Classic serotonergic psychedelics act primarily via 5-HT2A receptor agonism, yet their therapeutic effects and biological responses are heterogeneous. Biological sex remains an underexamined source of this variability because many clinical and preclinical studies have not been designed to test sex-by-treatment effects. Recent preclinical findings, together with more limited human evidence, suggest that sex and endocrine state can modulate serotonergic mechanisms relevant to psychedelic action, including 5-HT1A autoregulatory feedback, 5-HT2A signaling, serotonin clearance, neuroendocrine coupling, and neuroplastic cascades. This review synthesizes how sex- and state-sensitive serotonergic regulation may influence psychedelic signaling and outlines priorities for sex-informed translational research in preclinical and clinical settings.

For 3000 years, psychedelics have been used in religious contexts to enhance spiritual thinking, well-being, and a sense of community. In the last few years, a renaissance in the use of psychedelic drugs for mental disorders has occurred in Western society; consequently, a pressing scientific need to elucidate the intricate mechanisms underlying their actions has arisen. Psychedelics mainly bind to serotonin (5-HT) receptors, particularly 5-HT2A receptors, but may also bind to other receptors. Unlike conventional psychotropic drugs used in psychiatry, psychedelics introduce a distinctive complexity. They not only engage in receptor activation, but also exert influence over specific neural circuits, thereby facilitating transformative cognitive experiences and fostering what many have identified as a spiritual contemplation or mystical experience. This comprehensive review describes clinical studies that have examined the propensity of psychedelics to enhance spiritual, mystical, and transcendent cognitive states. This multifaceted nature, encompassing diverse components and paradigms, necessitates careful consideration during the investigation of psychedelic mechanisms of action to avoid oversimplification. The present review endeavours to elucidate the mechanisms underlying the actions of 2 principal psychedelic substances, psilocybin and lysergic acid diethylamide (LSD), with a focus on monoamine and glutamate receptor mechanisms; molecular aspects, such as neuroplasticity and epigenetics; as well as the impact of psychedelics on brain circuits, including the default mode network and the cortico-striato-thalamo-cortical network. Given their distinctive and intricate mechanisms of action, psychedelics necessitate a novel conceptual framework in psychiatry, offering insight into the treatment of mental health disorders and facilitating the integration of the realms of brain, mind, and spirituality.

Artificial intelligence (AI) is reshaping medicine, promising advances in diagnosis, monitoring, and treatment, and psychiatry will be no exception. Yet the field remains fragmented: ethical guidelines, technical standards, and clinical workflows have evolved in parallel, creating uncertainty about how to integrate AI safely and meaningfully into psychiatric care. Existing frameworks often address isolated domains (explainability, data protection, or harm prevention [HP]) without providing a coherent structure that connects them to everyday clinical realities. This article introduces a global framework for the responsible integration of AI in psychiatry, built on 4 non-negotiable system capabilities: Explainable AI to ensure transparency and trust; Shared Decision-Making to protect patient autonomy; Electronic Health Record integration to secure continuity and accountability; and HP to embed multilayered safety controls. Together, these pillars define a responsibility-by-design approach that aligns technological development with psychiatry's ethical foundations. The framework offers clinicians, policymakers, and developers a roadmap for aligning innovation with human values and measurable improvements in clinical outcomes. By translating ethical commitments into auditable, non-negotiable system capabilities, it establishes a concrete foundation for regulatory oversight, guideline endorsement, and responsible AI deployment in psychiatry.

