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Psychedelics, historically celebrated for their cultural and spiritual significance, have emerged as potential breakthrough therapeutic agents due to their profound effects on consciousness, emotional processing, mood, and neural plasticity. This review explores the mechanisms underlying psychedelics' effects, focusing on their ability to modulate brain connectivity and neural circuit activity, including the default mode network (DMN), cortico-striatal thalamo-cortical (CSTC) loops, and the relaxed beliefs under psychedelics (REBUS) model. Advanced neuroimaging techniques reveal psychedelics' capacity to enhance functional connectivity between sensory cerebral areas while reducing the connections between associative brain areas, decreasing the rigidity and rendering the brain more plastic and susceptible to external changings, offering insights into their therapeutic outcome. The most relevant clinical trials of 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and lysergic acid diethylamide (LSD) demonstrate significant efficacy in treating treatment-resistant psychiatric conditions such as post-traumatic stress disorder (PTSD), depression, and anxiety, with favorable safety profiles. Despite these advancements, critical gaps remain in linking psychedelics' molecular actions to their clinical efficacy. This review highlights the need for further research to integrate mechanistic insights and optimize psychedelics as tools for both therapy and understanding human cognition. [ABSTRACT FROM AUTHOR]

Antipsychotic medications are a vast class of drugs used for the treatment of psychotic disorders such as schizophrenia. Although numerous compounds have been developed since their introduction in the 1950s, several patients do not adequately respond to current treatments, or they develop adverse reactions that cause treatment discontinuation. Moreover, in the past few decades, discoveries in the pathophysiology of psychotic disorders have opened the way for experimenting with novel compounds that have alternative mechanisms of action, with some of them showing promising results in early trials. The scope of this review was to summarize the novel antipsychotics developed, their current experimental status, and their mechanisms of action. In particular, we analyzed the main classes of investigational antipsychotics, such as monoamine, glutamate, acetylcholine, cannabinoid receptor modulators, enzyme inhibitors, ion channel modulators, and mixed receptor modulators. In addition, the safety profiles and adverse effects of these drugs were carefully evaluated, considering the relevance of these aspects for patients' drug adherence and quality of life, especially in the long-term treatment. Lastly, we tried to understand which compounds have greater potential to be approved by the principal drug regulatory agencies in the next years and if they could be used for diseases other than psychotic disorders. [ABSTRACT FROM AUTHOR]

Objectives: Opioid use disorder (OUD) and cancer gained attention as co-occurring diseases in the last 2 decades due to the possible relationship between opioid prescriptions for cancer pain and the risk of developing substance use disorder in cancer patients. However, little is known about patients previously diagnosed with OUD who develop cancer and how to manage both OUD symptoms and control pain. Methods: The present case series deals with this subpopulation and proposes a dose escalation of methadone to control both the cancer-related pain and drug addiction symptoms. Results: This approach is peculiar because methadone is not used as a first-line treatment in cancer pain management and is not often used as a second-line treatment as well. Our 4 patients experienced good clinical control of symptoms and no major adverse reactions. Significance of results: The subgroup of patients with OUD who develop cancer could be the perfect population to reconsider the use of methadone as a first-line treatment for cancer pain. Prospective studies are needed to evaluate the efficacy and safety of increasing doses of methadone in these patients to validate our clinical approach. [ABSTRACT FROM AUTHOR]

Previous studies have reported inconsistent results about exogenous melatonin's sleep‐promoting effects. A possible explanation relies on the heterogeneity in administration schedule and dose, which might be accountable for differences in treatment efficacy. In this paper, we undertook a systematic review and meta‐analysis of double‐blind, randomized controlled trials performed on patients with insomnia and healthy volunteers, evaluating the effect of melatonin administration on sleep‐related parameters. The standardized mean difference between treatment and placebo groups in terms of sleep onset latency and total sleep time were used as outcomes. Dose−response and meta‐regression models were estimated to explore how time of administration, dose, and other treatment‐related parameters might affect exogenous melatonin's efficacy. We included 26 randomized controlled trials published between 1987 and 2020, for a total of 1689 observations. Dose−response meta‐analysis showed that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4 mg/day. Meta‐regression models showed that insomnia status (β = 0.50, p < 0.001) and time between treatment administration and the sleep episode (β = −0.16, p = 0.023) were significant predictors of sleep onset latency, while the time of day (β = −0.086, p < 0.01) was the only significant predictor of total sleep time. Our results suggest that advancing the timing of administration (3 h before the desired bedtime) and increasing the administered dose (4 mg/day), as compared to the exogenous melatonin schedule most used in clinical practice (2 mg 30 min before the desired bedtime), might optimize the efficacy of exogenous melatonin in promoting sleep. [ABSTRACT FROM AUTHOR]

