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 Janeckova 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
February 1, 2025
Martin Kuchař, Klara Gotwaldova, Jan Borovička et al.
1 citation
Tryptamine concentrations in psychotropic mushrooms vary enormously, which may alter medicinal effects compared to chemically pure psilocybin. Storage conditions strongly affect alkaloid decay: the greatest degradation occurred in fresh mushrooms stored at −80°C, while the least decay was seen in dried biomass kept in the dark at room temperature. The study measured psilocybin, psilocin, baeocystin, norbaeocystin, and aeruginascin in a large sample set of mushroom genera, using freshly cultivated Psilocybe cubensis fruit bodies for stability monitoring, and analyzed mycelium and individual fruiting body parts with validated UHPLC-MS/MS.
The International Journal of Neuropsychopharmacology
February 1, 2025
Clara Cavallotto, Giacomo D’andrea, Andrea Miuli et al.
1 citation
In patients with treatment-resistant depression, combining the antidepressant vortioxetine with esketamine nasal spray was as effective as the standard combination of an SSRI or SNRI with esketamine in reducing depressive symptoms over three months. The vortioxetine combination showed a larger effect in reducing emotional blunting and was linked to fewer treatment-emergent side effects, including dissociative symptoms. These findings suggest vortioxetine plus esketamine may be a valuable alternative, though larger randomized trials are needed to confirm the results.
The International Journal of Neuropsychopharmacology
May 27, 2016
Jee-Hyung Suh, Tae Young Lee, Jun Soo Kwon
1 citation
Psilocybin, a hallucinogen that mimics psychotic symptoms, alters brain connectivity in ways similar to psychosis. In a double-blind placebo-controlled trial with 20 healthy subjects, standard coherence analysis showed decreased connectivity in theta, alpha, and beta brainwave bands, particularly in frontotemporal and frontoparietal regions, along with frontal interhemispheric disconnection. Changes in higher frequencies were less significant and often opposite. In contrast, eLORETA connectivity analysis found no changes in lower frequencies but increased connectivity in high gamma (50-100 Hz). These preliminary results suggest psilocybin-induced connectivity changes align with those seen in psychotic patients.
The International Journal of Neuropsychopharmacology
July 6, 2026
Shabah M. Shadli, Neda Nasrollahi, Calvin K. Young et al.
Ketamine at low doses (0.5-1.0 mg/kg I.M.) quickly reduces symptoms in treatment-resistant major depressive disorder (TR-MDD), post-traumatic stress disorder (TR-PTSD), and obsessive-compulsive disorder (TR-OCD), but its neural effects differ by diagnosis. EEG recordings of resting frontal activity before and after ketamine or fentanyl showed that TR-PTSD patients had dose- and band-frequency-dependent power changes (especially alpha at 0.5 mg/kg), while TR-MDD patients showed no such changes. TR-OCD responses differed qualitatively from both. Correlations between EEG power changes and symptom scale improvements varied by band and electrode across different disorder-specific scales. Ketamine's effects and their therapeutic links vary by brain site and frequency band depending on the DSM diagnosis, suggesting disorder-specific systems require a ketamine-sensitive factor to generate the disorder.
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 5, 2026
Hiroyuki Uchida, Gabriella Gobbi, Joseph Zohar et al.
Between 2013 and 2026, neuropsychopharmacology advanced from stagnation to momentum, producing several first-in-class treatments: rapid-acting drugs for treatment-resistant depression (intranasal esketamine), psychedelic-assisted therapy for PTSD and depression, neuroactive steroid GABA-A receptor positive allosteric modulators (brexanolone, zuranolone) for postpartum depression, non-dopaminergic muscarinic agonists (xanomeline-trospium) for schizophrenia, orexin receptor antagonists for insomnia, and anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early Alzheimer's disease.
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.
The International Journal of Neuropsychopharmacology
August 1, 2025
Bernard Lerer, T. Tal, Ilana Pogodin et al.
Combining psilocybin with NMDAR modulators D-serine or D-cycloserine may enhance therapeutic benefits while reducing adverse effects. In mice, psilocybin alone increased head twitch response, a proxy for hallucinogenic effects, but co-administration of D-serine or D-cycloserine reduced this response dose-dependently. The combinations also decreased MK-801-induced hyperactivity, modeling antipsychotic effects, whereas psilocybin alone did not. Additionally, psilocybin with D-serine boosted GAP43 protein expression across four brain regions and overall synaptic protein levels in the hippocampus, while psilocybin with D-cycloserine elevated PSD95 levels across all regions. These results suggest that such combinations could optimize psilocybin's therapeutic potential by mitigating side effects and enhancing neuroplasticity.
The International Journal of Neuropsychopharmacology
August 1, 2025
Nicolo Fabila, Nimshitha Pavathuparambil Abdul Manaph, V Rudkowsky et al.