Schizophrenia (SCZ) is a chronic psychiatric disorder characterized by positive, negative, and cognitive symptoms that remain insufficiently controlled by current dopamine- and serotonin-based antipsychotics. Emerging evidence implicates melatonin MT2 receptors in the regulation of the sleep-wake cycle, circadian rhythms and cortical inhibition, both altered in SCZ. Here, we investigated the neuropharmacological effects of the selective MT2 partial agonist UCM924 in the MK-801 model of SCZ-like dysfunctions in male mice. UCM924 (10 mg/kg, intraperitoneally) was selected as a dose not affecting basal locomotion. Acute administration of MK-801 (0.3 mg/kg) induced hyperlocomotion, social interaction abnormalities, and impaired spatial working memory. UCM924 normalized MK-801-induced hyperactivity and social deficits but did not improve cognitive performance. Immunofluorescence analysis revealed that UCM924 increased c-Fos activation in parvalbumin-positive interneurons of the prefrontal cortex, with no effect on tyrosine hydroxylase-positive neurons in the ventral tegmental area. Local field potential recordings showed that UCM924 alone reduced gamma-band power (12-90 Hz) in both regions, whereas MK-801 markedly enhanced it. Co-administration of MK-801 and UCM924 resulted in MK-801-dominant oscillatory patterns, suggesting limited efficacy of MT2 activation in restoring network synchronization. These findings indicate that MT2 receptor stimulation selectively enhances prefrontal inhibitory tone and ameliorates behavioral abnormalities related to positive-like and negative-like symptoms, without normalizing cognitive and electrophysiological deficits. Overall, MT2 receptor-selective drugs may represent promising candidates for targeting specific symptom domains in SCZ through mechanisms distinct from current antipsychotics.

Background Neuropathic pain (NP) is a chronic and debilitating condition that remains difficult to treat, with opioids like morphine often leading to tolerance and reduced efficacy over time. Cannabidiol (CBD) has emerged as a potential therapeutic for NP even in morphine tolerance conditions; however, its effects on nociceptive modulation and neurotransmitter metabolism in morphine-tolerant NP models remain poorly understood. This study investigated the impact of CBD on mechanical hypersensitivity and on tryptophan (TRP) metabolism via the serotonin (5-HT) and kynurenine (KYN) pathways and dopamine (DA) in Wistar rats with NP and morphine tolerance. Methods NP was induced using the spared nerve injury (SNI) model. Animals received morphine (5 mg/kg, subcutaneous (sc), twice daily) for 7 days to induce tolerance. On Day 8, rats were treated with CBD (20 mg/kg, ip) or vehicle. Mechanical hypersensitivity was assessed, and TRP metabolism and DA were evaluated in different brain regions and serum. Results Repeated morphine induced tolerance to its analgesic effects. CBD significantly reduced mechanical hypersensitivity in non-tolerant rats, with a modest effect in morphine-tolerant animals. In tolerant rats, CBD increased 5-hydroxytryptophan (5-HTP)/TRP ratio in hippocampus and midbrain and reduced KYN levels in the hippocampus, indicating a shift toward 5-HT synthesis. CBD also lowered DA and the 5-HTP/TRP ratio in the brainstem, and decreased serum TRP and 5-HT. Conclusions CBD treatment in NP morphine-tolerant rats exerted a modest effect on mechanical hypersensitivity and was associated with a partial counteraction of metabolic dysregulation by reducing KYN production and shifting TRP metabolism toward 5-HT synthesis (increased 5-HTP/TRP ratio). These findings suggest that CBD modulates 5-HT tone through region-specific mechanisms associated with the development of morphine tolerance.

Promising clinical evidence suggests that psychedelic compounds, like lysergic acid diethylamide (LSD), have therapeutic value for treatment of psychiatric disorders. However, they often produce hallucinations and dissociative states, likely mediated by the serotonin (5-HT) receptor 5-HT2A, raising challenges regarding therapeutic scalability. Given the reported antipsychotic effects of cannabidiol (CBD) and its promiscuous binding at many receptors, we assessed whether CBD could modulate 5-HT2A signalling. Activation of the 5-HT2A intracellular signalling events were assessed using resonance energy transfer- or fluorescence-based biosensors in HEK 293 cells and in rat primary cortical neurons. In 5-HT2A-transfected HEK 293 T cells, CBD antagonized LSD-mediated Gq activation in a saturable way, while leaving β-arrestin2 recruitment unaffected. CBD decreased Gq activation mediated by the 5-HT2A-specific agonist DOI as well as LSD-mediated activity in primary rat neonatal cortical neurons. Using Site Identification by Ligand Competitive Saturation (SILCS) simulations, we also predicted that the putative binding site of CBD overlapped with that of oleamide, a positive allosteric modulator of 5-HT2A, and could displace the binding of orthosteric ligands toward the external binding pocket. Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT2A.

