Neuropsychopharmacology
May 11, 2011
Janelle H. P. van Wel, Kim P. C. Kuypers, Eef L. Theunissen et al.
52 citations
Blocking the 5-HT(2A) receptor with ketanserin prevented MDMA-induced impairment on a word-learning task, but not on spatial or prospective memory tasks. Blocking the 5-HT(1A) receptor with pindolol had no effect on any memory task. MDMA alone significantly impaired performance in all three memory tasks. The findings indicate that MDMA-induced verbal memory impairment is mediated by 5-HT(2A) receptor stimulation.
Neuropsychopharmacology
September 20, 2021
Andre Zamani, Kalina Christoff, Robin Carhart‐Harris
50 citations
The prefrontal cortex contains multiple subregions linked to different large-scale brain networks, supporting a wide range of mental phenomena from goal-directed thought and executive functions to mind-wandering and psychedelic experiences. A key dimension distinguishing conscious experiences is the stability or variability of mental states over time, which is central to the dynamic framework of thought (DFT) and the relaxed beliefs under psychedelics (REBUS) model. This review synthesizes these frameworks to explain how prefrontal subregions may differentially contribute to the stability and variability of thought and conscious experience, and suggests future research directions.
Neuropsychopharmacology
February 14, 2017
Ishan C Walpola, Timothy Nest, Leor Roseman et al.
50 citations
MDMA (100 mg) reduces functional connectivity between the right insula and the salience network in the brain, indicating a disintegration of this network. This decrease in connectivity correlates with higher baseline trait anxiety and more intense acute experiences of altered bodily sensations under the drug. The findings suggest that insular disintegration is a neurobiological signature of the MDMA experience, linking the drug's effects on brain activity to individual differences in anxiety and bodily awareness.
Neuropsychopharmacology
July 21, 2023
Jennifer M. Mitchell, Brian T. Anderson
47 citations
Over the last five years, clinical research into psychedelic medicines has expanded rapidly, with data from a Phase 3 industry trial, a multicenter Phase 2 industry trial, and multiple early-phase trials now published in peer-reviewed journals. This narrative review summarizes recent findings and ongoing clinical trials involving various classes of psyche-manifesting substances that may help treat a broad range of conditions. The review also discusses methodological considerations, unique challenges, and next steps for research, emphasizing the experiential nature of these therapies.
Neuropsychopharmacology
September 12, 2020
Justin Hudak, Adam W. Hanley, William R. Marchand et al.
46 citations
Among people receiving Mindfulness-Oriented Recovery Enhancement for opioid misuse, those who showed higher levels of endogenous theta brainwave activity during meditation subsequently required lower doses of opioids. Theta oscillations, which are linked to relaxation and focused attention, may serve as a neural marker predicting treatment response.
Neuropsychopharmacology
April 25, 2023
Peter Bedford, Daniel J. Hauke, Zheng Wang et al.
43 citations
Lysergic acid diethylamide (LSD) predominantly strengthens interregional connections and reduces self-inhibition across the brain, except in occipital and subcortical regions where connections weaken and self-inhibition increases. These patterns suggest LSD perturbs the brain's excitation/inhibition balance. Whole-brain effective connectivity, assessed via regression dynamic causal modelling of resting-state fMRI data from 45 participants in two placebo-controlled trials, discriminated LSD from placebo with 91.11% accuracy and correlated with global subjective effects, indicating potential for decoding subjective experiences.
Neuropsychopharmacology
November 20, 2020
Felix Müller, Friederike Holze, Patrick C. Dolder et al.
43 citations
The non-hallucinogenic drug MDMA reduces functional connectivity within several resting-state brain networks, including the default mode network, visual networks, and the sensorimotor network. These decreases closely match those previously reported for hallucinogenic drugs like LSD. The findings suggest that such connectivity changes are not specific to serotonergic hallucinogens but can be induced by monoaminergic stimulation without marked subjective drug effects. However, alterations within the default mode network may help explain the antidepressant effects of some of these substances.
Neuropsychopharmacology
April 23, 2024
Julia Colcott, Olivia Carter, Sally Meikle et al.
37 citations
A comprehensive systematic review and meta-analysis of 13 studies found that MDMA-assisted psychotherapy (MDMA-AP) is associated with increased odds of side effects compared to control conditions. In Phase 2 trials, MDMA-AP roughly doubled the odds of any side effect during medication sessions and in the following week. In Phase 3 trials, the odds of any adverse event during treatment were about 3.5 times higher with MDMA-AP than with placebo-assisted psychotherapy. Most side effects were transient and mild or moderate. However, the evidence had very low to moderate certainty, most trials had high risk of bias, and none adequately followed CONSORT Harms 2022 reporting guidelines, highlighting the need for further safety research.
Neuropsychopharmacology
January 24, 2020
Carla Agurto, Guillermo Cecchi, Raquel Norel et al.
