Efficacy Of Dose Research Articles

DOD-BART: machine learning-based dose optimization design incorporating patient-level prognostic factors via Bayesian additive regression trees

ABSTRACT Dose optimization is a critical stage of drug development in oncology and other disease areas. Early phase clinical trials are inherently heterogeneous due to their exploratory nature. The process of identifying an optimal dose involves careful considerations of the patient population, evaluation of therapeutic potential, and exploration of the dose-response and dose-toxicity relationships to ensure that it is safe and effective for the intended use. However, the complex mechanism of actions and uncertainties during dose optimization often introduce substantial gaps between those early phase trials and phase 3 randomized control trials. These gaps can indeed increase the chances of failure. To address these challenges, we propose a novel seamless phase I/II design, namely DOD-BART design, which utilizes machine learning technique, specifically Bayesian Additive Regression Trees (BART) to fully incorporate patient-level prognostic factors and outcomes. Our design provides a streamlined approach for dose exploration and optimization, automatically updated with emerging data to allocate patients to the most promising dose levels. DOD-BART elucidates disease relationships, analyzes and synthesizes emerging data, augments operational efficiency, and guides dose optimization for suitable population. Simulation studies demonstrate the robust performances of the DOD-BART design across a variety of realistic settings, with high probabilities of correctly identifying the optimal dose, allocating patients more to tolerable and efficacious dose levels, making less biased estimates, and efficiently utilizing patients’ data.

Reprogramming the genome of M13 bacteriophage for all-in-one personalized cancer vaccine.

Peptide-based vaccines face limitations in immunogenicity and stability, and challenges in co-delivering antigens and adjuvants effectively. Virus-based nanoparticles, particularly M13 bacteriophage, present a promising solution due to their genetic modifiability, intrinsic adjuvanticity, and efficient antigen presentation capabilities. Here we developed a programmable M13 phage-based personalized cancer vaccine enabling single-step antigen-adjuvant assembly. Specifically, we designed a reprogrammed (RP) phage platform that precisely regulates Toll-like receptor 9 activation by programming its genome sequence and modulates antigen density through genetic engineering. Vaccination studies with RP phages demonstrated that the immune response could be modulated by fine-tuning the adjuvanticity and antigen density, revealing an optimal antigen dose and adjuvanticity for maximum vaccine efficacy. The RP phage induced a remarkable 24-fold increase in neoantigen-specific CD8 + T cells and eradicated established MC-38 tumors when combined with anti-PD-1 therapy. These findings highlight the RP phage's potential as a powerful nanovaccine platform for personalized cancer vaccines.

Preclinical assessment of the PI3Kα selective inhibitor inavolisib and prediction of its pharmacokinetics and efficacious dose in human

1. Small molecule inhibitors of the PI3K pathway have been extensively investigated as potential anticancer agents. Among the effectors in this pathway, PI3Kα is the kinase most frequently associated with the development of tumours, through mutations and amplifications of the PIK3CA gene encoding the p110α catalytic subunit. 2. Inavolisib (GDC-0077) is a potent and PI3Kα-selective inhibitor that also specifically triggers the degradation of the mutant p110α protein. 3. We characterised inavolisib ADME properties in preclinical in vitro and in vivo studies, assessed its efficacy in the PIK3CA mutant KPL-4 breast cancer xenograft model, and predicted its pharmacokinetics and efficacious dose in humans. 4. Inavolisib had a moderate permeability (1.9•10−6 cm/s) in MDCK cells and was a P-gp and Bcrp1 substrate. It appeared metabolically stable in hepatocytes incubations from human and preclinical species. The systemic clearance was low in mouse, monkey and dog and high in rat. Oral bioavailability ranged from 57.5% to 100%. Inavolisib was efficacious in the KPL-4 sub-cutaneous xenograft model. 5. The PK/PD model parameters estimated from the efficacy study, combined with PBPK model-predicted human PK profiles, projected that a dose of 3 mg could lead to clinical response. Inavolisib is currently being tested in phase 3 trials.

