Search Results (148)

Background: The COVID-19 pandemic and related containment measures profoundly affected child and adolescent mental health, with increasing evidence of a rise in psychiatric symptomatology and healthcare burden. This study aimed to evaluate temporal changes in neuropsychiatric presentations before, during, and after the COVID-19 pandemic in a pediatric clinical population. Methods: In this retrospective single-center study, 505 children and adolescents referred to a pediatric neuropsychiatry service were included and stratified into three periods: pre-pandemic (n = 112), pandemic (n = 231), and post-pandemic (n = 162). Clinical and healthcare-related variables were retrospectively collected, including reasons for referral, psychiatric diagnoses, premorbid conditions, and pharmacological treatments. Comparative analyses were performed to identify temporal variations in psychopathological profiles and clinical management. Results: A significant increase in psychiatric symptomatology emerged in the post-pandemic period compared with the pre-pandemic period. In particular, eating disorders, mood disturbances, self-harm, and somatic symptom presentations showed a marked increase over time, presenting as recurrent and associated phenotypes that peaked or consolidated after the acute emergency. The pandemic period was primarily characterized by a greater need for psychopharmacological intervention, specifically driven by the clinical need to manage acute behavioral crises. Overall, findings indicated a persistent increase in the complexity and severity of neuropsychiatric presentations beyond the acute phase of the pandemic. Conclusions: The COVID-19 pandemic was associated with substantial changes in pediatric neuropsychiatric presentations and treatment needs. The persistence of the increased psychopathological burden in the post-pandemic period highlights long-term mental health trajectories associated with the pandemic era. These emerging patterns of phenotypic complexity demonstrate that child and adolescent psychiatric services must transition from single-diagnosis models toward integrated care networks. Practically, strengthening community-based early intervention and creating rapid-access crisis support are essential to manage severe emotional dysregulation in the community and reduce acute psychiatric hospitalizations. Full article

Background/Objectives: The rates of obesity and binge-eating disorder (BED) have increased markedly over the last few decades. The onset of these conditions has been associated in part with the disruption of neural pathways that regulate food reward. Existing literature has implicated the endogenous opioid system as an important mediator of pleasure and reinforcing behaviors associated with food intake. While the relationship between opioids and food intake has been studied extensively, how dysregulated opioid signaling contributes to compulsive eating still remains unclear. Therefore, the aim of this review is to analyze the role of opioid peptides and receptors, and their interactions with dopamine in hedonic feeding. Methods: We conducted a narrative review of preclinical and clinical trials, incorporating studies that were relevant to opioid-mediated feeding and food reward. Results: β-endorphins appear to modulate the hedonic value of food, but their effects appear to be context-dependent. Enkephalins may influence motivational drive toward food, while nociceptin signaling has been linked to the preferential consumption of palatable foods under binge-like conditions. Consistent with these findings, NOP antagonism has been reported to reduce binge-like intake of a high-fat diet (HFD) without affecting homeostatic eating patterns. Lastly, chronic mu-opioid receptor (MOP) activation by palatable foods may induce neuroadaptive changes, including receptor desensitization, dopamine D2 receptor downregulation, and reward hypofunctionality, which overlap with mechanisms associated with substance use disorders. Conclusions: Altered MOP signaling may disrupt the hedonic and behavioral mechanisms that regulate feeding behavior. Pharmacological therapies targeting opioid and opioid-dopamine interactions may show promise for treating obesity and BED. However, additional research is still needed to clarify peptide-specific mechanisms, sex differences, and long-term neurobiological consequences associated with hedonic and compulsive eating. Full article