Psilocybin, at a dose of 2 mg/kg, did not reduce compulsive eating in a rat model of binge eating disorder. Female rats given intermittent access to a high-fat/high-sugar diet for 10 weeks showed no change in how quickly they started eating or how much they ate after psilocybin treatment, compared to saline. The compound may have affected freezing behavior, suggesting possible modulation of fear-related learning and memory circuits, though analysis is ongoing. Binge eating disorder is the most common eating disorder and current treatments are limited. Psilocybin is known to promote neuroplasticity, but at this dose it did not alter compulsive-like eating behavior in the conditioned suppression test.
The International Journal of Neuropsychopharmacology
August 1, 2025
Guy M. Goodwin
A single 25-mg dose of synthetic psilocybin (COMP360) produced larger and more durable reductions in depression severity than a 1-mg control in adults with treatment-resistant depression. Dose-dependent improvements on the Montgomery-Asberg Depression Rating Scale were evident from day 2, remained statistically significant through week 6, and were numerically still present at week 12. The intensity of the psychedelic experience, particularly feelings of boundlessness, was linked to better clinical outcomes. Over 90% of adverse events were mild or moderate. The findings suggest COMP360 may become a useful treatment for treatment-resistant depression, though suicidality remains a concern.
The International Journal of Neuropsychopharmacology
August 1, 2025
Valeria Bruno, Bruce Richardson, Martha López-canul et al.
In adult male rats, a high dose of psilocybin (10 mg/kg) did not produce rewarding effects in the conditioned place preference (CPP) paradigm, as there was no significant difference in time spent in the drug-paired compartment versus the vehicle-paired compartment. Psilocybin increased head-twitching, dog-shaking, and defecation while decreasing grooming, body licking, and rearing during conditioning sessions. These behavioral differences disappeared 48 hours after the last injection, indicating no long-term changes. The findings suggest psilocybin lacks rewarding properties and does not cause physical dependence, supporting its safety profile and therapeutic potential.
The International Journal of Neuropsychopharmacology
August 1, 2025
Hiroe Tani
Psychedelics like LSD and psilocybin are being studied again as treatments for mental illnesses, with recent rigorous trials investigating their use for depression, terminal illness, addiction, obsessive-compulsive disorder, and post-traumatic stress disorder. Psilocybin, a serotonin 2A receptor agonist, has shown rapid and robust antidepressant effects when combined with psychological support, with benefits lasting several months to a year after one or two sessions. Australia has approved psilocybin for treatment-resistant depression. Neuroimaging studies suggest psilocybin modulates brain circuits involved in mood disorders. A clinical trial in Japan is examining ketamine and psilocybin for treatment-resistant depression.
The International Journal of Neuropsychopharmacology
August 1, 2025
C Foldi
Psilocybin, the psychoactive compound in “magic” mushrooms, improves cognitive flexibility and body weight outcomes in an animal model of anorexia nervosa called activity-based anorexia. The compound's effects on learning are mediated by specific serotonin receptor subtypes, whose transcription is transiently altered in the prefrontal cortex within 24 hours after administration. Computational modeling reveals that enhanced cognitive flexibility is underpinned by altered dopamine signaling in the ventral striatum. These findings are translationally relevant for clinical use of psilocybin in anorexia nervosa, as individuals with the condition show both impaired cognitive flexibility and diminished reward processing.
The International Journal of Neuropsychopharmacology
August 1, 2025
N Acevdo, David Castle, Susan L. Rossell
Obsessive compulsive disorder, body dysmorphic disorder, and anorexia nervosa share overlapping cognitive-behavioral and neurobiological features, yet conventional treatments often yield suboptimal outcomes. Psilocybin-assisted psychotherapy shows transdiagnostic potential by improving insight, emotional regulation, and well-being. This paper presents a protocol for an open-label basket trial testing psilocybin-assisted psychotherapy across these three conditions. The protocol was developed from scoping reviews, an international Delphi study on best practices, and qualitative interviews with patients. It uses a transdiagnostic, non-directive approach, includes a psychoeducation booklet and video, a treatment manual for clinicians, clinician- and patient-reported outcomes, opt-in additional support, and long-term follow-up.
The International Journal of Neuropsychopharmacology
August 1, 2025
Yuko Ohtani, Hiroe Tani, Shiori Honda et al.
A higher baseline ratio of glutamate+glutamine (Glx) to GABA in the dorsal anterior cingulate cortex predicted greater improvement in depressive symptoms after ketamine treatment in adults with treatment-resistant depression. In the ketamine group, a reduction in this Glx/GABA ratio correlated with symptom improvement, but no such association appeared in the placebo group. The findings suggest that the balance between excitatory and inhibitory neurotransmission in this brain region may serve as a biomarker for predicting antidepressant response to ketamine.
