The International Journal of Neuropsychopharmacology
August 1, 2025
Bernard Lerer, Michal Brownstien, Mitchell A. Lazar et al.
Psilocybin and a psychedelic mushroom extract reduced compulsive marble burying and excessive self-grooming in mouse models of obsessive-compulsive disorder (OCD). A single dose of psilocybin remained effective for more than 21 days in SAPAP3-knockout mice, which model OCD and Tourette's syndrome. The mushroom extract showed slightly greater efficacy than psilocybin alone. Two novel compounds, one hallucinogenic and one non-hallucinogenic, were also effective in both mouse models. The non-hallucinogenic compound HBL20017 may offer therapeutic benefit for OCD without inducing psychedelic effects.
The International Journal of Neuropsychopharmacology
August 1, 2025
Andrew S. Gibbons, Paul Liknaitzky, Suresh Sundram
Generalised Anxiety Disorder (GAD) is often treated with psilocybin-assisted therapy (PAT), but only about 44% of participants respond. This multi-omic study compared blood samples from 11 responders and 13 non-responders after a 6-week PAT regime. Five genes were differentially expressed between groups, including CTXN2-AS1 and HLA-V. A panel of four genes (CTXN2-AS1, DUT-AS1, HLA-V, and PARP16) could distinguish 45% of responders from all other participants. These findings suggest potential blood biomarkers for predicting PAT response in GAD, though validation in larger cohorts is needed.
The International Journal of Neuropsychopharmacology
August 1, 2025
C Donegan, D Daldagen-Bueno, Robin J Murphy et al.
In an open label trial, 17 people with major depressive disorder took 15 doses of LSD at home and one in a clinic over 8 weeks. Afterward, participants reported increased connectedness to self, others, and nature; greater motivation for activities; improved mood; and better coping with negative situations. Some experienced side effects or no change in symptoms. The findings suggest that microdosing LSD may create a positive feedback loop where improved mood, behavioral activation, and connectedness reinforce each other, and that adding a titration protocol and encouraging psychologically beneficial activities could enhance benefits and reduce side effects.
The International Journal of Neuropsychopharmacology
August 1, 2025
Thibault Renoir, J. Gattuso, Bilgenur Bezcioglu et al.
Acute psilocybin reduced compulsive grooming in male mice for up to one week and in both sexes shortly after dosing, but chronic psilocybin did not improve anxiety-like, depressive-like, or compulsive-like behaviors or social deficits. The findings suggest acute psilocybin may help reduce compulsive behaviors, while repeated low-dose use offers limited benefits. The study used SAPAP3 knockout mice, a model of obsessive-compulsive disorder, and found differences in serotonin receptor signaling between genotypes. Results highlight the need for caution as psychedelic-assisted therapy gains approval, especially regarding microdosing.
The International Journal of Neuropsychopharmacology
February 1, 2025
Martha López-canul, Vivienne Nguyen, Antonio Inserra et al.
Acute administration of psilocybin reduced mechanical allodynia in a rat model of neuropathic pain but had no effect on acute thermal pain in mice. In the neuropathic pain model, psilocybin at 3 mg/kg and 10 mg/kg significantly increased mechanical withdrawal thresholds at 0.5, 1, and 2 hours after administration compared to vehicle, with no difference between the two doses. In the hot plate test, psilocybin did not raise the thermal withdrawal threshold. These preliminary findings suggest psilocybin's pain-reducing action may specifically target neuropathic pain rather than generalized acute nociception, indicating potential for treating neuropathic pain.
The International Journal of Neuropsychopharmacology
February 1, 2025
Leonard Lerer, Kathleen Spear, Jeet Varia et al.
In a zebrafish model of depression, both synthetic psilocybin and an extract from psychedelic mushrooms reversed stress-induced behavioral changes, making the fish behave similarly to non-stressed controls. The mushroom extract produced more neurotransmitter precursors in the brain than synthetic psilocybin, though no significant behavioral differences between the two treatments were observed. Whole-brain metabolomics revealed increases in GABA, vitamin B6, glutamine, and NADH, along with a decrease in xanthosine, suggesting possible neuroplastic effects. This work demonstrates the potential of zebrafish models for studying psychedelic compounds.
