The International Journal of Neuropsychopharmacology
January 11, 2013
Tori L. Schaefer, Curtis E. Grace, A Braun et al.
24 citations
In rats, treatment with the recreational drug MDMA during a developmental period equivalent to the human third trimester causes long-term spatial and egocentric learning and memory deficits, along with serotonin reductions. Pretreatment with the antidepressant citalopram, a selective serotonin reuptake inhibitor, did not prevent these cognitive deficits. Unexpectedly, citalopram alone produced learning deficits as severe as those caused by MDMA. These are the first findings showing cognitive impairments from developmental exposure to a selective serotonin reuptake inhibitor, suggesting the need for further research on the long-term safety of antidepressants during pregnancy.
The International Journal of Neuropsychopharmacology
August 10, 2022
Anne Weigand, Matti Gärtner, Milan Scheidegger et al.
22 citations
Activity in the pregenual anterior cingulate cortex (pgACC) during emotional stimulation can predict how well a single intravenous infusion of ketamine will relieve depression symptoms in people with major depressive disorder. In 24 patients, pgACC activity was linked to an increase in glutamate in the same brain region 24 hours after the infusion, and this glutamate increase was associated with greater symptom improvement. The findings suggest pgACC activity may serve as a neuroimaging biomarker for early treatment response to ketamine.
The International Journal of Neuropsychopharmacology
April 7, 2020
Michel Nijs, Ewa Wajs, Leah Aluisio et al.
21 citations
For patients with treatment-resistant depression, adjusting how often they use esketamine nasal spray based on their symptoms can help maintain or improve treatment response. In an open-label study of 778 patients, those who responded to twice-weekly esketamine during a 4-week induction phase then had their treatment frequency reduced to weekly. After four weeks of weekly treatment, 26% of 580 responders continued to improve, 50% maintained benefit, and 24% worsened. When frequency was further reduced to every other week, 19% improved, 49% maintained benefit, and 32% worsened. For patients who lost remission after reducing frequency, increasing back to weekly led to 47% improving, 43% staying the same, and 10% worsening. These results suggest that personalizing esketamine treatment frequency can optimize outcomes.
The International Journal of Neuropsychopharmacology
February 8, 2017
Alexander Bryson, Olivia Carter, Trevor R. Norman et al.
19 citations
Functional neurological disorders are common, have poor outcomes, and few treatments exist. Their cause is unknown, but leading theories suggest a disturbance in how the mind represents the body, with abnormal top-down cognitive influences on sensorimotor function despite intact neural pathways. Recent studies indicate that 5-HT2A agonists, such as psychedelics, alter brain activity in ways that disrupt hierarchical dynamics and modulate networks involved in self-processing. Converging evidence suggests these agents may hold unique therapeutic potential for these disorders. Given the personal and societal burden, the authors argue a clinical trial to test this hypothesis is warranted.
The International Journal of Neuropsychopharmacology
February 14, 2014
Vibe G. Frøkjær, David Erritzøe, Klaus K. Holst et al.
19 citations
Prefrontal serotonin transporter binding is positively associated with the cortisol awakening response, a measure of hypothalamic-pituitary-adrenal-axis output, in both MDMA users and non-users. MDMA users showed a significantly higher cortisol awakening response than non-users. The findings suggest that the inhibitory control on HPA-axis output is less efficient after recent MDMA use, likely through mechanisms beyond those compensated by reduced serotonin transporter levels.
The International Journal of Neuropsychopharmacology
November 29, 2024
Helen M Collins
18 citations
Psychedelics are being investigated as treatments for several mental health conditions, including obsessive–compulsive disorder (OCD). Since the 1960s, case studies have reported improvements in obsessive and compulsive behaviors after recreational psychedelic use. A small 2006 open-label trial found that psilocybin significantly reduced OCD symptoms, and rodent models show reduced compulsive behaviors after psilocybin. However, the mechanisms remain unclear, with hypotheses involving acute pharmacological effects, neuroplasticity changes, and altered resting state neural networks. This review evaluates evidence for psychedelics in OCD treatment, discusses mechanisms, and notes ongoing trials addressing current knowledge gaps.
The International Journal of Neuropsychopharmacology
January 12, 2022
Genís Ona, Frederic Sampedro, Sergio Romero et al.