Background Neuropathic pain (NP) is a chronic and debilitating condition frequently comorbid with insomnia. However, the alterations in sleep architecture under NP conditions and the mechanisms underlying both pain and sleep disturbances remain poorly understood. The reticular thalamic nucleus (RTN) plays a crucial role in non-rapid eye movement sleep (NREMS) and pain processing, but its involvement in NP-related sleep disruptions has not been fully elucidated. Methods To investigate sleep-related electrophysiological changes in NP, we performed continuous 24-hour EEG/EMG recordings in rats exhibiting allodynia following L5-L6 spinal nerve lesions. Additionally, we assessed the in vivo neuronal activity of the RTN in both NP and sham-operated control rats. Spectral analyses were conducted to examine alterations in sleep oscillatory dynamics. RTN neuronal responses to nociceptive pinch stimuli were classified as increased, decreased, or unresponsive. Results NP rats exhibited a significant reduction in NREMS (-20%, p < 0.001) and an increase in wakefulness (+19.13%, p < 0.05) compared to controls, whereas rapid eye movement sleep (REMS) remained unchanged. Sleep fragmentation was pronounced in NP animals (p < 0.0001), with frequent brief awakenings, particularly during the inactive/light phase. Spectral analysis revealed increased delta and theta power during both NREMS and REMS. RTN neurons in NP rats displayed a higher basal tonic firing rate, along with increased phasic activity (number of bursts), although the percentage of spikes in bursts remained unchanged. Conclusions NP is characterized by disrupted sleep architecture, reduced NREMS, and heightened RTN neuronal firing activity with partial compensation of burst activity. Given that RTN burst activity is essential for optimal NREMS, its disruption may contribute to NP-induced sleep impairments. These findings suggest that altered EEG signals, alongside dysregulated RTN neuronal activity, may serve as potential brain markers for NP-related insomnia.

Despite the growing prevalence of autism, no pharmacological interventions have been approved for core symptoms. The endocannabinoid system (ECS) has recently gained interest as a potential target for treating autism. Cannabidiol (CBD), a compound found in Cannabis sativa , is a potential treatment due to its tolerability and promising early results in fragile X syndrome patients. Here, we aimed to evaluate CBD’s efficacy in treating social deficits and restrictive/repetitive behaviours in Shank3 and Fmr1 knockout (KO) mice. Male and female mice were tested in the 3-chamber social apparatus or for self-grooming and in the open field (baseline), followed by five daily treatments with vehicle or CBD (s.c., 5 mg/kg for males, 50 mg/kg for females), and retested post-treatment. At baseline and following vehicle treatment, male and female Shank3 and Fmr1 KO mice exhibited deficits in social novelty, which were restored to control levels following CBD administration. Meanwhile, self-grooming (increased in Shank3 KO mice) and open-field exploration (decreased locomotion in Shank3 KO mice) were not affected by CBD. Females had hippocampal CBD levels ~ 11.6 times higher than males (consistent with dosing) and exhibited elevated anandamide (AEA) levels in CBD-treated groups. Transcriptomic analysis of the hippocampus revealed few sex- and strain-specific differentially expressed genes (DEGs) and only three mRNAs regulated by CBD ( Vwf and Lcn2 in females and Grm2 in Shank3 KO mice). These findings highlight the potential for CBD as a treatment for social deficits in syndromic autism and indicate that the therapeutic effect may be driven by dose-, sex-, or strain-specific mechanisms.