A Model‐Based Trial Design With a Randomization Scheme Considering Pharmacokinetics Exposure for Dose Optimization in Oncology

ABSTRACTThe primary purpose of an oncology dose‐finding trial for novel anticancer agents has been shifting from determining the maximum tolerated dose to identifying an optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. In 2022, the FDA Oncology Center of Excellence initiated Project Optimus to reform the paradigm of dose optimization and dose selection in oncology drug development and issued a draft guidance. The guidance suggests that dose‐finding trials include randomized dose–response cohorts of multiple doses and incorporate information on pharmacokinetics (PK) in addition to safety and efficacy data to select the OD. Furthermore, PK information could be a quick alternative to efficacy data to predict the minimum efficacious dose and decide the dose assignment. This article proposes a model‐based trial design for dose optimization with a randomization scheme based on PK outcomes in oncology. A simulation study shows that the proposed design has advantages compared to the other designs in the percentage of correct OD selection and the average number of patients assigned to OD in various realistic settings.

Model-informed drug development for antimicrobials: translational pharmacokinetic-pharmacodynamic modelling of apramycin to facilitate prediction of efficacious dose in complicated urinary tract infections.

The use of mouse models of complicated urinary tract infection (cUTI) has usually been limited to a single timepoint assessment of bacterial burden. Based on longitudinal in vitro and in vivo data, we developed a pharmacokinetic-pharmacodynamic (PKPD) model to assess the efficacy of apramycin, a broad-spectrum aminoglycoside antibiotic, in mouse models of cUTI. Two Escherichia coli strains were studied (EN591 and ATCC 700336). Apramycin exposure-effect relationships were established with in vitro time-kill data at pH 6 and pH 7.4 and in mice with cUTI. Immunocompetent mice were treated with apramycin (1.5-30 mg/kg) starting 24 h post-infection. Kidney and bladder tissue were collected 6-96 h post-infection for cfu determination. A PKPD model integrating all data was developed and simulations were performed to predict bacterial burden in humans. Treatment with apramycin reduced the bacterial load in kidneys and bladder tissue up to 4.3-log compared with vehicle control. In vitro and in vivo tissue time-course efficacy data were integrated into the PKPD model, showing 76%-98% reduction of bacterial net growth and 3- to 145-fold increase in apramycin potency in vivo compared with in vitro. Simulations suggested that an 11 mg/kg daily dose would be sufficient to achieve bacterial stasis in kidneys and bladder in humans. PKPD modelling with in vitro and in vivo PK and PD data enabled simultaneous evaluation of the different components that influence drug effect, an approach that had not yet been evaluated for antibiotics in the cUTI model and that has potential to enhance model-informed drug development of antibiotics.

A Phase 2 Study of PEGylated Recombinant Human Growth Hormone for 52 Weeks in Short Children Born Small for Gestational Age in China.

Children born small for gestational age (SGA) are at increased risk of health issues. This study evaluated the efficacy, safety and optimal dose of PEGylated-recombinant human growth hormone (PEG-rhGH) in these children. In this multicentre, randomised, open-label, Phase 2 trial conducted at nine clinical sites in China, patients were randomised 1:1 to receive subcutaneous injections of PEG-rhGH at 0.1 mg/kg/week (low dose) or 0.2 mg/kg/week (high dose) for 52 weeks. Ninety-six children were born SGA. The primary endpoint was the change in height standard deviation score (HT-SDS) at Week 52. At Week 52, the change in HT-SDS in the high- and low-dose groups was 0.923 ± 0.352 (p < 0.0001) and 0.511 ± 0.336 (p < 0.0001), respectively (least-squares means difference, 0.410; 95% confidence interval 0.270-0.551; p < 0.0001). Height velocity (9.94 ± 1.55 vs. 8.37 ± 1.50 cm/year) was also significantly higher in the high-dose than in the low-dose group (p < 0.0001). Change in insulin-like growth factor (IGF)-1 SDS was 1.867 ± 1.747 and 1.168 ± 1.193 in the high- and low-dose groups, respectively (p = 0.0189). IGF-1/IGF binding protein-3 and bone maturity were improved in both groups at Week 52. Most treatment-emergent adverse events were mild to moderate; the safety profile was similar in both groups. PEG-rhGH at either dose for 52 weeks was effective and well tolerated in children born SGA. Patients in the high-dose group achieved greater improvement in HT-SDS than in the low-dose group. ClinicalTrials. gov identifier: NCT02375620.

