The International Journal of Neuropsychopharmacology
September 12, 2011
Oz Malkesman, Daniel Austin, Tyson Tragon et al.
91 citations
D-serine, a co-agonist at NMDA receptors, produces antidepressant-like effects in rodents. A single acute dose of D-serine reduced immobility in the forced swim test without affecting motor function, reversed sexual reward-seeking deficits caused by serotonin depletion, and reversed learned helplessness behavior. Mice lacking NMDA receptor NR1 subunits in forebrain excitatory neurons showed a depression-like phenotype and did not respond to D-serine. These findings suggest D-serine has antidepressant-like effects and support the idea of complex glutamatergic dysfunction in depression, though it remains unclear whether D-serine shares a convergent mechanism with NMDA antagonists like ketamine.
The International Journal of Neuropsychopharmacology
June 5, 2015
Marta Valle, Montserrat Puntes, Jimena Coimbra et al.
75 citations
Salvinorin-A, a compound from the plant Salvia divinorum that activates kappa-opioid receptors, produces dose-dependent changes in perception and body awareness. In eight healthy volunteers with prior psychedelic experience, vaporized salvinorin-A at 0.25, 0.50, and 1 mg caused detachment from external reality, elaborate visions, and auditory phenomena. Lower doses increased bodily sensations, while the highest dose produced a complete loss of contact with the body. The effects on body awareness followed an inverted-U pattern, suggesting the kappa-opioid receptor plays a key role in regulating sensory perception, interoception, and the sense of body ownership.
The International Journal of Neuropsychopharmacology
August 1, 2014
Maurizio S Riga, Guadalupe Soria, Raúl Tudela et al.
75 citations
5-MeO-DMT, a natural hallucinogen found in ayahuasca, disrupts brain activity in the medial prefrontal cortex (mPFC) of rodents, increasing firing in 51% and decreasing it in 35% of pyramidal neurons, while reducing the power of low-frequency cortical oscillations (<4 Hz) by 31%. This effect, which depends on 5-HT1A and 5-HT2A receptor activation, resembles disruptions caused by other psychotomimetic agents like phencyclidine and DOI. Antipsychotic drugs (haloperidol, clozapine, risperidone) and an mGlu2/3 agonist reversed the oscillation reduction. 5-MeO-DMT also decreased blood-oxygen level dependent (BOLD) responses in visual cortex and mPFC. The findings suggest these cortical alterations underlie hallucinogenic effects and may aid antipsychotic drug development.
The International Journal of Neuropsychopharmacology
October 31, 2014
Elizabeth D. Ballard, Níall Lally, Allison C. Nugent et al.
74 citations
Suicidal ideation in treatment-resistant major depression is linked to activity in the infralimbic cortex (Brodmann area 25). In 19 medication-free patients, higher baseline metabolism in this brain region correlated with more severe suicidal thoughts, but not with overall mood. A single ketamine infusion (0.5 mg/kg) reduced both suicidal ideation and metabolism in the infralimbic cortex, and the degree of metabolic decrease matched the degree of symptom improvement. Other brain areas examined—the amygdala and subgenual anterior cingulate cortex—showed no significant association with suicidal ideation or depression. The infralimbic cortex may be a specific neural substrate for suicidal thinking, distinct from general mood.
The International Journal of Neuropsychopharmacology
August 30, 2017
Tom P. Freeman, Rebecca Pope, Matthew B. Wall et al.
67 citations
Cannabis dampens the brain's response to music in regions involved in reward and emotion, including the auditory cortex, hippocampus, amygdala, and ventral striatum. However, when cannabis also contains cannabidiol, these dampening effects are offset, and brain activity does not differ from placebo. Despite reduced neural responses, both types of cannabis increased participants' self-reported desire to listen to music and enhanced sound perception. The findings suggest that cannabidiol may mitigate some of cannabis's effects on brain reward systems.
The International Journal of Neuropsychopharmacology
August 13, 2013
Adam L. Halberstadt, Mark A. Geyer
66 citations
Serotonergic hallucinogens such as mescaline, psilocybin, and LSD produce a 'model psychosis' in healthy individuals that resembles positive symptoms of schizophrenia by acting through the serotonin 5-HT2A receptor. Evidence that the serotonergic system contributes to schizophrenia in some patients has led to animal models based on hallucinogen effects. This review examines the behavioral effects of hallucinogens in four such models, the receptor and neurochemical mechanisms involved, and their translational relevance. Despite challenges in modeling hallucinogen effects in nonverbal species, these models have provided insights into the link between serotonin and schizophrenia and identified receptor targets for developing new therapeutic agents.