BACKGROUND:Autism Spectrum Disorder (ASD) is a neurodevelopmental condition associated with increased risk of psychiatric, gastrointestinal, and metabolic comorbidities. Recent studies highlight the bidirectional role of the gut microbiome (GM) and endocannabinoidome (eCBome)-axis in the gut-brain axis, suggesting its therapeutic potential for ASD and comorbidities. METHODS:We investigated the eCBome-GM-brain axis in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1-/y) mouse model, known as a genetic model of ASD, to identify therapeutic targets. Fecal GM composition was analysed by 16S rDNA sequencing, brain eCBome profile by HPLC-MS/MS and qRT-PCR, and fecal short chain fatty acids by GC-FID. RESULTS:Significant eCBome-GM-brain axis dysregulation was observed in Fmr1-/y compared to wild-type mice. GM analyses revealed potential gut dysbiosis, increased permeability, and inflammation. Specifically, elevated Akkermansia and Eubacterium siraeum-linked to gut barrier dysfunction-and Ruminococcus and Clostridium, associated with ASD severity, were identified. Concurrently, decreased levels of the gut health biomarker Roseburia and the taxa Helicobacter and Anaeroplasma were observed. Brain region-specific eCBome alterations underscored neuroinflammation. In the HPC, reduced anti-inflammatory dihomogamma-linolenic acid (DGLA) was accompanied by elevated pro-inflammatory 12-hydroxy-heptadecatrienoic acid, a mediator of microglial activation. In the PFC, decreased DGLA, 1/2-linoleoylglycerol, and N-linoleoyl-ethanolamine suggested neuroinflammation; elevated prostaglandin D2, a marker of autophagy impairment, underscores further mechanisms of dysfunction. Upregulation of cannabinoid type 2 and PPAR-γ receptor genes in the PFC suggested a compensatory response to neuroinflammation. Correlations between eCBome and GM alterations highlighted potential links between gut dysbiosis, systemic inflammation, and neurodevelopmental atypicalities. CONCLUSIONS:The Fmr1-/y ASD mouse model harbors significant eCBome-GM-brain axis alterations. This study highlights specific GM taxa and eCBome components as potential therapeutic targets for clinical validation in Fragile X Syndrome and ASD.

Psilocybin and lisuride are 5-HT2A receptor agonists, but only psilocybin elicits the head twitch response (HTR) in rodents, a behavior commonly used as a proxy for hallucinogenic activity. This study aimed to compare their effects on serotonin (5-HT) and dopamine (DA) neuronal activity, as well as related behavioral outcomes, to elucidate the mechanisms underlying their divergent effects. Adult male C57BL/6N mice were administered intraperitoneal injections of psilocybin (0.3-3 mg/kg), lisuride (0.1-0.5 mg/kg), or vehicle. In vivo electrophysiological recordings were performed in the dorsal raphe nucleus (DRN) and substantia nigra (SN) to monitor 5-HT and DA neuronal firing. MDL 100907 (0.2 mg/kg) pretreatment was used to determine 5-HT2A receptor specificity. Behavioral assessments included HTR testing 10 min post-injection, followed by either the forced swim test (FST), open field test (OFT), or elevated plus maze (EPM) at 20 min post-injection. Psilocybin-induced inhibition, but not lisuride-induced inhibition, of 5-HT neuron firing was blocked by MDL 100907. Both drugs reduced DA neuron firing, however, lisuride's effect was more sensitive to 5-HT2A receptor antagonism. Psilocybin elicited HTR, while lisuride did not. In the FST, only high-dose lisuride reduced immobility time. Both drugs reduced locomotor activity in the OFT and EPM. Principal Component Analysis (PCA) sufficiently separated the effects of each drug from each other, indicating distinct effect profiles. Although both drugs target 5-HT2A receptors, they engage distinct neurobiological pathways. Psilocybin produces psychedelic-like, 5-HT-dominant effects, whereas lisuride displays DA-linked improvements in coping behavior, informing future development of serotonergic therapeutics.

