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
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
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
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
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
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 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
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
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
Martha Lopez 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
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
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.