The International Journal of Neuropsychopharmacology
April 10, 2018
Jessica R. Gilbert, Julia S. Yarrington, Kathleen E. Wills et al.
58 citations
Ketamine, a drug that modulates glutamate signaling, produces rapid antidepressant effects. In a double-blind, crossover, placebo-controlled study, 18 people with major depressive disorder and 18 healthy controls each received a single intravenous infusion of ketamine (0.5 mg/kg) and a saline placebo. Magnetoencephalography measured brain activity during tactile stimulation 6 to 9 hours after each infusion. Dynamic causal modeling revealed that ketamine altered NMDA receptor-mediated connectivity differently in the two groups: backward connections were enhanced in depressed subjects, while forward connections were enhanced in controls. Among depressed subjects, improved mood correlated with reduced NMDA and AMPA connectivity in the somatosensory network. The findings indicate that AMPA- and NMDA-mediated glutamatergic signaling is central to ketamine's antidepressant action.
The International Journal of Neuropsychopharmacology
July 9, 2008
Thibault Renoir, Eleni Païzanis, Malika El Yacoubi et al.
58 citations
A single sentence summary is not possible because the abstract contains multiple distinct findings. Four weeks after administering MDMA to mice, the potency of a 5-HT1A receptor agonist to inhibit serotonin neuron firing in the dorsal raphe nucleus doubled, and the hypothermic response to 8-OH-DPAT increased, indicating supersensitivity of 5-HT1A autoreceptors. Brain serotonin levels decreased without changes in citalopram binding. MDMA treatment also reduced hippocampal cell proliferation by 30% and increased immobility in the forced swim test, suggesting depressive-like behavior. These effects were absent in mice lacking the serotonin transporter, indicating the transporter is required for these delayed, antidepressant-opposite effects that may contribute to MDMA-induced mood disorders.
The International Journal of Neuropsychopharmacology
May 10, 2021
Natalie Gukasyan, David B. Yaden, Matthew W. Johnson et al.
56 citations
Psychedelic substances produce unusual changes in conscious experience, leading some to propose they offer unique insights into consciousness. However, psychedelics are unlikely to provide information relevant to the "hard problem of consciousness," which involves explaining how first-person experience emerges. Instead, they bear on multiple "easy problems of consciousness," involving relations between subjectivity, brain function, and behavior. This review discusses common meanings of "consciousness" regarding psychedelics and considers models of their effects on the brain linked to explanatory claims about consciousness. It calls for epistemic humility about psychedelic research's potential to explain the hard problem while noting ways psychedelics may advance study of specific aspects of consciousness.
The International Journal of Neuropsychopharmacology
August 28, 2019
Jiancheng Zhang, Youge Qu, Lijia Chang et al.
56 citations
A single injection of (R)-ketamine (10 mg/kg) rapidly reversed the loss of dendritic spines in the medial prefrontal cortex and hippocampus of mice that had become susceptible after chronic social defeat stress. Spine density was measured three hours after treatment and was significantly increased in the prelimbic area of the medial prefrontal cortex, the Cornu Ammonis3 region, and the dentate gyrus of the hippocampus. The findings suggest that (R)-ketamine's rapid restoration of spine density in these brain regions may underlie its fast-acting antidepressant effects.
The International Journal of Neuropsychopharmacology
December 19, 2014
Mark J. Niciu, David A. Luckenbaugh, Dawn F. Ionescu et al.
55 citations
A single low-dose infusion of the anesthetic ketamine produces rapid antidepressant effects in people with treatment-resistant major depressive disorder. In this trial, depressed individuals with a family history of alcohol use disorder showed a longer-lasting antidepressant response to ketamine compared to those without such a family history. Adding the drug riluzole did not extend or enhance ketamine's antidepressant durability. The findings suggest that family history of alcohol use disorder may predict a more durable ketamine response, which should be accounted for in future ketamine depression studies.
The International Journal of Neuropsychopharmacology
March 25, 2010
Joyce Colussi‐mas, Richard J. Wise, Alex Howard et al.
51 citations
In rats that learned to self-administer MDMA, a later injection of the drug triggered renewed drug-seeking behavior. The strength of this drug seeking was greater in rats that had acquired self-administration more quickly and in those that showed larger MDMA-induced increases in dopamine in the dorsal striatum. Rats that never learned to self-administer MDMA or that received the drug passively did not show this effect. The findings suggest that individual differences in initial sensitivity to MDMA's reinforcing effects and in the drug's ability to elevate striatal dopamine influence the propensity to seek the drug after a period of abstinence.
The International Journal of Neuropsychopharmacology
December 28, 2014
Stephanie M. Gorka, Daniel A. Fitzgerald, Harriet de Wit et al.