BACKGROUND:Neuropathic pain (NP) is a chronic and debilitating condition frequently comorbid with insomnia. However, the alterations in sleep architecture under NP conditions and the mechanisms underlying both pain and sleep disturbances remain poorly understood. The reticular thalamic nucleus (RTN) plays a crucial role in non-rapid eye movement sleep (NREMS) and pain processing, but its involvement in NP-related sleep disruptions has not been fully elucidated. METHODS:To investigate sleep-related electrophysiological changes in NP, we performed continuous 24-hour electroencephalogram/electromyogram (EEG/EMG) recordings in rats exhibiting allodynia following L5-L6 spinal nerve lesions. Additionally, we assessed the in vivo neuronal activity of the RTN in both NP and sham-operated control rats. Spectral analyses were conducted to examine alterations in sleep oscillatory dynamics. Reticular thalamic nucleus neuronal responses to nociceptive pinch stimuli were classified as increased, decreased, or unresponsive. RESULTS:Neuropathic pain rats exhibited a significant reduction in NREMS (-20%, P < .001) and an increase in wakefulness (+ 19.13%, P < .05) compared to controls, whereas rapid eye movement sleep (REMS) remained unchanged. Sleep fragmentation was pronounced in NP animals (P < .0001), with frequent brief awakenings, particularly during the inactive/light phase. Spectral analysis revealed increased delta and theta power during both NREMS and REMS. Reticular thalamic nucleus neurons in NP rats displayed a higher basal tonic firing rate, along with increased phasic activity (number of bursts), although the percentage of spikes in bursts remained unchanged. CONCLUSIONS:Neuropathic pain is characterized by disrupted sleep architecture, reduced NREMS, and heightened RTN neuronal firing activity with partial compensation of burst activity. Given that RTN burst activity is essential for optimal NREMS, its disruption may contribute to NP-induced sleep impairments. These findings suggest that altered EEG/EMG signals, alongside dysregulated RTN neuronal activity, may serve as potential brain markers for NP-related insomnia.

Background: In recent years, there has been a resurgence of scientific interest in psychedelics, including psilocybin, for their potential in treating neuropsychiatric disorders. However, the reward-related effects of psilocybin and its impact on behavior remain underexplored.Aims: We aimed to evaluate the potential rewarding effects of high doses of psilocybin and its effects on rat behavior.Methods: Sprague-Dawley rats were exposed to the conditioned place preference (CPP) paradigm. Over an 8-day period, rats were administered either psilocybin (10 mg/kg, i.p.) or vehicle (0.9% saline, i.p.) on odd conditioning days, while receiving vehicle (0.9% saline, i.p.) on even conditioning days. The potential rewarding effect induced by psilocybin was assessed 48 hours after the last psilocybin injection. Behavioral assessments, including head twitch, body shaking, grooming, body licking, defecation pellets, and rearing, were conducted during the CPP exposure.Results: Psilocybin did not induce CPP in rats, highlighting its lack of reinforcing effects under these conditions. However, this regimen of administration led to modifications in the behavioral profile during CPP test by increasing head twitching, wet-wet-dog shaking, and defecation pellets and decreasing grooming, body licking, and rearing compared to the vehicle group. Importantly, 48 hours after the final psilocybin injection, no behavioral differences were observed between psilocybin and vehicle groups.Conclusion: Psilocybin at this regimen (10 mg/kg, every other day) does not induce CPP, but induces changes in behavior, which disappear 48 hours after the last injection. More research is needed to better evaluate the addiction liability of psychedelics using different paradigms, doses, and protocols.

