The international journal of neuropsychopharmacology
August 1, 2010
Nicolas Tournier, Lucie Chevillard, Bruno Megarbane et al.
122 citations
Several drugs used in addiction treatment and substances of abuse inhibit the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro, which could alter their distribution in the body, including across the blood-brain barrier. Norbuprenorphine, buprenorphine, methadone, ibogaine, and THC inhibited P-gp in a concentration-dependent manner, with norbuprenorphine being the strongest. Buprenorphine, norbuprenorphine, ibogaine, and THC inhibited BCRP. Cocaine, amphetamine, nicotine, morphine, and others did not inhibit either transporter. Norbuprenorphine and methadone were transported by P-gp, but no tested compounds were transported by BCRP. The clinical relevance of norbuprenorphine's interaction with P-gp remains unclear.
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
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
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
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
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 28, 2024
Michael J Mueller, Helena D Aicher, Dario A 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
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
December 1, 2024
Craig Chepke, Richard 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
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
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.
The international journal of neuropsychopharmacology
May 1, 2024
Gessica Piras, Cristina Cadoni, Francesca Caria et al.
3 citations
The synthetic stimulant 2-Cl-4,5-MDMA, an NPS linked to severe intoxications, increased dopamine and serotonin levels in the nucleus accumbens shell and medial prefrontal cortex of rats in a dose-, brain area-, and age-dependent manner. In adult rats, dopamine rose more markedly in both brain areas, while adolescent rats showed a greater serotonin increase in the nucleus accumbens shell. The drug stimulated locomotion and stereotyped activity more in adolescents but did not trigger 50-kHz ultrasonic vocalizations, suggesting no positive affective properties. These findings indicate age-dependent neurochemical and behavioral effects, helping to assess health risks from human use.
The international journal of neuropsychopharmacology
June 6, 2025
Benjamin Spurny-Dworak, Thomas Liebe, Samantha Graf et al.
2 citations
A single subanesthetic dose of intranasal esketamine rapidly increases the volume of specific right thalamic structures in healthy young adults. In a placebo-controlled crossover study with 26 participants, magnetic resonance imaging revealed significant enlargement of the right thalamus, the pulvinar anterior nucleus, and the right mediodorsal lateral parvocellular nucleus after esketamine administration. These structural changes occurred in thalamic regions that relay visual information to the cortex, suggesting that ketamine's effects on visual perception may arise from rapid adaptations in these brain areas. The findings highlight the thalamus as a key target for modeling schizophrenia symptoms and understanding ketamine's mechanism of action.
The international journal of neuropsychopharmacology
October 1, 2024
Nicholas E Bulthuis, Josephine C McGowan, Liliana R Ladner et al.
2 citations
Ketamine, a rapid-acting antidepressant, requires a specific NMDA receptor subunit (GluN2B) on adult-born neurons in the hippocampus to produce its effects, but this requirement differs between sexes. In male mice, GluN2B on 6-week-old adult-born neurons is necessary for ketamine to reduce behavioral despair, suppress feeding anxiety, and alter fear behavior. In female mice, GluN2B on these neurons is needed only for reducing feeding anxiety. Removing GluN2B from younger 2-week-old neurons did not replicate these effects. Eliminating adult neurogenesis increased fear expression, which ketamine administration counteracted. These findings indicate that 6-week-old adult-born hippocampal neurons partially mediate ketamine's rapid antidepressant actions, suggesting a target for improving treatment efficacy.
The international journal of neuropsychopharmacology
August 1, 2025
Klára Šíchová, Barbara Mallarino, Lucie Janečková et al.
1 citation
Hexahydrocannabinol (HHC), a new psychoactive substance used as a legal alternative to ∆9-tetrahydrocannabinol, crosses the blood-brain barrier, exhibits mild toxicity, and induces behavioral effects similar to tetrahydrocannabinol in male Wistar rats. A 1:1 mixture of (9R)-HHC and (9S)-HHC was given at doses of 1, 5, and 10 mg/kg. Two hours after the highest dose, peak concentrations appeared in blood and brain tissue. The OECD 423 test classified HHC as Category 4, with an estimated lethal dose of 1000 mg/kg. Compared to controls, 10 mg/kg HHC reduced movement, increased anxiety, and impaired sensory processing, highlighting dose-dependent anxiogenic properties and impact on information processing.
The international journal of neuropsychopharmacology
June 2, 2026
John R Kelly, Christopher Sheridan, Patricia Iusan et al.
Classical serotonergic psychedelics like psilocybin show emerging evidence of therapeutic potential across depression, anxiety, and substance use disorders, with indications of transdiagnostic efficacy. Early-phase studies yielded encouraging results, but recent larger-scale phase 3 trials for treatment-resistant depression have shown more modest effects. No regulatory approvals from the U.S. FDA or EMA exist, though a few countries permit psychedelic therapies in regulated clinical settings. The long-term trajectory and real-world impact within public health systems remain uncertain. This paper examines challenges for integrating psychedelic therapies into Ireland's public healthcare system, covering regulatory approval, Health Technology Assessment, service implementation, workforce capacity, and evaluation of long-term patient outcomes.
The international journal of neuropsychopharmacology
May 3, 2026
Kuan-I Liu, Wei-Chen Lin, Cheng-Ta Li et al.
Intravenous ketamine rapidly reduces depressive symptoms in treatment-resistant depression, but its effects vary by symptom. In a pooled analysis of two randomized controlled trials involving 154 adults, ketamine significantly improved total depression scores and seven individual symptoms, including suicidal thoughts. However, the degree of treatment resistance, measured by the Maudsley Staging Method, moderated improvements in apparent sadness and inner tension: patients with higher resistance showed less benefit. In contrast, the anti-suicidal effect of ketamine remained robust regardless of resistance severity. These exploratory findings suggest that symptom-specific treatment strategies may be needed, with ketamine potentially serving as an acute intervention for suicidal crises across resistance levels, while highly refractory patients may require augmentation for certain affective symptoms.