43 citations
Δ(9)-Tetrahydrocannabinol (THC) enhances functional connectivity between specific amygdala subregions (basolateral and superficial) and the rostral anterior cingulate/medial prefrontal cortex during social threat processing in healthy adults. This effect may help reduce threat perception or improve socio-emotional regulation, shedding light on the neurocircuitry underlying affective processes. The findings come from a double-blind, placebo-controlled, within-subjects study with 16 participants using functional magnetic resonance imaging.
The International Journal of Neuropsychopharmacology
May 16, 2017
André Schmidt, Felix Müller, Patrick C. Dolder et al.
41 citations
Methylphenidate and modafinil, but not MDMA (ecstasy), improved the ability to stop a motor response in healthy adults. Using brain imaging, methylphenidate broadly activated frontal, temporal, and parietal regions, including the anterior cingulate cortex and presupplementary motor area, more than modafinil did. Modafinil increased activation in the right middle frontal gyrus and parietal lobule, while MDMA activated the right middle/inferior frontal gyrus and superior parietal lobule without improving performance. The findings suggest that methylphenidate may be superior to modafinil and MDMA for enhancing cognitive performance related to response inhibition in healthy people.
The International Journal of Neuropsychopharmacology
July 23, 2020
Danilo de Gregorio, Joshua Dean Conway, Martha López-canul et al.
39 citations
Chronic exposure to a low dose of THC (1 mg/kg) during adolescence in rats leads to depressive-like behaviors (increased immobility in the forced swim test and anhedonia in the sucrose preference test) and anxiety-like behavior (fewer open-arm entries in the elevated plus maze). Adult exposure also produces anxiety but not depressive-like behaviors. Both adolescent and adult THC exposure reduce the activity of serotonin neurons in the dorsal raphe, while noradrenergic neurons in the locus coeruleus remain unaffected. These findings suggest that the serotonin system is vulnerable to chronic low-dose THC, and that adolescents are particularly susceptible to THC-induced depressive effects.
The International Journal of Neuropsychopharmacology
October 14, 2010
María Juliana Orejarena, Laurence Lanfumey, Rafaël Maldonado et al.
38 citations
The serotonin 5-HT2A receptor plays a crucial role in the reinforcing and addictive properties of MDMA. In experiments with mice, those lacking the 5-HT2A receptor showed reduced self-administration of MDMA at both 0.125 and 0.25 mg/kg per infusion compared to normal mice. MDMA increased horizontal locomotion more in the knockout mice than in normal mice. Dopamine release in the nucleus accumbens was lower in knockout mice both at baseline and after MDMA challenge. Cue-induced reinstatement of MDMA-seeking behavior was blocked by a selective 5-HT2A receptor antagonist at 0.5 mg/kg. These findings suggest that 5-HT2A receptors are essential for MDMA's reinforcing effects and for relapse triggered by drug-associated cues, likely through modulation of dopamine activity in the brain's reward pathway.
The International Journal of Neuropsychopharmacology
June 6, 2025
Naim Zaki, Li Nancy Chen, Rosanne Lane et al.
32 citations
In a long-term extension study (SUSTAIN-3) involving 1,148 adults with treatment-resistant depression, esketamine nasal spray combined with an oral antidepressant was evaluated for safety and efficacy over up to 79 months (median 45.8 months). Common adverse events included headache (36.9%), dizziness (33.9%), and nausea (33.6%). Nine participants died, with causes including COVID-19 and suicide. Depressive symptoms, measured by the MADRS, improved during the initial induction phase (average reduction of 12.8 points) and this improvement was maintained during the optimization/maintenance phase. At the end of maintenance, 49.6% of participants were in remission. No new safety concerns emerged, and depression improvement generally persisted for those continuing treatment.
The International Journal of Neuropsychopharmacology
February 12, 2016
Marta Valle, Montserrat Puntes, Jimena Coimbra et al.
31 citations
Salvinorin-A, a terpene from the plant Salvia divinorum, induces an intense but short-lasting altered state of awareness similar to classical psychedelics, but it acts on kappa-opioid receptors rather than serotonin-2A receptors. In a double-blind, placebo-controlled study with 24 healthy volunteers experienced with psychedelics, inhalation of 1 mg of vaporized salvinorin-A severely reduced external sensory perception, caused intense visual and auditory modifications, and increased systolic blood pressure, cortisol, and prolactin. These effects were effectively blocked by the opioid antagonist naltrexone (50 mg orally) but not by the serotonin-2A antagonist ketanserin (40 mg orally), confirming that salvinorin-A's mechanism involves kappa-opioid receptor agonism and not serotonin-2A agonism.