17 citations
Kappa opioid receptor (KOR) agonists like salvinorin-A produce psychotomimetic effects through largely unknown mechanisms. In a double-blind, crossover, randomized, placebo-controlled study, acute administration of salvinorin-A increased delta and gamma brain waves while decreasing alpha waves, as measured by electroencephalography. Single-photon emission computed tomography revealed significant decreases in regional cerebral blood flow across frontal, temporal, parietal, and occipital cortices, with increases in the medial temporal lobe, amygdala, hippocampal gyrus, and cerebellum. Subjective effects resembled other psychotomimetic drugs but were distinctly dissociative, with no dysphoria reported. KOR agonism by salvinorin-A induces dramatic psychotomimetic effects alongside generalized reductions in cortical blood flow and electrical activity.
The International Journal of Neuropsychopharmacology
March 1, 2003
Tarek Zghoul, Pierre Blier
13 citations
LSD enhances the inhibitory effect of serotonin on neurons in the orbitofrontal cortex, a brain region linked to obsessive-compulsive disorder (OCD), while reducing serotonin's inhibitory effect in the hippocampus, a region linked to depression. In rats under anesthesia, LSD applied directly to neurons decreased their firing rate and boosted serotonin's inhibitory action in the orbitofrontal cortex, but weakened it in the hippocampus. After four daily injections of LSD, the same pattern persisted 24 hours after the last dose, suggesting a lasting change in serotonin responsiveness. This enhancement in the orbitofrontal cortex may explain why some hallucinogens have anti-OCD effects that outlast their psychotomimetic action.
The International Journal of Neuropsychopharmacology
October 1, 2024
Gargi Mandal, Madeline Kirkpatrick, Silvia Alboni et al.
12 citations
Both enantiomers of ketamine—arketamine (R-ketamine) and esketamine (S-ketamine)—prevented cytokine-induced reductions in hippocampal neurogenesis and increases in apoptosis in a fetal hippocampal progenitor cell line. The protective effects were mediated by inhibition of specific inflammatory cytokines: R-ketamine blocked IL-1β-induced production of IL-2 and IL-13, while S-ketamine blocked IL-1β-induced tumor necrosis factor-alpha. Both enantiomers also prevented IL-1β-induced activation of the neurotoxic kynurenine pathway, but neither prevented IL-6-induced kynurenine pathway activation. The findings suggest ketamine's antidepressant mechanisms involve pro-neurogenic and anti-inflammatory actions that depend on the inflammatory context.
The International Journal of Neuropsychopharmacology
December 14, 2022
David Williamson, Ibrahim Turkoz, Ewa Wajs et al.
11 citations
Dissociation encompasses distinct phenomena, some linked to esketamine treatment and potentially overlapping with psychosis symptoms. In a post hoc analysis of data from an open-label, phase 3 study of esketamine plus a newly initiated oral antidepressant in patients with treatment-resistant depression, dissociation was reported as an adverse event in 14.3% (109/764) of patients. CADSS scores generally aligned with investigator-reported dissociation severity, but no cutoff point reliably distinguished presence from absence of dissociation events. Hallucinations occurred in 5 patients, and no delusions were reported, indicating psychotic symptoms were uncommon.
The International Journal of Neuropsychopharmacology
December 3, 2021
Benjamin Hackl, Hannes Todt, Helmut Kubista et al.
11 citations
Psilocybin, the hallucinogen in magic mushrooms, is being studied for psychiatric disorders, but safety concerns arose after reports of cardiac events and QT interval prolongation linked to its metabolite psilocin. Clinical concentrations of psilocin do not significantly inhibit the hERG potassium channel, a key risk factor for adverse cardiac effects. Therefore, hERG channel blockage by psilocin is not responsible for psilocybin-associated cardiotoxicity.
The International Journal of Neuropsychopharmacology
December 28, 2024
Michael J Mueller, Helena Aicher, Dario Dornbierer et al.
10 citations
A new pharmaceutical formulation combining pure DMT and harmine produced ayahuasca-like psychological effects lasting 2-3 hours in 31 healthy male volunteers, with consistent drug levels and no serious adverse events. DMT reached peak plasma concentrations of 22.1 ng/mL, while buccal harmine reached 32.5 ng/mL in a sustained-release profile but caused no distinguishable subjective effects on its own. All drug conditions were safe and well tolerated, suggesting the formulation could reduce risks and improve therapeutic outcomes for mental health disorders.