Chemical composition and pharmacological aspects of Malaysian stingless bee propolis: An up‑to‑date systematic review.

Propolis is a sticky substance produced by stingless bees for construction and defence of their hive. It has notable anti-inflammatory, antioxidant, antibacterial, antifungal, anti-hyperglycemic, and wound healing effects. The present review summarised and examined the phytochemical properties, mode of action and current research prospects of Malaysian propolis. A database search using Google Scholar, Web of Science and ScienceDirect generated 780 references; 30 relevant articles were included in the present review, of which 23 were in vitro studies and 7 were in vivo or animal studies. Propolis demonstrated antioxidant, antibacterial, antifungal, anti-inflammatory and anti-hyperglycemic properties, indicating potential as a wound healing agent. Despite favourable findings, due to the scarcity of studies in the literature, more in-depth research and clinical validation on the synergistic effects, efficacy and optimum dosage of propolis are needed.

Vitamin D for very preterm infants-determining the how, when, and why.

A recent survey study found that 400 IU/day vitamin D is the most common dose in United States neonatal intensive care units. Results of clinical trials are inconsistent, and, therefore, have not determined the optimal vitamin D dose for efficacy and safety in the neonatal intensive care unit. Future studies must consider the unique attributes of perinatal vitamin D metabolism and the potential role of vitamin D in immune function and organ development. IMPACT: Preterm infant vitamin D metabolism is a complex yet important area of research.

AI in Clinical Trials and Drug Development: Challenges and Potential Advancements.

Artificial intelligence (AI) is one of the fastest-growing fields in various industries, including engineering, architecture, medical and clinical research, aerospace, and others. AI, which is a combination of machine learning (ML), deep learning (DL), and human intelligence (HI), is revolutionizing drug discovery and development by making it more cost-effective and efficient. It is also being used in fields such as medicinal chemistry, molecular and cell biology, pharmacology, pharmacokinetics, formulation development, and toxicology. AI plays a crucial role in clinical testing by enhancing patient stratification, patient sample evaluation, and trial design, assisting in the identification of biomarkers, determining efficacy criteria, dose selection, trial length, and target patient population selection. The primary objective of this study is to emphasize the importance of AI in clinical trials and drug development, while also exploring the existing challenges and potential advancements in AI within the healthcare industry. A comprehensive literature review was conducted, covering the period from 1998 to 2023. The Science Direct, PubMed, and Google Scholar databases were searched for relevant information. A variety of publications, including Research Gate, Nature, MDPI, and Springer Link, provided pertinent data. This study aimed to gain a deeper understanding of the use of AI in clinical research and drug development, as well as its potential and limitations. We also discuss the benefits and main data limitations of the traditional trial and drug development approach. AI approaches are currently being used to overcome research obstacles and eliminate conceptual or methodological limitations. After discussing possible obstacles and coping mechanisms, we provide several recommendations to help individuals understand the challenges and difficulties associated with clinical research and drug development. It is essential for pharmaceutical companies to have a cutting-edge AI strategy if AI is to become a routine tool for clinical research and drug development.

Efficacy and threshold dose of intensive training targeting mobility for children with cerebral palsy: A systematic review and meta-analysis.

https://onlinelibrary.wiley.com/doi/10.1111/dmcn.16040

An Insight of Plant Source, Toxicological Profile, and Pharmacological Activities of Iridoid Loganic Acid: A ComprehensiveReview.

This study evaluates the pharmacological effects of iridoid glucoside loganic acid, a plant constituent with diverse properties, based on literature, and explores the underlying cellular mechanisms for treating several ailments. Data were collected from reliable electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar, etc. The results demonstrated the anti-inflammatory, anti-oxidant, and other protective effects of loganic acid on metabolic diseases and disorders such as atherosclerosis, diabetes, and obesity, in addition to its osteoprotective and anticancer properties. The antioxidant activity of loganic acid demonstrates its capacity to protect cells from oxidative damage and mitigates inflammation by reducing the activity of inflammatory cytokines involving TNF-α and IL-6, substantially upregulating the expression of PPAR-γ/α, and decreasing the clinical signs of inflammation-related conditions related to hypertriglyceridemia and atherosclerosis. Meanwhile, loganic acid inhibits bone loss, exhibits osteoprotective properties by increasing mRNA expression levels of bone synthesizing genes such as Alpl, Bglap, and Sp7, and significantly increases osteoblastic proliferation in preosteoblast cells. Loganic acid is an anti-metastatic drug that reduces MnSOD expression, inhibits EMT and metastasis, and prevents cellular migration, proliferation, and invasion in hepatocellular carcinoma cells. However, additional clinical trials are required to assess its safety, efficacy, and human dose.