Background: Endometriosis is a chronic, estrogen-dependent inflammatory disorder associated with pain and immune dysregulation. Omega-3 (n-3) fatty acids and fish-derived bioactive lipids may modulate inflammation and metabolism. This study investigated whether adding fish-derived lipids (FDLs) to a Healthy Eating Plate diet improves inflammatory markers, gut inflammation, pain, and quality of life in women with endometriosis. Methods: In this 12-week randomized controlled trial, 46 women with confirmed endometriosis were assigned to either a Healthy Eating Plate diet alone (control group, CG) or the same diet plus FDLs (intervention group, IG). Primary outcomes included serum cytokine concentrations (interleukin [IL]-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha [TNF-α]) and fecal calprotectin (CAL). Secondary outcomes included pain intensity measured using the visual analog scale (VAS) and health-related quality of life assessed with the Endometriosis Health Profile-30 (EHP-30). Results: IL-10 levels (pg/mL) increased in the IG (32.5 ± 51.5 to 265 ± 508; p = 0.024) with a significant adjusted effect (ANCOVA: 5.07 [95% CI: 1.32–19.48], p = 0.019). Other cytokines showed heterogeneous responses, and CAL levels remained unchanged. EHP-30 Pain scores improved within both groups (CG p = 0.016; IG p = 0.002) without significant between-group change or adjusted effects (all p > 0.05). VAS scores decreased within the IG (5.0 ± 2.1 to 4.3 ± 2.1; p = 0.011), although there were no between-group differences in change and ANCOVA (all p > 0.05). However, ≥1-point responder rates were higher in the IG vs. CG (73.9% vs. 34.8%): adjusted RR = 2.11 (95% CI: 1.16; 3.89; p = 0.014). Conclusions: Overall, FDL supplementation was associated with a selected regulatory immune signal, reflected mainly by the IL-10 response, while most inflammatory, pain-related, and quality-of-life outcomes did not show consistent significant between-group effects. The observed greater likelihood of pain reduction in the FDL-supplemented group of women with endometriosis, along with the IL-10 response, should be interpreted with caution and confirmed in larger studies with longer follow-up/intervention time, taking into account the potential mechanisms of biological response. Full article

Background: Bariatric surgery is the most effective long-term treatment for severe obesity; however, a subset of patients fails to achieve optimal weight loss. This study investigated the role of psychiatric disorders and transdiagnostic psychopathological traits in predicting weight loss outcomes two years after surgery. Methods: This prospective naturalistic study included 125 consecutive bariatric surgery candidates undergoing routine preoperative psychiatric assessment. Psychiatric comorbidities, emotional dysregulation and ADHD-related dimensions were assessed using structured clinical interviews and self-report questionnaires. Weight outcomes were evaluated at 24 months after bariatric surgery, with post-surgical inadequate weight loss defined as percentage of excess weight loss (%EWL) < 50%. Results: Of the 125 patients initially assessed, 89 underwent bariatric surgery and 48 completed the follow-up. At 24 months, 10 patients (20.8%) showed inadequate weight loss. Poorer weight outcomes were associated with older age, sleeve gastrectomy, and lifetime mood disorders, whereas no significant associations emerged with anxiety disorders or binge eating disorder. Patients with inadequate weight loss showed higher levels of emotional dysregulation, while no differences emerged for other ADHD-related dimensions. Emotional dysregulation remained significantly associated with poorer weight outcomes in multivariate analysis. Conclusions: Emotional dysregulation may represent a transdiagnostic factor influencing bariatric surgery outcomes, supporting the importance of integrating emotional and cognitive dimensions into preoperative assessment and postoperative care. Full article

Introduction: The widespread use of digital devices has significantly increased screen time among children and adolescents, raising concerns about its effects on dietary behaviors and health outcomes. This narrative review aimed to examine the relationship between screen exposure, unhealthy eating behaviors, and associated physical and mental health risks in pediatric populations. Methods: A narrative review of the literature was conducted using PubMed, Scopus, and Web of Science databases, with the final search updated on 30 April 2026. Studies involving individuals aged 0–18 years were included if they investigated screen time, dietary behaviors, obesity, cardiometabolic risk, sleep, or mental health outcomes. Observational studies, interventional studies, systematic reviews, and meta-analyses were considered. Findings were synthesized qualitatively according to pre-specified thematic domains, with greater interpretive weight given to systematic reviews, meta-analyses, randomized trials, longitudinal cohorts, and large population-based studies. Results: Excessive screen time was consistently associated with unhealthy eating behaviors, including increased snacking, mindless eating, breakfast skipping, and higher consumption of ultra-processed and energy-dense foods. Digital food marketing and exposure to food advertising may influence children’s food preferences and intake. High screen exposure was also associated with sedentary behavior, sleep disturbances, circadian dysregulation, and altered appetite-related hormones such as leptin and ghrelin. These pathways may contribute to, or be consistent with, obesity, insulin resistance, dyslipidemia, hypertension, and metabolic syndrome, although most evidence remains observational. Moreover, excessive screen use was associated with anxiety, depression, emotional eating, binge-eating behaviors, and body image dissatisfaction, particularly among adolescents. Conclusions: Screen time may represent a modifiable behavioral and environmental correlate of dietary habits, metabolic health, and psychological wellbeing in children and adolescents. Prevention strategies should focus not only on reducing screen duration but also on improving the quality and context of media use through family-based interventions, school programs, digital literacy, promotion of physical activity, and regulation of digital food marketing. Further longitudinal and interventional studies are needed to clarify causal relationships and develop effective prevention strategies. Full article