The International Journal of Neuropsychopharmacology
May 27, 2016
Filip Tylš, Michaela Viktorinová, Dominika Prokopcova et al.
10 citations
Among first-episode, drug-naive Han Chinese patients with schizophrenia, 24.5% had impaired glucose tolerance, compared to none of the healthy controls. Patients also had higher fasting and two-hour glucose levels, greater insulin resistance, and higher waist circumference, BMI, and triglycerides. Those with impaired glucose tolerance were older, had later schizophrenia onset, and scored higher on total and negative symptom scales, but showed no greater cognitive impairment except on an emotional intelligence measure. Abnormal glucose metabolism may be linked to clinical symptoms but not cognitive impairment in early schizophrenia.
The International Journal of Neuropsychopharmacology
November 1, 2024
Randall L. Morrison, Jaskaran Singh, Ella Daly et al.
9 citations
In patients with treatment-resistant depression, adding esketamine nasal spray to a newly initiated oral antidepressant did not harm cognitive function over the short or long term. Across three short-term double-blind studies (747 patients aged 18–64 years) and one long-term maintenance study (137 patients aged 65 or older), cognitive performance on tests of psychomotor function, attention, and memory either remained stable or slightly improved from baseline to the end of treatment. At the start, patients showed mild-to-moderate cognitive impairment. The correlation between depression severity and cognitive performance was weak. The analysis found no evidence that esketamine worsens cognition in treatment-resistant depression.
The International Journal of Neuropsychopharmacology
April 1, 2024
Sumra Sajid, Hanga C Galfalvy, John G Keilp et al.
9 citations
In a randomized, midazolam-controlled trial of 40 suicidal, depressed participants given intravenous ketamine, acute dissociative and psychotomimetic effects were not associated with changes in suicidal ideation or depressive symptoms from before to after infusion. Norketamine showed a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection, suggesting dissociation may be more an effect of the parent drug. Dehydronorketamine correlated with dissociative symptoms at multiple time points. No evidence was found that ketamine's acute, transient dissociative or psychotomimetic effects contribute to its antidepressant or anti-suicidal actions.
The International Journal of Neuropsychopharmacology
May 25, 2025
Ines Erkizia-Santamaría, Nerea Martínez-Álvarez, Leyre Salinas-Novoa et al.
7 citations
The intensity of acute psychedelic effects from psilocybin is inversely related to cortical serotonin levels. In mice, the head-twitch response—a behavioral measure of psychedelic-like effects—was lower in animals lacking the serotonin 2A receptor and was dose-dependently reduced by the antidepressant citalopram, which increases synaptic serotonin. Conversely, depleting serotonin with p-chlorophenylalanine potentiated the response. A serotonin 1A receptor agonist also decreased the response, indicating functional interaction between receptor types. These findings suggest that prior antidepressant treatment may influence individual variability in acute responses to psilocybin, with implications for optimizing psychedelic-based therapies.
The International Journal of Neuropsychopharmacology
December 1, 2024
Craig Chepke, Richard C. Shelton, Gerard Sanacora et al.
7 citations
Esketamine nasal spray, approved for treatment-resistant depression and major depressive disorder with suicidal thoughts, rarely causes respiratory depression after marketing. Analysis of 47 months of postapproval safety data found 50 cases of respiratory depression among patients, with 8 strongly linked to the drug. The estimated incidence is 1 case per 20,000 treatment sessions. Symptoms are manageable and resolve with minor support. Monitoring, including pulse oximetry, is recommended during postdose observation.
The International Journal of Neuropsychopharmacology
February 4, 2025
Yingliang Dai, Ben J. Harrison, Christopher G. Davey et al.
6 citations
Ketamine, a fast-acting antidepressant, works by blocking N-methyl-D-aspartate receptors. While its molecular mechanisms are known, its large-scale neurocognitive effects are less clear. This synthesis links ketamine treatment to changes in brain systems for reward processing, interoception, and self-related cognition. The authors suggest that ketamine's antidepressant effects arise from dynamic, multi-level influences across these functional domains.
The International Journal of Neuropsychopharmacology
April 26, 2021
Alison Wakeford, Alexander M. Sherwood, Thomas E Prisinzano et al.