Psychiatric disorders often require pharmacological interventions to alleviate symptoms and improve quality of life. However, achieving an optimal therapeutic outcome is challenging due to several factors, including variability in the individual response, inter-individual differences in drug metabolism, and drug interactions in polytherapy. Therapeutic drug monitoring (TDM), by measuring drug concentrations in biological samples, represents a valuable tool to address these challenges, by tailoring medication regimens to each individual. This review analyzes the current landscape of TDM in psychiatric practice, highlighting its significance in optimizing drug dosages, minimizing adverse effects, and improving therapeutic efficacy. The metabolism of psychiatric medications (i.e., mood stabilizers, antipsychotics, antidepressants) often exhibits significant inter-patient variability. TDM can help address this variability by enhancing treatment personalization, facilitating early suboptimal- or toxic-level detection, and allowing for timely interventions to prevent treatment failure or adverse effects. Furthermore, this review briefly discusses technological advancements and analytical methods supporting the implementation of TDM in psychiatric settings. These innovations enable quick and cost-effective drug concentration measurements, fostering the widespread adoption of TDM as a routine practice in psychiatric care. In conclusion, the integration of TDM in psychiatry can improve treatment outcomes by individualizing medication regimens within the so-called precision medicine. [ABSTRACT FROM AUTHOR]

Therapeutic strategies that augment insulin release from pancreatic [beta]-cells are considered beneficial in the treatment of type 2 diabetes. We previously demonstrated that activation of [beta]-cell [M.sub.3] muscarinic receptors (M3Rs) greatly promotes glucose-stimulated insulin secretion (GSIS), suggesting that strategies aimed at enhancing signaling through [beta]-cell M3Rs may become therapeutically useful. M3R activation leads to the stimulation of G proteins of the [G.sub.q] family, which are under the inhibitory control of proteins known as regulators of G protein signaling (RGS proteins). At present, it remains unknown whether RGS proteins play a role in regulating insulin release. To address this issue, we initially demonstrated that MIN6 insulinoma cells express functional M3Rs and that RGS4 was by far the most abundant RGS protein expressed by these cells. Strikingly, siRNA-mediated knockdown of RGS4 expression in MIN6 cells greatly enhanced M3R-mediated augmentation of GSIS and calcium release. We obtained similar findings using pancreatic islets prepared from RGS4-deficient mice. Interestingly, RGS4 deficiency had little effect on insulin release caused by activation of other [beta]-cell GPCRs. Finally, treatment of mutant mice selectively lacking RGS4 in pancreatic [beta]-cells with a muscarinic agonist (bethanechol) led to significantly increased plasma insulin and reduced blood glucose levels, as compared to control littermates. Studies with [beta]-cell-specific M3R knockout mice showed that these responses were mediated by [beta]-cell M3Rs. These findings indicate that RGS4 is a potent negative regulator of M3R function in pancreatic p-cells, suggesting that RGS4 may represent a potential target to promote insulin release for therapeutic purposes. knockout mice/muscarinic receptor/RGS proteins/G protein-coupled receptor doi/ 10.1073/pnas.1003655107

Impaired functioning of pancreatic [beta] cells is a key hallmark of type 2 diabetes. [beta] cell function is modulated by the actions of different classes of heterotrimeric G proteins. The functional consequences of activating specific [beta] cell G protein signaling pathways in vivo are not well understood at present, primarily due to the fact that [beta] cell G protein-coupled receptors (GPCRs) are also expressed by many other tissues. To circumvent these difficulties, we developed a chemical-genetic approach that allows for the conditional and selective activation of specific [beta] cell G proteins in intact animals. Specifically, we created two lines of transgenic mice each of which expressed a specific designer GPCR in [beta] cells only. Importantly, the two designer receptors differed in their G protein-coupling properties ([G.sub.q/11] versus [G.sub.s]). They were unable to bind endogenous ligand(s), but could be efficiently activated by an otherwise pharmacologically inert compound (clozapine-N-oxide), leading to the conditional activation of either[beta] cell [G.sub.q/11] or [G.sub.s] G proteins. Here we report the findings that conditional and selective activation of [beta] cell [G.sub.q/11] signaling in vivo leads to striking increases in both first- and second-phase insulin release, greatly improved glucose tolerance in obese, insulin-resistant mice, and elevated [beta] cell mass, associated with pathway-specific alterations in islet gene expression levels. Selective stimulation of [beta] cell Gs triggered qualitatively similar in vivo metabolic effects. Thus, this developed chemical-genetic strategy represents a powerful approach to study G protein regulation of [beta] cell function in vivo. beta cells | G protein-coupled receptors | transgenic mice | type 2 diabetes www.pnas.org/cgi/doi/10.1073/pnas.0906593106