33 citations
Computer-extracted speech features from acoustic, semantic, and psycholinguistic domains can detect mental states after controlled administration of MDMA and intranasal oxytocin. In a double-blind, placebo-controlled study with 31 healthy adults, speech tasks during peak drug effects yielded cross-validated accuracies up to 87% in the training/validation set and 92% in independent datasets for classifying drug conditions. Oxytocin-driven changes were mostly captured by acoustic features related to emotion and prosody, while MDMA-related mental states manifested across multiple speech domains. The experimental task—whether involving interaction with another individual—also affected speech responses. These results suggest speech analysis can provide objective markers of drug-induced mental states.
Neuropsychopharmacology
August 22, 2022
Yanning Zuo, Attilio Iemolo, Patricia Montilla‐Perez et al.
24 citations
High doses of THC given to adolescent mice impaired memory and social behaviors, with sex- and brain region-specific molecular changes. In females, THC affected endocannabinoid signaling in the dorsal medial striatum and inflammation in the ventral tegmental area; in males, it altered synaptic transmission in the nucleus accumbens. Gene coexpression networks identified four key driver genes—Hapln4, Kcnc1, Elavl2, Zcchc12—in the nucleus accumbens of both sexes that link to addiction processes, synaptic transmission, brain development, and lipid metabolism, and are also associated with genetic susceptibility to cannabis use disorder in humans.
Neuropsychopharmacology
March 8, 2019
M. Madsen, Patrick M. Fisher, Daniel Burmester et al.
21 citations
correction
No Summary
Neuropsychopharmacology
September 1, 2017
Elizabeth G Pitts, Adelaide R Minerva, Erika B Chandler et al.
20 citations
MDMA and its enantiomers increase affiliative social behaviors and vocalizations in group-housed squirrel monkeys, while methamphetamine has only modest effects. Pretreatment with a 5-HT_2A receptor antagonist or a 5-HT_2C receptor agonist reduces MDMA-induced social behaviors, whereas a 5-HT_1A receptor antagonist does not affect affiliative vocalizations and even increases social contact. These results indicate that the prosocial effects of MDMA depend on 5-HT_2A, but not 5-HT_1A, receptors, aligning with findings in humans and rodents. Understanding these neurochemical mechanisms may aid in developing therapeutics that retain MDMA's social benefits with fewer drawbacks.
Neuropsychopharmacology
May 28, 2024
Natalie Ertl, Tom P. Freeman, Claire Mokrysz et al.
19 citations
Cannabis use disrupts resting-state functional connectivity in key brain networks—default mode, executive control, salience, hippocampal, and limbic striatal—similarly in adolescents (16–17 years) and young adults (26–29 years). Cannabidiol (CBD) did not counteract the effects of delta-9-tetrahydrocannabinol (THC) and, in some cases, further reduced connectivity both within networks and across the whole brain. These findings challenge the assumption that CBD makes cannabis safer and indicate that the adolescent brain is not more vulnerable to cannabis-induced connectivity disruptions than the adult brain.
Neuropsychopharmacology
April 19, 2023
N. Murphy, Amanda J. F. Tamman, Marijn Lijffijt et al.
18 citations
A single low-dose infusion of ketamine in older military veterans with treatment-resistant depression temporarily increases the brain's neural complexity, measured by electroencephalogram (EEG) markers Lempel-Ziv complexity and multiscale entropy, within 30 minutes after infusion. These effects vary over time, with some complexity measures decreasing later. However, these changes in complexity were not linked to reductions in depressive symptoms after seven days. The findings suggest that ketamine produces broad, time-varying effects on brain dynamics beyond previously studied gamma oscillations, offering a potential non-linear marker of the drug's action.
Neuropsychopharmacology
August 25, 2020
M. Madsen, Gitte M. Knudsen
15 citations
No Summary
Neuropsychopharmacology
December 19, 2024
Livio Erne, Severin B Vogt, Lorenz Müller et al.
14 citations
Continuous intravenous infusions of DMT produce dose-dependent subjective effects that plateau after 30 minutes, with a ceiling effect for good drug effect at 1.8 mg/min. The highest dose tested (2.4 mg/min) caused greater anxious ego dissolution and significant anxiety compared to placebo. DMT showed dose-proportional pharmacokinetics and moderate acute tolerance. When participants could self-titrate their dose, they chose moderate to strong psychedelic effects comparable to the 1.8 mg/min rate. These findings can guide dose selection in future DMT research and show that subjective effects can be rapidly adjusted through dose titration.
Neuropsychopharmacology
November 12, 2025
Hannah M. Kramer, Meghan Hibicke, Jason W. Middleton et al.
7 citations
A single dose of psilocybin or the selective 5-HT2A receptor agonist 25CN-NBOH reduces immobility in the forced swim test in rats for at least three months, with no decrease in effect size over that period. Both drugs produced similar behavioral effects, indicating that 5-HT2A receptor activation alone is sufficient for long-lasting changes. In the medial prefrontal cortex, layer 5 excitatory pyramidal neurons showed altered resting membrane potential, firing rates, and synaptic excitation months after treatment. However, no changes were found in synaptic density, spine classification, or expression of presynaptic and postsynaptic markers. The results suggest that enduring functional plasticity, rather than structural plasticity, underlies the long-term behavioral effects of psychedelics.