Background: Anorexia Nervosa (AN) is a severe eating disorder. Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are two Neurodevelopmental Disorders (NDDs), frequently co-occurring with each other (ADHD+ASD). The present study aimed to clarify cognitive and behavioral profiles, with a specific focus on emotional regulation, executive functions and empathy, in three groups of female adolescents. Methods: A total of 102 female adolescents aged 12–18 years were recruited. Participants were divided into three groups (AN: n = 30, ADHD: n = 47, ADHD+ASD: n = 25). All participants underwent a psychometric and a multidimensional clinical assessment. Group differences were analyzed through ANOVA with Bonferroni corrections. Results: Adolescents with ADHD+ASD scored significantly higher than the ADHD group in verbal comprehension. The AN group performed significantly better than both the ADHD and ADHD+ASD groups in working memory, and significantly better than the ADHD+ASD group in processing speed. Both the AN and ADHD+ASD groups were characterized by significantly greater impairment in global functioning than the ADHD group. No significant differences were found among the three groups on the Attention Switching, Attention to Detail, and Imagination subscales of the Autism Spectrum Quotient. Behaviorally, AN participants exhibited higher internalizing symptoms (anxiety and depression), the ADHD group presented more prominent externalizing behaviors (aggressive, rule-breaking, and attention problems), and the comorbid ADHD+ASD group demonstrated significantly more pronounced social problems. Most measures used to assess emotional dysregulation did not reveal significant differences among the three groups. Both the ADHD and ADHD+ASD groups showed significantly greater impairment in executive functioning than the AN group. Regarding empathic abilities, mixed results emerged. Conclusions: Findings suggest the coexistence of condition-specific features and shared vulnerabilities in female adolescents with AN, ADHD, and ADHD+ASD. These data underscore the importance of investigating the female phenotype from a transdiagnostic perspective to facilitate early detection and tailored interventions. Full article

Background: Obesity is a multifactorial metabolic disorder characterized by chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, dysregulated adipogenesis, and alterations in the gut microbiota, which collectively contribute to insulin resistance and cardiometabolic complications. In this context, dietary patterns rich in bioactive compounds have gained relevance as potential strategies to modulate these interconnected pathways. Objective: To assess the potential of the Milpa Diet (a sustainable, plant-dominant Mesoamerican eating pattern centered on the ancient three sisters’ polyculture of maize, beans, and squash, along with chili) as a culturally relevant, multi-axis functional dietary pattern, and to evaluate the molecular mechanisms underlying obesity-associated with metabolic dysfunction. Methods: A scoping review of preclinical and clinical studies was conducted using Medline via PubMed, Scopus, and Web of Science databases. The ChEMBL database was also used to identify chemical structures. The search focused on evidence related to inflammation, oxidative stress, adipogenesis, lipotoxicity, mitochondrial function, and gut microbiota modulation in the context of the main foods of the Milpa Diet, including maize, legumes, chili peppers, nopal, and quelites. Studies were selected based on peer-review status and their relevance to molecular, metabolic, and functional outcomes. Results: The current evidence shows that the core components of the Milpa Diet provide dietary fiber and a broad range of bioactive compounds, such as flavonoids, carotenoids, capsaicinoids, phenolic acids, pigments, and vitamins, which exhibit antioxidant and anti-inflammatory effects. These compounds have been associated with modulation of adipogenesis and lipotoxicity, preservation of mitochondrial function, and favorable regulation of gut microbiota composition and activity, collectively influencing metabolic pathways relevant to obesity. Conclusions: Overall, mechanistic and emerging clinical evidence suggests that the Milpa Diet represents a multi-axis nutritional strategy with potential to mitigate obesity-related metabolic dysfunction through coordinated effects on inflammation, oxidative stress, adipogenesis, lipotoxicity, mitochondrial function, and gut microbiota regulation. Although comprehensive clinical trials evaluating this dietary pattern as an integrated intervention remain limited, current evidence supports its relevance for future translational research, public health strategies, and the development of sustainable dietary models aimed at improving metabolic health. Full article