Phase I First-in-Human Dose Escalation Study of the oral Casein Kinase 1α and Cyclin Dependent Kinase 7/9 inhibitor BTX-A51 in advanced MDS and AML.

BTX-A51, a first-in-class oral small molecule inhibitor of casein kinase 1α (CK1α) and cyclin dependent kinase (CDK) 7 and 9, induces apoptosis of leukemic cells by activating p53 and inhibiting expression of Mcl1. Here, we report on the results of the phase 1 clinical trial of BTX-A51 in patients with relapsed or refractory AML and MDS. Thirty-one patients were enrolled into 8 dose-escalation cohorts at BTX-A51 doses ranging from 1mg to 42mg dosed three days/week for 21 or 28 days out a 28-day cycle. The recommended phase 2 dose was 21mg dosed three days/week for 4 weeks of a 28-day cycle. BTX-A51 increased expression of p53 and reduced expression of MCL1 and RNA polymerase II phosphorylation on pre- and post-treatment immunocytochemistry studies. Overall, 3 patients (10%) experienced complete remission with incomplete count recovery (CRi). All 3 responding patients had RUNX1 mutations and the CR/CRi rate for RUNX1 -mutated patients receiving BTX-A51 at efficacious doses (11mg or higher) was 30%. Ex-vivo studies confirmed higher efficacy of BTX-A51 on RUNX1 -mutated myeloblasts and demonstrate synergy with azacitidine and venetoclax. Although the overall efficacy was modest, this study lays the groundwork for future studies with improved patient selection and combination approaches.

Prediction of Cardiac ATTR Depletion by NI006 (ALXN2220) Using Mechanistic PK/PD Modeling.

NI006 (aka ALXN2220) is a therapeutic antibody candidate in phase III clinical development for the depletion of amyloid transthyretin (ATTR) in patients with ATTR cardiomyopathy, an infiltrative cardiomyopathy leading to increased left ventricular wall thickness (LVWT). The mode-of-action consists in removal of disease-causing amyloid accumulations by activating phagocytic immune cells, a mechanism without precedent in cardiology. To select a safe and potentially efficacious dose range and treatment duration for a combined first-in-human and proof-of-concept clinical phase Ib study, we developed a mechanistic pharmacokinetic and pharmacodynamic (PK/PD) model that can predict NI006 exposure, its effects on cardiac amyloid load and on LWVT, which is a predictor of heart failure in this disease. The PK/PD model predictions supported 0.3 mg/kg monthly dosing as a safe starting dose and identified 10-60 mg/kg monthly as the potentially efficacious dose range with substantial and dose dependent cardiac amyloid burden reduction within 4 months for 60 mg/kg and 10 months for 10 mg/kg. These predictions were in good agreement with the observed primary results of the clinical phase Ib study where amyloid burden was measured by imaging. This novel translational PK/PD model provided important predictions to guide the design of the phase Ib study of NI006, indicating the value of this approach to integrate preclinical results into clinical trial design and increase translational success.