The International Journal of Neuropsychopharmacology
February 1, 2025
Rebecca Harding, Natalie Ertl, Rayyan Zafar
Both escitalopram and psilocybin therapy reduced impulsivity and anhedonia in people with major depressive disorder, but they altered brain connectivity in different ways. Psilocybin increased connectivity between the amygdala and the left anterior insula and putamen, and between the limbic striatal network and the bilateral insula, paracingulate, and temporoparietal junction. Escitalopram decreased connectivity between the amygdala and the right cerebellum and occipital cortex, and between the limbic striatum and the insula. The escitalopram-induced reduction in limbic striatal–insula connectivity correlated with reduced anhedonia. These results suggest the two treatments affect reward-related brain circuitry through distinct mechanisms.
The International Journal of Neuropsychopharmacology
February 1, 2025
Martine Skumlien, Tom P. Freeman, Daniel L. Hall et al.
In weekly cannabis users, cannabis suppresses the brain's anticipatory reward response to money, and cannabidiol (CBD) does not moderate this effect. The adolescent reward circuitry is not differentially sensitive to the acute effects of cannabis on reward anticipation. This double-blind, placebo-controlled, crossover study with 23 adults (26-29 years) and 24 adolescents (16-17 years) used functional magnetic resonance imaging (fMRI) to measure brain activity during a monetary reward anticipation task after inhaling cannabis with tetrahydrocannabinol (THC), THC plus CBD, or placebo. THC acutely reduced reward anticipation activity in the ventral striatum and right insula compared with placebo. THC plus CBD also reduced activity in these regions. The effects were the same in adolescents and adults.
The International Journal of Neuropsychopharmacology
February 1, 2025
Zitong Wang, Yanbo Zhang, Xin-Min Li
Psilocybin at 1.0 mg/kg reduced depressive-like behavior and cognitive impairment in stressed Wistar rats but not in treatment-resistant Wistar-Kyoto rats. It downregulated ACTH and corticosterone in Wistar rats, upregulated TSH and melatonin in both strains, and increased BDNF levels in blood and brain regions including the prefrontal cortex, amygdala, hippocampus, and hypothalamus. Psilocybin also upregulated CB1R and TrkB, activated Akt, ERK, and mTOR pathways, and increased 2-AG levels across brain regions. The findings suggest psilocybin mitigates stress-induced HPA axis dysregulation by modulating BDNF signaling mediated by the endocannabinoid system, offering insights into antidepressant mechanisms.
The International Journal of Neuropsychopharmacology
February 1, 2025
Hui-Ju Wu, *Mu-Hong Chen, Wei-Chen Lin
People with treatment-resistant depression have higher blood levels of neurofilament light chain (NFL), a marker of nerve cell damage, than healthy individuals. Among 71 patients with treatment-resistant depression randomly assigned to receive a single low-dose infusion of ketamine (0.5 mg/kg, 0.2 mg/kg) or placebo, higher baseline NFL concentrations were linked to worse depressive symptoms afterward, as measured by the Hamilton Depression Rating Scale. This suggests that NFL levels might help predict how well someone will respond to low-dose ketamine treatment for depression.
The International Journal of Neuropsychopharmacology
February 1, 2025
Sofia Nasini, Sara Tidei, Benedetta Barzon et al.
Repeated low-dose psilocybin (0.05 mg/kg) given to adult male mice for 30 days was safe and well tolerated, with no effect on body weight. The treatment produced anxiolytic-like effects: mice spent more time in the light compartment of the light/dark box, showed shorter latency to choose the first arm in the T-maze, and reduced grooming in the open field. No changes were seen in the elevated plus maze, forced swim test, or sociability test. In the cued Morris water maze, psilocybin-treated mice reached the submerged platform faster across all three days and made more successful trials on days 1 and 2, suggesting possible enhancement of spatial memory and learning that requires further study.
The International Journal of Neuropsychopharmacology
May 24, 2018
Dino Luethi, Matthias E. Liechti
Rapidly measuring the in vitro pharmacological activity of new psychoactive substances can help predict their psychoactive doses and effects in humans, aiding in the appropriate legal scheduling of these substances.
The International Journal of Neuropsychopharmacology
May 27, 2016
Xiangyang Zhang, Dachun Chen, Raymond J. Cho et al.
Psilocybin, a hallucinogen that models acute psychosis, alters brain connectivity in ways similar to psychotic disorders. In a double-blind placebo-controlled trial with 20 healthy subjects, standard coherence analysis showed decreased connectivity in theta, alpha, and beta bands, especially in frontotemporal and frontoparietal regions and between frontal hemispheres. Higher frequencies showed less significant changes, often in the opposite direction. Lagged coherence analysis revealed increased connectivity in high gamma (50-100 Hz) but no changes in lower frequencies. These preliminary findings suggest psilocybin induces brain connectivity changes characteristic of psychosis, supporting its use as a model for studying psychotic symptoms.