6 citations
Synthetic cathinones produce behavioral effects similar to either psychostimulants like methamphetamine or entactogens like MDMA, depending on their dopaminergic or serotonergic activity. In squirrel monkeys trained to distinguish methamphetamine or MDMA from a placebo, cathinones such as MDPV, α-PVP, and methcathinone fully substituted for methamphetamine but only partially for MDMA, indicating primarily dopamine-mediated effects. Conversely, mephedrone and methylone fully substituted for MDMA but not for methamphetamine, suggesting a primary role for serotonin. These differences in interoceptive effects in nonhuman primates may reflect the subjective effects these drugs produce in humans.
The International Journal of Neuropsychopharmacology
May 27, 2016
Tomáš Páleníček, Filip Tylš, Michaela Viktorinová et al.
6 citations
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The International Journal of Neuropsychopharmacology
June 1, 2024
Thomas Liebe, Lena Vera Danyeli, Zümrüt Duygu Sen et al.
5 citations
Ketamine, an NMDA antagonist used as a rapid-acting antidepressant, disrupts the functional connectivity between the locus coeruleus (LC) and the thalamus, which is linked to a reduction in behavioral alertness. In a placebo-controlled, cross-over study with 35 healthy male participants (average age 25.1 years), ultra-high field 7T functional MRI revealed that acute disruption of the LC alertness network by ketamine correlates with decreased alertness. These findings highlight ketamine's effects beyond the glutamatergic system, suggesting a new mechanism involving noradrenergic pathways that may contribute to its antidepressant properties.
The International Journal of Neuropsychopharmacology
October 1, 2025
Igor D. Bandeira, Luke A. Jelen, Jason Tucciarone et al.
4 citations
This review examines the current evidence for ketamine and esketamine in treating major depression, focusing on efficacy, safety, and mechanisms of action. The authors synthesize findings from clinical trials and mechanistic studies, noting that ketamine can produce rapid antidepressant effects, though the durability and optimal dosing regimens remain under investigation. They discuss potential adverse effects and the need for careful patient selection and monitoring. The review highlights ongoing research into biomarkers and treatment protocols to improve outcomes and reduce relapse rates, while acknowledging that long-term safety data are still limited.
The International Journal of Neuropsychopharmacology
January 30, 2024
Blake A Fordyce, Bryan L. Roth
4 citations
Psychedelic compounds from natural sources have been consumed for centuries. Modern scientists now use computational tools, cellular assays, and behavioral metrics to study how these compounds cause changes across molecular, cellular, circuit, and system levels. This paper reviews the history of psychedelics in science, medicine, and culture, outlines current pharmacological research techniques, and identifies gaps in knowledge about the physiological changes induced by psychedelics, the limits of their therapeutic potential, and how to improve treatments becoming accessible worldwide.
The International Journal of Neuropsychopharmacology
March 29, 2025
Michal Lazar, Michal Brownstien, Alexander Botvinnik et al.
3 citations
Mice lacking the SAPAP3 gene (SAPAP3-KO) develop excessive self-grooming at 4–6 months, modeling obsessive-compulsive disorder (OCD). Before that, juvenile (10–13 week) homozygous knockout mice showed anxiety-like behaviors—less time in open field centers and elevated plus maze open arms, fewer marbles buried, and fewer buried Oreos found—compared to wild-type mice. Psilocybin (4.4 mg/kg) did not improve these behaviors. In adult (but not juvenile) male homozygous knockout mice, levels of the synaptic proteins GAP43, synaptophysin, and SV2A increased across multiple brain regions; SV2A also increased in the frontal cortex of adult female homozygotes. These age-dependent protein changes may reflect compensatory plasticity linked to the OCD-like phenotype.
The International Journal of Neuropsychopharmacology
February 4, 2025
Yulin Feng, Yinghua Lv, Juan Yang et al.
3 citations
Combination therapies outperform monotherapy for treatment-resistant depression, achieving an additional 6.5% reduction in depression scores over 12 weeks. The most effective combinations were olanzapine with fluoxetine and quetiapine with SSRIs/SNRIs. Injectable treatments, particularly ayahuasca, produced rapid effects, with a 77% reduction in depression scores at 15 days. Intranasal treatments reached efficacy sooner than oral ones, with 28-day efficacy similar to the 12-week efficacy of the olanzapine-fluoxetine combination. Dropout rates due to adverse events were similar across methods (4.5%-5.2%), but total dropouts were highest for oral (17.9%) and lowest for intranasal routes (10.6%). There was considerable variation in headache, dizziness, and nausea incidence across administration routes.