The International Journal of Neuropsychopharmacology
April 24, 2014
Hong‐yi Chiu, Ming‐huan Chan, Mei-Yi Lee et al.
31 citations
A single-day 'binge' dosing regimen of methamphetamine in male mice impaired recognition memory, reduced social behaviors, and increased sensitivity to a hallucinogenic drug that activates serotonin 5-HT2A receptors. The heightened behavioral, molecular, and electrophysiological responses to the hallucinogen were linked to an up-regulation of 5-HT2A receptors in the medial prefrontal cortex, while 5-HT2C and 5-HT1A receptors remained unchanged. These findings suggest that methamphetamine-induced changes in 5-HT2A receptor expression may contribute to psychosis-like behaviors and could inform therapies for methamphetamine-related psychiatric disorders.
The International Journal of Neuropsychopharmacology
June 10, 2013
José L. Moreno, Javier González-Maeso
30 citations
Psychedelic drugs like LSD and dissociative drugs like PCP produce psychotic and cognitive symptoms in healthy people that resemble aspects of schizophrenia. Serotonin 5-HT2A and metabotropic glutamate 2 receptors are involved in how these drugs work. This review examines recent studies using LSD-like and PCP-like drugs in rodents that link these receptors to the biology of schizophrenia and its treatment.
The International Journal of Neuropsychopharmacology
July 5, 2021
Sven Melker Hagsäter, Robert Pettersson, Christopher Pettersson et al.
29 citations
Activating the 5-HT2A serotonin receptor with drugs such as psilocybin reduces conditioned fear in male rats, an effect blocked by a 5-HT2A inverse agonist. Inverse agonists alone did not change fear behavior, but they unmasked a fear-reducing effect of the SSRI escitalopram, which by itself had no effect. These results suggest that 5-HT2A receptor activation is not required for normal conditioned freezing but can dampen fear when over-activated. In the presence of an SSRI, the 5-HT2A receptor appears to oppose the anti-freezing effect of increased serotonin levels.
The International Journal of Neuropsychopharmacology
December 29, 2020
Mu-Hong Chen, Wan-Chen Chang, Wei-Chen Lin et al.
28 citations
Depression involves disrupted communication between the frontal cortex and striatum. In 48 patients with treatment-resistant depression, those with lower baseline connectivity in these circuits showed greater symptom improvement after a single low-dose (0.2 mg/kg) ketamine infusion, but not after a higher dose (0.5 mg/kg) or placebo. Reduced connectivity between the superior frontal cortex and striatum predicted treatment response. Patients had weaker frontostriatal connections than healthy controls.
The International Journal of Neuropsychopharmacology
December 2, 2008
Sami Ben Hamida, A. Tracqui, Anne Pereira de Vasconcelos et al.
27 citations
Taking the club drug ecstasy (MDMA) together with alcohol (ethanol) increases the drug's levels in the blood and brain, which may explain why alcohol amplifies MDMA's stimulant effects. In rats, alcohol raised MDMA concentrations in the blood, hippocampus, frontal cortex, and striatum within 15 to 60 minutes after injection, without changing the proportion converted to its active metabolite MDA. MDMA and MDA accumulated more in the striatum and cortex than in the hippocampus. These higher brain and blood levels suggest that combining alcohol with MDMA could increase the risk of neurotoxicity and potential for abuse.
The International Journal of Neuropsychopharmacology
August 1, 2005
Eszter Kirilly, Anita Benkő, Linda Ferrington et al.
26 citations
A single dose of MDMA (15 mg/kg) in male Dark Agouti rats caused lasting damage to the serotonin system, shown by 30–60% reductions in paroxetine binding in the forebrain and decreased brain glucose metabolism in aggression-related areas. Despite this neurotoxicity, aggressive behaviors (biting, boxing, wrestling) were not significantly different from controls three weeks later, and the acute anti-aggressive effects of MDMA and two 5-HT1B receptor agonists remained intact. The findings suggest that aggressive behavior and the acute anti-aggressive action of MDMA are preserved even with substantial serotonergic damage, at least under the social isolation conditions of the resident-intruder test.
The International Journal of Neuropsychopharmacology
November 22, 2017
André Schmidt, Felix Müller, Patrick C. Dolder et al.
25 citations
Modafinil, but not methylphenidate or MDMA, increased brain activity in a limbic-cortical-striatal-pallidal-thalamic circuit and the amygdala when healthy subjects viewed fearful faces. Activation in frontal brain regions correlated with increased feelings of fearfulness and depressiveness after modafinil. Despite modafinil's cognitive enhancement effects, potential adverse effects on emotion processing should be considered.