Abstract Background Pain is a major health problem resulting in a high degree of suffering, physical, psychological and social impairments, and exorbitant health care costs1-2. Effective pain treatments are limited and are often accompanied by significant side effects3. Preclinical and clinical studies suggest that psychedelics, specifically psilocybin, can reset brain areas of functional connectivity that have a profound impact on central neuropathic states4. 5HT2A receptors have been implicated in both nociceptive pathways and the mechanism of action of psychedelics4. However, the effect of psychedelics on pain mechanisms is not fully understood. Aim and Objectives In this study, we examined the effect of psilocybin two models of pain: hot plate to investigate acute pain responses and the sciatic nerve ligation to assess the neuropathic pain antiallodynic responses. Method The hot plate test (HPT, Ugo Basile, Italy) was used to determine the acute thermal nociception. Mice (C57BL/6) were randomized and either veh (saline i.p.) or psilocybin (3 mg/kg i.p.) was administered. Mice were introduced to the hot plate at an initial temperature of 37° C with a near linear increase of 3° C per min. The nociceptive endpoint was established as the temperature eliciting a fast hind paw lick and/or paw withdrawal. To investigate chronic pain, we induced neuropathic pain (Sciatic Nerve Ligation) in Wistar rats. Neuropathy was determined using the von Frey (VF) filaments 14 days post-surgery. Animals who developed neuropathy were treated acutely with psilocybin (3 and 10 mg/kg, i.p.) or vehicle (saline, i.p.) and mechanical allodynia was assessed at time 0 (before administration), 0.5, 1, 2, 3, and 4 hours after administration. Results Acute systemic administration of psilocybin (3 mg/kg, i.p) did not increase thermal withdrawal threshold compared to vehicle-treated mice (t=0.4557, p= 0.6607, vehicle mean: 15.6 ± 2.657, n=5; psilocybin mean: 17.28 ± 2.556, n=5). On the other hand, in the NP model, psilocybin at the doses of 3 mg/kg and 10 mg/kg significantly increased mechanical withdrawal threshold compared to vehicle at time 0.5 hours (3mg/kg, p=0.0066, 10mg/kg, p=0.0012), 1 hour (3mg/kg, p=0.0043, 10mg/kg, p=0.0110), and 2 hours (3mg/kg, p=0.0051, 10mg/kg, p=0.0410), with no significant differences between doses of 3 and 10 mg (two-way ANOVA repeated measures, followed by Bonferroni’ s post-hoc test) Discussion and Conclusion These preliminary findings suggest that acute systemic administration of psilocybin has antiallodynic effect on NP, concurring with previous findings5-6, but demonstrates no nociceptive effect on acute thermal pain. Furthermore, this suggests that the action of psilocybin on pain reduction may specifically target NP, rather than generalized nociception of acute pain. Therefore, psilocybin may have a potential in the treatment neuropathic pain. References 1.-Raffaeli, W., &Arnaudo, E. (2017). Pain as a disease: An overview. Journal of Pain Research, 10, 2003–2008. https://doi.org/10.2147/JPR.S138864 2.- Loeser, J. D., &Melzack, R. (1999). Pain: An overview. The Lancet, 353(9164), 1607–1609. https://doi.org/10.1016/S0140-6736(99)01311-2 3.-Curatolo, M., &Bogduk, N. (2001). Pharmacologic Pain Treatment of Musculoskeletal Disorders: Current Perspectives and Future Prospects. The Clinical Journal of Pain, 17(1), 25. 4.-Castellanos, J. P., Woolley, C., Bruno, K. A., Zeidan, F., Halberstadt, A., &Furnish, T. (2020). Chronic pain and psychedelics: A review and proposed mechanism of action. Regional Anesthesia &Pain Medicine, 45(7), 486–494. https://doi.org/10.1136/rapm-2020-101273 5.- Kolbman, N., Liu, T., Guzzo, P., Gilligan, J. P., Mashour, G. A., Vanini, G., &Pal, D. (2023). Intravenous psilocybin administration attenuates mechanical hypersensitivity in a rat model of chronic pain [Preprint]. Neuroscience. https://doi.org/10.1101/2023.08.26.554802 6.-Lyes, M., Yang, K. H., Castellanos, J., &Furnish, T. (2023). Microdosing psilocybin for chronic pain: A case series. Pain, 164(4), 698–702. https://doi.org/10.1097/j.pain.0000000000002778

Background The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways. Here, we hypothesized that the eCB system is associated with an enhanced Kyn production in relation to the severity of depressive symptoms. Methods Eighty-two subjects (51 patients with a diagnosis of depressive disorder (DSM-5) and 31 healthy volunteers), were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Scale, and Global Clinical Impression. Serum concentrations of eCBs ( N -arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)); structurally related fatty acyl compounds 2-oleoylglycerol (2-OG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA); Trp, Kyn, Kyn/Trp ratio (an index of Trp degradation into Kyn) and 5-HT were also determined. Results Following a principal component analysis including the severity of depression, Kyn and the Kyn/Trp ratio appear to be directly associated with 2-AG, AEA, and PEA. Interestingly, these biomarkers also permitted to distinguish the population into two main clusters: one of individuals having mild/severe depressive symptoms and the other with an absence of depressive symptoms. Using parametric analysis, higher serum levels of 2-AG, Kyn, and the ratio Kyn/Trp and lower levels of Trp and 5-HT were found in individuals with mild/severe depressive symptoms than in those without depressive symptoms. While in asymptomatic people, PEA was directly associated to Trp, and OEA indirectly linked to 5-HT, in individuals with depressive symptoms, these correlations were lost, and instead, positive correlations between AEA and 2-AG, PEA and AEA, and PEA vs 2-AG and OEA concentrations were found. Conclusions Parametric and non-parametric analyses suggest a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay among inflammation, stress, and depression. The enhanced relationships among the biomarkers of the 2-AG and AEA pathways and related lipids seen in individuals with depressive symptoms, but not in asymptomatics, suggest an altered metabolism of the eCB system in depression.