The International Journal of Neuropsychopharmacology
August 1, 2025
Yana Babii, C. Barbara, Dorota Bederska‐łojewska et al.
Hallucinogens from different classes, such as scopolamine and psilocybin, show rapid antidepressant effects that are enhanced by blocking group II metabotropic glutamate (mGlu2/3) receptors. In mice, scopolamine reversed depressive-like behaviors induced by chronic mild stress, and a selective M1 muscarinic antagonist produced dose-dependent antidepressant effects potentiated by an mGlu2 receptor negative allosteric modulator. Scopolamine increased extracellular dopamine, serotonin, and glutamate in the frontal cortex, while the mGlu2 modulator had opposite effects on glutamate. A low dose of the mGlu2/3 antagonist LY341495 boosted the antidepressant effect of low-dose psilocybin in the tail suspension test, with rapid onset and long duration, while also reducing hallucinogenic-like head twitch responses. Combined targeting of these systems may allow lower doses and fewer side effects while maintaining antidepressant efficacy.
The International Journal of Neuropsychopharmacology
August 1, 2025
Susan Meikle, Olivia Carter, Paul Liknaitzky et al.
A small pilot trial of psilocybin with psychotherapy for treatment-resistant depression found a clinically meaningful reduction in depressive symptoms three weeks after the second dose, with an average improvement of 7.14 points on the depression scale and a large effect size. However, individual responses varied widely: two participants showed lasting improvement, three relapsed, and two saw no substantial benefit. Mindset before dosing and spiritual or perceptual experiences during the session predicted treatment trajectory, but prior expectations did not. The study supports further research into tailoring psychedelic therapy to individual differences.
The International Journal of Neuropsychopharmacology
August 1, 2025
S Kasper
A personal literature overview argues that the psychedelic experience induced by psilocybin and similar drugs is often treated as a necessary part of therapy, echoing past attitudes toward side effects of older antidepressants and antipsychotics. The author contends that this neglect of side effects remains unresolved in clinical psychopharmacology. Recent animal studies show antidepressant-like effects through opioid and glutamatergic pathways, not solely serotonergic activation. The author concludes that developing non-hallucinogenic antidepressants would be safer and therapeutically beneficial for depressed patients.
The International Journal of Neuropsychopharmacology
August 1, 2025
Giovanni Martinotti, Clara Cavallotto, G D’andrea et al.
Psilocybin, a psychedelic compound that acts on serotonin receptors, shows promise for treatment-resistant depression, with remission rates up to 70% in some studies. The antidepressant and psychedelic effects may be separable, with the latter linked to 5-HT2A receptors. By co-administering the 5-HT2A antagonist ketanserin, psilocybin's hallucinogenic effects can be minimized, reducing bias from the mystical experience and improving clinical feasibility. A proposed study will randomly assign 68 treatment-resistant depression patients to receive either non-psychedelic psilocybin (two 25 mg doses, preceded by ketanserin) or accelerated repetitive transcranial magnetic stimulation (arTMS). Outcomes will be compared at day 60 using psychometric tests, EEG, and fMRI.
The International Journal of Neuropsychopharmacology
August 1, 2025
B. D. Richardson, Marco Pileggi, Thomas Prudhomme et al.
Psilocybin and lisuride both bind to 5-HT2A receptors, but only psilocybin produces hallucinogenic effects. In adult male mice, both drugs inhibited serotonin neuron activity in the dorsal raphe nucleus and dopamine neuron firing in the substantia nigra. A 5-HT2A antagonist blocked psilocybin's serotonin inhibition but not lisuride's, suggesting different mechanisms. Only lisuride showed an antidepressant-like effect at the highest doses. Psilocybin, but not lisuride, elicited head-twitch responses, and lisuride blocked those induced by psilocybin. Both drugs reduced locomotion. The findings indicate lisuride has antidepressant and sedative effects without hallucinogenic action, likely due to its distinct effects on serotonin and dopamine neurons.
The International Journal of Neuropsychopharmacology
August 1, 2025
Cassandra J. Hatzipantelis, David E. Olson, Danielle S. Stolzenberg
In a mouse model of peripartum mood disorder, a single dose of psilocybin did not improve impaired caregiving, maternal withdrawal, or anxiety-like behaviors; treated dams were more anxious and had increased risk of overall behavioral impairments two weeks after injection. In contrast, virgin female mice given the same dose showed reduced anxiety and lower risk of behavioral impairments. Additionally, a single postnatal exposure to psilocybin through breastmilk increased the risk of behavioral phenotypes related to mood and sociability disorders in both male and female offspring when they reached adulthood. These findings suggest psilocybin may pose risks during the postpartum period for mothers and their offspring.