Neuropsychopharmacology
August 6, 2024
Nathan H. Heller, Frederick S. Barrett
4 citations
No Summary
Neuropsychopharmacology
February 18, 2026
Itishree Sahoo, Sairam Masadi, Ashwath Maheswari et al.
3 citations
Adolescent mice given psilocybin every other day from postnatal days 40-50 showed long-term changes in brain structure and function when tested in adulthood. Brain imaging revealed reduced volume and altered water diffusivity in several regions, with males more affected than females. Functional connectivity increased globally and regionally, notably between the prefrontal cortex and hypothalamus, thalamus, and midbrain. Mice showed reduced brain sensitivity to rewarding and aversive odors, and males had lower levels of epigenetic and neuroplasticity protein markers in the prefrontal cortex. Behaviorally, female mice showed reduced mobility in the open field test, while no differences appeared in the light/dark box test. These findings indicate that adolescent psilocybin exposure produces lasting developmental consequences, especially in males.
Neuropsychopharmacology
July 6, 2024
David Martin, Angel M. Delgado, Donna J. Calu
3 citations
A psychedelic 5-HT2A/2C agonist, DOI, increases dopamine signals in the nucleus accumbens core of rats during a learned reward task. The drug boosts dopamine responses to rewards and the cues that directly precede them, but not to earlier, distal cues. This effect occurs independently of changes in reward value, suggesting DOI amplifies prediction error signaling—a mechanism that may help disrupt entrenched associations or facilitate new learning. The findings point toward psychedelic strategies that engage error-driven learning for therapeutic benefit.
Neuropsychopharmacology
February 13, 2026
Fabrizio Ascone, Valeria Buzzelli, Francesca Mottarlini et al.
2 citations
In a rat model of Fragile X Syndrome (FXS), psilocybin microdosing rescued deficits in novel object recognition memory. This benefit persisted even when serotonin receptors (5HT2AR or 5HT1AR) were blocked, but was abolished by blocking the TrkB receptor, indicating that the effect depends on BDNF/TrkB signaling rather than classical serotonergic pathways. At the molecular level, psilocybin normalized mature BDNF, increased TrkB, and restored downstream AKT signaling in the prefrontal cortex—pathways linked to synaptic plasticity and cognition. These results suggest psilocybin microdosing could be a promising therapeutic strategy for neurodevelopmental disorders like FXS and autism spectrum disorder, potentially dissociating therapeutic benefits from hallucinogenic effects.
Neuropsychopharmacology
January 16, 2026
Philip D. Harvey, Charles B. Nemeroff
2 citations
Interest in psychedelic therapies is booming, yet no psychedelic treatment has been approved for any psychiatric condition. The one large-scale MDMA development program that reached the FDA was disapproved for reasons that could also apply to classical psychedelic trials. This review defines psychedelics, surveys current therapies, targeted conditions, compounds under investigation, and research strategies. Some interventions combine drugs with psychotherapy, bringing both benefits and challenges. Debate continues over whether the psychedelic experience itself is essential for therapeutic effect, complicating blinded trials. The review also addresses societal issues like deregulation of formerly illegal substances and regulatory hurdles, including alternatives to blinded trials and whether targets like adjustment disorder pose problems under current standards.
Neuropsychopharmacology
September 12, 2025
Jakub Vohryzek, Andrea I. Luppi, Selen Atasoy et al.
2 citations
The brain's function depends on its structural wiring, and psychedelics alter this relationship. Using connectome harmonic decomposition, a method linking brain activity to the network of white matter pathways, the authors show that under N,N-dimethyltryptamine (DMT), the brain's harmonic repertoire shifts similarly to that seen with psilocybin, LSD, and ketamine. Repertoire entropy—a measure of the diversity of brain states—increases under DMT. For the first time, the energy spectrum difference and repertoire entropy of connectome harmonics track the intensity of subjective experience in real time, indicating a close coupling between brain network dynamics and conscious experience.
Neuropsychopharmacology
April 22, 2025
Johannes G. Ramaekers
1 citation
No Summary
Neuropsychopharmacology
July 18, 2026
James J Gattuso, Ahmed Kamal, Jennyfer M. Payet et al.
In a mouse model of schizophrenia lacking the metabotropic glutamate receptor 5 (mGlu5), psilocybin (1 mg/kg) caused hyperlocomotion, while normal mice showed no such effect. Male knockout mice also had a stronger head-twitch response, indicating enhanced serotonin 2A receptor signaling. Psilocybin increased neural activity in the claustrum of normal but not knockout mice, showing that intact mGlu5 signaling is needed for this effect. Psilocybin did not change anxiety-like behavior but increased immobility in a stress test. Notably, it produced a sustained normalization of sensorimotor gating in female knockout mice nine days after treatment, suggesting sex-dependent long-term effects.