The International Journal of Neuropsychopharmacology
November 12, 2021
Benjamin Z Roberts, Arpi Minassian, Adam L. Halberstadt et al.
People with HIV often develop cognitive problems linked to disrupted fronto-striatal brain circuits, which are also affected by cannabis. HIV transgenic rats, which model HIV-associated neurocognitive disorder, showed a significant prepulse inhibition deficit compared to healthy controls, mirroring the sensorimotor gating impairment seen in people with HIV. Acute treatment with THC (1 and 3 mg/kg) reduced prepulse inhibition in control rats but not in HIV transgenic rats, indicating a relative insensitivity to THC's disruptive effects on fronto-striatal function. Cannabidiol (1, 10, and 30 mg/kg) had only minor, genotype-independent effects on prepulse inhibition. This reduced sensitivity may help explain higher cannabis use rates among people with HIV.
The International Journal of Neuropsychopharmacology
July 23, 2021
Sunjeev K. Kamboj, Hannah Zhao, Luzia Troebinger et al.
Nitrous oxide (N2O), an anesthetic gas that blocks NMDA receptors, produces subjective rewarding effects similar to those of moderate-dose ketamine. Healthy volunteers randomly assigned to inhale 50% N2O reported liking and wanting effects comparable in size to those seen with ketamine. Impulsivity increased how much participants liked N2O, while depressive symptoms decreased how much they wanted more. These opposite directional influences suggest impulsivity may predispose and depression may protect against N2O abuse. N2O may serve as a safe substitute for ketamine in studying reward-related NMDA receptor function in humans.
The International Journal of Neuropsychopharmacology
April 1, 2017
Katie Walsh, Ravi Das, Sunjeev K. Kamboj
Heavy drinkers with a family history of alcohol-use disorders show a distinct subjective response to nitrous oxide (N2O) inhalation compared to those without such familial risk. During 50% N2O inhalation, the 23 participants with an ostensible family history reported a higher ratio of stimulant to sedative effects than the 37 without that risk. This pattern closely resembles that previously observed with ketamine, suggesting a common mechanism involving N-methyl-D-aspartate receptors (NMDARs). N2O may offer a safer, more accessible alternative to ketamine for studying heritable NMDAR dysregulation in neuropsychiatric disorders.
The International Journal of Neuropsychopharmacology
October 31, 2014
David D Aguilar, Li Chen, Daniel J Lodge
Rats treated with phencyclidine (PCP) to model schizophrenia showed increased dopamine neuron activity in the ventral tegmental area. Increasing endogenous cannabinoid levels with URB-597 normalized this aberrant activity. The ventral pallidum was identified as the site where URB-597 acts to restore normal dopamine neuron activity. The authors propose that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part through the ventral pallidum.
The International Journal of Neuropsychopharmacology
October 31, 2014
Samuel A Barnes, Stephen J Sawiak, Daniele Caprioli et al.
Sub-chronic exposure to the NMDA receptor antagonist phencyclidine (PCP) in rats produced localized reductions in grey matter density in the hippocampus, anterior cingulate cortex, ventral striatum, and amygdala, along with reduced cortical thickness in the insular cortex. PCP-treated rats also showed impaired sustained visual attention on a 5-choice serial reaction time task, especially under higher attentional load, but no significant effect on attentional filtering in an acoustic startle paradigm. These findings indicate that NMDA receptor antagonism can cause brain structural abnormalities in regions implicated in schizophrenia and dissociable attentional deficits.
The International Journal of Neuropsychopharmacology
July 1, 2012
Akihiro Mouri, Takenao Koseki, Shiho Narusawa et al.
Different mouse strains show distinct behavioral responses to the psychosis-inducing drug phencyclidine (PCP). C57BL/6N, C57BL/6J, ddY, and ICR mice were compared. PCP caused greater hyperactivity and increased immobility in the forced swim test in ddY mice than in C57BL/6N and C57BL/6J, with ICR mice showing the least effect. However, no strain differences appeared in recognition memory impairment after chronic PCP withdrawal. These findings offer practical guidance for comparing genetic and drug-induced psychosis models in the C57BL/6 strain, which is commonly used in genetic studies, and suggest that strain differences may help identify biological mechanisms underlying PCP-induced behaviors relevant to major mental illnesses.