Background/Objectives: Fibromyalgia (FM) is a complex disease with symptoms such as brain fog, widespread body pain, sleep disturbances, and mood changes, and its etiology is not clearly understood. Our main aim in this study was to evaluate emotional eating and emotional dysregulation in patients with FM and examine the possible effects of these disorders on disease severity. Materials and Methods: This observational study included 94 patients with FM (6 males, 88 females; mean age: 44.64 ± 9.04 years; range, 19–65 years) and 76 controls (7 males, 69 females; mean age: 41.91 ± 10.874 years; range, 18–64 years). The patient and control group participants completed a form including sociodemographic data. Participants also completed the Fibromyalgia Impact Questionnaire (FIQ), Emotional Eating Questionnaire (EEQ), and Difficulties in Emotion Regulation Scale (DERS). Results: In unadjusted comparisons, DERS-goals and DERS-strategies scores were higher in the FM group than in controls; however, these differences did not remain statistically significant after Bonferroni correction. In the linear regression model, it was found that the total score of the Difficulties in Emotion Regulation Scale (DERS-Total) (p = 0.010) was the only variable that significantly affected the FIQ value. Even though the patient group had slightly higher EEQ scores, there was no statistically significant difference between the two groups (p = 0.721). Conclusions: Emotional regulation difficulties were associated with FM symptom severity, whereas emotional eating did not differ significantly between groups and was not associated with symptom severity. These findings suggest that emotion-related psychological processes should be considered within the biopsychosocial framework of FM. Full article

Abdominal obesity (AO), assessed through waist circumference (WC), has become a validated complementary anthropometric marker for cardiometabolic risk assessment. Growing evidence suggests that emotional eating (EE), characterized by food intake in response to emotions rather than physiological hunger cues, may be linked to AO by promoting dysregulated eating patterns rich in palatable and energy-dense foods. This behavior may contribute, directly or indirectly, to excess visceral fat accumulation. An analysis of the current evidence was conducted to examine the psychological, physiological, neuroendocrine, and gut–brain axis mechanisms underlying the association between EE and AO, as well as to explore emerging interventions for its management. A narrative review of studies published between 2015 and 2025 was carried out using PubMed and Google Scholar. Search terms related to EE, AO, physiological mechanisms, hedonic hunger, diet quality, gut microbiota, and mindful eating were employed. The findings indicate that EE is associated with emotional dysregulation, chronic activation of the hypothalamic–pituitary–adrenal (HPA) axis, increased cortisol levels, low-grade inflammation, alterations in neurotransmitters such as dopamine, serotonin, and neuropeptide Y (NPY), as well as intestinal dysbiosis. These mechanisms favor impulsive consumption of palatable foods, visceral fat gain, and metabolic deterioration. Interventions such as mindful eating show positive effects in reducing EE; however, their anthropometric impact still requires further validation. In conclusion, EE represents an important behavioral factor in the development and maintenance of AO. Its management requires a multidimensional approach integrating emotional regulation, dietary modification, and psychobehavioral strategies. Full article

Background/Objectives: Feeding and Eating Disorders (FEDs) are among the most challenging mental disorders due to their pervasive symptomatology and high relapse rates. While considerable research has focused on the role of personality in the onset and maintenance of FEDs, it remains unclear whether specific personality dimensions and emotion dysregulation mechanisms predict clinical severity and purging behaviors. This study aimed to explore the role of personality dimensions, emotion dysregulation, and purging behaviors in predicting psychological distress in patients with FEDs, adopting a dimensional and integrated perspective. Methods: A sample of cisgender women in a semi-residential treatment for FEDs or obesity (n = 124) was recruited in southern Italy and assessed using a psychodiagnostics survey, including the Eating Disorder Inventory-3 (EDI-3), the Symptom Checklist-90-R (SCL-90-R), and the Personality Inventory for DSM-5 (PID-5). Results: Patients with bulimia nervosa exhibited higher psychological distress compared to patients with other FEDs and Obesity, which was not significantly determined by the co-occurrence of personality disorders. Negative affectivity, detachment, and purging symptoms were significantly related to psychological distress in patients with FEDs and Obesity (p ranging from 0.028 to <0.001). Moreover, the results showed an indirect effect of emotion regulation on the relationship between self-esteem and purging symptoms in patients with FEDs and Obesity (β = 0.107; p = 0.046). Conclusions: These findings suggest that specific personality dimensions, emotion dysregulation, and purging symptoms are associated with psychological distress in individuals with FEDs and Obesity. Therefore, it is necessary to reflect on the impact of these psychological components in planning tailored treatment for FED patients. Full article