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose–response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1receptors in the LC-NE neurons. In conclusion, MT1receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.

Sleep, constituting approximately one-third of the human lifespan, is a crucial physiological process essential for physical and mental well-being. Normal sleep consists of an orderly progression through wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep, all of which are tightly regulated. Melatonin, often referred to as the "hormone of sleep," plays a pivotal role as a regulator of the sleep/wake cycle and exerts its effects through high-affinity G-protein coupled receptors known as MT1 and MT2. Selective modulation of these receptors presents a promising therapeutic avenue for sleep disorders. This review examines research on the multifaceted role of melatonin in sleep regulation, focusing on selective ligands targeting MT1 and MT2 receptors, as well as studies involving MT1 and MT2 knockout mice. Contrary to common beliefs, growing evidence suggests that melatonin, through MT1 and MT2 receptors, might not only influence circadian aspects of sleep but likely, also modulate the homeostatic process of sleep and sleep architecture, or could be the molecule linking the homeostatic and circadian regulation of sleep. Furthermore, the distinct brain localization of MT1 and MT2 receptors, with MT1 receptors primarily regulating REM sleep and MT2 receptors regulating NREM sleep, is discussed. Collectively, sleep regulation extends beyond the circulating levels and circadian peak of melatonin; it also critically involves the expression, molecular activation, and regulatory functions of MT1 and MT2 receptors across various brain regions and nuclei involved in the regulation of sleep. This research underscores the importance of ongoing investigation into the selective roles of MT1 and MT2 receptors in sleep. Such research efforts are expected to pave the way for the development of targeted MT1 or MT2 receptors ligands, thereby optimizing therapeutic interventions for sleep disorders.

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the fi rst-in-class selective melatonin MT1 1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose-response - response manner, the fi ring activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 1 receptors in the LC-NE neurons. In conclusion, MT1 1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.

Developmental stuttering (DS) is a neurodevelopmental speech-motor disorder characterized by symptoms such as blocks, repetitions, and prolongations. Persistent DS often has a significant negative impact on quality of life, and interventions for it have limited efficacy. Herein, we briefly review existing research on the neurophysiological underpinnings of DS -specifically, brain metabolic and default mode/social-cognitive networks (DMN/SCN) anomalies- arguing that psychedelic compounds might be considered and investigated (e.g., in randomized clinical trials) for treatment of DS. The neural background of DS is likely to be heterogeneous, and some contribution from genetically determinants of metabolic deficiencies in the basal ganglia and speech-motor cortical regions are thought to play a role in appearance of DS symptoms, which possibly results in a cascade of events contributing to impairments in speech-motor execution. In persistent DS, the difficulties of speech are often linked to a series of associated aspects such as social anxiety and social avoidance. In this context, the SCN and DMN (also influencing a series of fronto-parietal, somato-motor, and attentional networks) may have a role in worsening dysfluencies. Interestingly, brain metabolism and SCN/DMN connectivity can be modified by psychedelics, which have been shown to improve clinical evidence of some psychiatric conditions (e.g., depression, post-traumatic stress disorder, etc.) associated with psychological constructs such as rumination and social anxiety, which also tend to be present in persistent DS. To date, while there have been no controlled trials on the effects of psychedelics in DS, anecdotal evidence suggests that these agents may have beneficial effects on stuttering and its associated characteristics. We suggest that psychedelics warrant investigation in DS.