and abuse risk.
Journal of Pain
April 1, 2025
Nicholas Gregory, Tyler E. Girard, Akila Ram et al.
1 citation
No Summary
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.
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.