Obesity resulting from melanocortin-4 receptor (MC4R) dysfunction is characterized by combined metabolic dysregulation and maladaptive reward-related behaviors that limit the durability of existing therapies. The endocannabinoid system is a central regulator of appetite, lipid metabolism, and reward processing; however, first-generation cannabinoid receptor 1 (CB1) antagonists were limited by adverse neuropsychiatric effects. SKNY-1 is an orally active tetrahydrocannabivarin (THCV) analog designed to engage pathway-biased CB1 signaling, modulate cannabinoid receptor 2 (CB2), and selectively inhibit monoamine oxidase B (MAO-B), with the objective of addressing both metabolic and behavioral components of obesity while minimizing central nervous system liability through biased CB1 signaling, CB2 modulation, and potential complementary MAO-B inhibition. Here, we integrated in vitro pharmacological profiling of SKNY-1 with in vivo evaluation in an adult mc4r(G894C) zebrafish model exhibiting obesity-associated metabolic and reward-related phenotypes. In vitro, SKNY-1 displayed low-potency modulation of CB1 cyclic AMP signaling (EC₅₀ ~30 µM) but more potent antagonism of the CB1 β-arrestin pathway (IC₅₀ ~6 µM), consistent with differential CB1 pathway modulation. SKNY-1 acted as a CB2 partial agonist (EC₅₀ ~0.1 µM), with antagonist activity emerging at higher concentrations, and selectively inhibited MAO-B at low affinity with no activity against MAO-A. In vivo, mc4r(G894C) zebrafish mutants exhibited dyslipidemia, hepatic triglyceride accumulation, altered appetite-regulatory gene expression, increased metabolic rate, and enhanced compulsive high-calorie feeding and nicotine-seeking behaviors. Oral administration of SKNY-1 for six days produced dose-dependent effects. Both doses normalized total cholesterol and low-density lipoprotein levels and reduced hepatic triglycerides toward wild-type values without affecting circulating triglycerides. The higher dose (200 ng per fish per day) induced significant body weight reduction while preserving body density and attenuated reward-associated feeding and nicotine-seeking behaviors. The lower dose (20 ng per fish per day) more effectively normalized the leptin a-to-ghrelin expression ratio. Collectively, these findings demonstrate that SKNY-1 engages integrated endocannabinoid and potential dopaminergic mechanisms to improve metabolic parameters and attenuate maladaptive reward-related behaviors in an MC4R-deficient vertebrate model, supporting its further translational investigation for obesity complicated by compulsive eating and substance-seeking behaviors. Full article

Background: Inadequate management of emotional responses, limited access to emotion regulation strategies, and difficulties in emotion regulation may co-occur with alexithymic traits and interoceptive inaccuracy or confusion. These dimensions may influence lifetime eating disorder spectrum manifestations. Objective: To assess, in a general population sample without Axis I psychiatric disorders, alexithymic traits, interoceptive confusion/inaccuracy, and difficulties in emotion regulation, and to explore their associations with eating disorder spectrum manifestations. Method: In this cross-sectional observational study, fifty-two participants aged 18–30 years, recruited via a university bulletin board, were assessed online using the Toronto Alexithymia Scale (TAS-20), Interoceptive Accuracy Scale (IAS), Interoceptive Confusion Questionnaire (ICQ), Eating Attitude Test (EAT-26), and Difficulties in Emotion Regulation Scale (DERS) (protocol #01/2025). Results: Interoceptive confusion (ICQ) showed significant positive correlations with TAS-20, DERS, and EAT-26 total scores. ICQ scores were associated with TAS-20 subscales ‘difficulty identifying feelings’ (DIF) and ‘difficulty describing feelings’ (DDF). Participants with TAS-20 scores > 51 (n = 35; 67.3%) had significantly higher EAT-26 scores on ‘dieting’ (p = 0.043) and ‘bulimia’ (p = 0.017), as well as higher ICQ (p = 0.001) and DERS (p = 0.001) total scores, with smaller differences in the DERS ‘impulse’ subscale (p = 0.037). Conclusions: Preliminary findings suggest a pattern of co-occurring traits characterized by alexithymia, interoceptive confusion, emotional dysregulation, impulsivity, and eating disorder spectrum features, supporting the study hypothesis. Full article

Background/Objectives: Intentional insulin omission (IIO), commonly referred to as diabulimia, is a high-risk behavioural phenomenon observed mainly in adolescents and young adults with type 1 diabetes mellitus (T1D). Defined as the deliberate reduction or omission of insulin to influence body weight, IIO lies at the intersection of metabolic management and eating disorder psychopathology. Despite serious health risks, including diabetic ketoacidosis, microvascular complications, and increased mortality, it remains under-recognised due to stigma, diagnostic ambiguity, and overlap with routine diabetes self-management. This review aimed to examine the prevalence, psychological mechanisms, and clinical consequences of IIO. Methods: On 1 April 2026, we conducted a systematic search of PubMed, Scopus, APA PsycInfo/PsycArticles and Cinahl for studies investigating intentional insulin omission and related metabolic and psychological outcomes in T1D. Clinical and epidemiological studies assessing prevalence, risk factors, and interventions were included. Results: Twenty-nine studies met the inclusion criteria. Prevalence estimates ranged from 20% to 45%, with higher risk among females, adolescents, and individuals experiencing diabetes-related distress or body dissatisfaction. Psychological factors—including fear of weight gain, emotion dysregulation, depressive symptoms, and identity conflicts—were associated with IIO onset and maintenance. IIO was consistently linked to poor glycaemic control, elevated HbA1c levels, and adverse metabolic and psychological outcomes. Screening tools such as the Diabetes Eating Problem Survey–Revised (DEPS-R) may support early identification, while effective management requires integrated multidisciplinary care. Conclusions: Although IIO is not formally classified as an eating disorder in current diagnostic systems, it shares important psychopathological features with eating disorders and may represent a diabetes-specific disordered eating behaviour with life-threatening consequences. Full article

Emotion dysregulation and altered interoceptive processing are increasingly recognized as core processes in eating disorder (ED) psychopathology. Difficulties in identifying, tolerating, and regulating negative emotional states may interact with reduced trust in bodily signals and distorted interpretation of hunger and satiety cues, contributing to maladaptive eating behaviors. The aim of this PRISMA-guided qualitative systematic review was to synthesize original empirical evidence on the interaction between emotion dysregulation and interoceptive processing in EDs, with particular attention to how emotional distress may be misinterpreted as physical hunger or food-related urges. A systematic search of PubMed and Scopus identified 78 records; after removal of duplicates and screening procedures, 24 original empirical studies were included in the qualitative synthesis. Across ED presentations, emotion dysregulation consistently emerged as a central transdiagnostic process associated with symptom severity, impulsivity, maladaptive eating behaviors, and related risk outcomes. Interoceptive alterations were widely reported, particularly involving reduced body trust and distorted interpretation of internal sensations rather than a uniform deficit in interoceptive sensitivity. The reviewed studies also showed that emotional states and cognitive expectations may shape the appraisal of hunger and satiety cues, contributing to the misinterpretation of emotional distress as physiological need across restrictive, binge-purge, and binge-eating presentations. The findings support a close interplay between emotion dysregulation and altered interoceptive processing in EDs and highlight the clinical relevance of interventions that integrate emotion regulation and interoceptive awareness to promote more adaptive eating behaviors. Full article

The endocannabinoid system (ECS) is a fundamental regulator of brain and body homeostasis, integrating neural, immune, and stress-related signaling pathways. Dysregulation of ECS components, including cannabinoid receptors (CB1 and CB2), endocannabinoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes (FAAH and MAGL), has been increasingly implicated in the pathophysiology of neuropsychiatric disorders, including mood, anxiety, psychotic, stress-related, and eating disorders. Altered endocannabinoid signaling contributes to maladaptive stress responses, emotional dysregulation, and impaired synaptic plasticity, highlighting the role of the ECS as a core integrative mechanism. Therapeutic strategies targeting ECS, particularly through FAAH inhibition and the use of plant-derived cannabinoids, such as cannabidiol (CBD), show promise in restoring endogenous homeostasis while minimizing the adverse cognitive and affective effects associated with direct CB1 activation. ECS function and treatment response are further influenced by genetic polymorphisms in CNR1, CNR2, FAAH, and MGLL, as well as epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation. Despite these advances, clinical translation remains limited by interindividual variability, the complexity of ECS interactions, and the relatively small size of existing clinical studies. Future research integrating longitudinal clinical trials with multi-omics approaches is essential to support the development of evidence-based, personalized interventions. Overall, understanding ECS mechanisms and dysregulation provides a valuable framework for the development of targeted therapies in neuropsychiatric disorders. Full article