Efficacy of pharmacological interventions for ADHD: protocol for an updated systematic review and dose–response network meta-analysis

BackgroundAttention-deficit/hyperactivity disorder (ADHD) affects approximately 5% of children globally, with symptoms often persisting into adulthood. While pharmacological interventions are commonly employed for management, understanding the optimal dosing for efficacy and tolerability remains crucial. This study aims to conduct a dose–response network meta-analysis to estimate the efficacy of pharmacological treatments across different doses, aiming to inform clinical decision-making and improve treatment outcomes.MethodsThis updated systematic review will include randomized controlled trials evaluating ADHD medication efficacy in children, adolescents, and adults. An updated search from a 2018 NMA will be conducted across multiple electronic databases with no language restrictions, using specific eligibility criteria focused on randomized controlled trials. The primary outcome will assess the severity of ADHD core symptoms, while secondary outcomes will consider treatment tolerability. A dose–response Bayesian hierarchical model will be used to estimate dose–response curves for each medication, identifying optimal dosing strategies.DiscussionWith this dose–response network meta-analysis, we aim to better understand the dose–response relationship of pharmacological treatment in ADHD, which could help clinician to the identification of optimal doses.Systematic review registrationOSF https://doi.org/10.17605/OSF.IO/3MY4A.

Management of Postural Orthostatic Tachycardia Syndrome in Pediatric Patients: A Clinical Review

Postural orthostatic tachycardia syndrome (POTS) is a chronic illness with unknown mortality and high morbidity, often diagnosed in the adolescent years. Published literature regarding POTS primarily focuses on the adult population, and guidance on treatment in pediatrics is sparse. The purpose of this clinical review is to evaluate the current literature on the management of POTS in pediatric patients. A search was conducted using the Cochrane database, Google Scholar, and PubMed. Studies were included if they evaluated the management of POTS, primarily in pediatric patients. Case reports and series were excluded. Eight published studies met the inclusion and exclusion criteria. To date, there are no US Food and Drug Administration-approved agents for the treatment of POTS. However, select pharmacological therapies have shown positive outcomes by addressing symptom origins, such as providing heart rate control, peripheral autonomic modulation, and targeting hypovolemia. Targeted pharmacological therapies studied in children and young adults include ivabradine, metoprolol, midodrine, pyridostigmine, intravenous crystalloid fluids, and fludrocortisone. Before adding pharmacotherapeutic interventions, non-pharmacologic interventions such as patient education, avoidance of symptom-triggering environments and medications, dietary fluid and sodium supplementation, exercise, and use of compression garments should be first attempted. Although the body of evidence for the management of POTS is expanding, additional research is needed to determine safe and efficacious dosing and establish clear guidelines for POTS in the pediatric population.

Antipsychotic Drugs: A Concise Review of History, Classification, Indications, Mechanism, Efficacy, Side Effects, Dosing, and Clinical Application.

The introduction of the first antipsychotic drug, chlorpromazine, was a milestone for psychiatry. The authors review the history, classification, indications, mechanism, efficacy, side effects, dosing, drug initiation, switching, and other practical issues and questions related to antipsychotics. Classifications such as first-generation/typical versus second-generation/atypical antipsychotics are neither valid nor useful; these agents should be described according to the Neuroscience-based Nomenclature (NbN). Antipsychotic drugs are not specific for treating schizophrenia. They reduce psychosis regardless of the underlying diagnosis, and they go beyond nonspecific sedation. All currently available antipsychotic drugs are dopamine blockers or dopamine partial agonists. In schizophrenia, effect sizes for relapse prevention are larger than for acute treatment. A major unresolved problem is the implausible increase in placebo response in antipsychotic drug trials over the decades. Differences in side effects, which can be objectively measured, such as weight gain, are less equivocal than differences in rating-scale-measured (subjective) efficacy. The criteria for choosing among antipsychotics are mainly pragmatic and include factors such as available formulations, metabolism, half-life, efficacy, and side effects in previous illness episodes. Plasma levels help to detect nonadherence, and once-daily dosing at night (which is possible with many antipsychotics) and long-acting injectable formulations are useful when adherence is a problem. Dose-response curves for both acute treatment and relapse prevention follow a hyperbolic pattern, with maximally efficacious average dosages for schizophrenia of around 5 mg/day risperidone equivalents. Computer apps facilitating the choice between drugs are available. Future drug development should include pharmacogenetics and focus on drugs for specific aspects of psychosis.

Safety, pharmacokinetics, and pharmacodynamics of ART-648, a PDE4 inhibitor in healthy subjects: A randomized, placebo-controlled phase I study.

Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad-spectrum anti-inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART-648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases. According to the estimated clinical doses based on an invitro whole-blood assay, a phase I study was designed. The purpose of this phase I study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following single and multiple administration of ART-648 in healthy subjects. PD was assessed by suppression of lipopolysaccharide-induced TNFα release in exvivo whole-blood assay. In the single rising dose study, ART-648 was safe and well tolerated with a dose-proportional increase in exposures up to 4 mg. Single doses of ART-648 demonstrated dose-dependent PD response, indicating target engagement at 2-8 mg doses. In the multiple rising dose study, doses up to 4 mg BID after careful titration were well tolerated, while doses up to 6 mg BID were tolerated not in all but the majority of subjects. In conclusion, ART-648 exhibits a favorable PK profile with robust target engagement at clinically safe and tolerated doses identified in healthy subjects.

Preparations, Applications, Patents, and Marketed Formulations of Nanoemulsions - A Comprehensive Review.

Nanoemulsions have emerged as versatile colloidal dispersions with promising applications in various fields, including pharmaceuticals, food, and cosmetics. These nano-sized emulsions, stabilized by surfactants, offer unique advantages such as enhanced ingredient penetration efficacy and versatile dosage forms. This article provides an extensive overview of nanoemulsions, covering their composition, methods of preparation, and applications in drug delivery, the food industry, and cosmetics. Various high-energy and low-energy methods for nanoemulsion preparation are discussed, along with their advantages and limitations. Additionally, the article highlights the potential of nanoemulsions in improving drug bioavailability, stability, and therapeutic efficacy, especially in oral, topical, parenteral, intranasal, ocular, and pulmonary drug delivery. Furthermore, nanoemulsions are explored as carriers for encapsulating flavoring agents, nutraceuticals, and natural preservatives in the food industry, as well as their use in cosmetic formulations. Current clinical trials involving nanoemulsions and recent patents in the field are also summarized, providing insights into ongoing research and development efforts. Lastly, a selection of marketed nanoemulsion formulations is presented, showcasing their practical applications and commercial availability. Overall, nanoemulsions hold great promise as effective delivery systems with broad applications across various industries.

Potent covalent irreversible inhibitor of KRAS G12C IBI351 in patients with advanced solid tumors: First-in-human phase I study

BackgroundIBI351 is an irreversible and covalent inhibitor of KRAS G12C. Despite FDA approval of two KRAS G12C inhibitors, there are still significant unmet clinical needs in Chinese patients and ongoing concerns about the optimal dosage. Herein, we presented the phase Ia/Ib study of IBI351 monotherapy in Chinese patients with advanced solid tumors harboring KRAS G12C mutation. MethodsIn phase Ia dose escalation, IBI351 at 250/450/700/900 mg once daily and 450/600/750 mg twice daily (BID) were evaluated. Potentially efficacious doses and optimal recommended phase 2 dose (RP2D) were further evaluated in patients with advanced non-small cell lung cancer (NSCLC) in phase Ia dose expansion and phase Ib. Safety, pharmacokinetics, and investigator-assessed tumor response were evaluated. ResultsAs of June 13, 2023, 176 patients were enrolled. IBI351 was well tolerated with no dose-limiting toxicity reported across all evaluated doses. The RP2D was determined as 600 mg BID by considering safety, efficacy and pharmacokinetics. A total of 168 patients (95.5 %) had at least one treatment-related adverse event (TRAE), and 64 patients (36.4 %) had grade 3 or higher TRAEs, most commonly gamma-glutamyl transferase increased (10.2 %) and anemia (6.8 %). For patients with NSCLC, the confirmed objective response rate (ORR) was 45.5 % across all doses. At 600 mg BID, the confirmed ORR was 46.8 % and median progression-free survival was 9.6 months with a median follow-up of 6.9 months. ConclusionsIBI351 was well tolerated in patients with advanced solid tumors and showed promising antitumor activity in advanced NSCLC patients with KRAS G12C mutation.

S-Adenosylmethionine (SAMe) for Central Nervous System Health: A Systematic Review.

Background/Objectives: S-adenosylmethionine (SAMe) is a natural compound used to improve mood-related symptoms. Our aim was to determine the efficacy, safety, and optimal dose of SAMe in Central Nervous System (CNS) signs (e.g., mood, behavior). Methods: We conducted a PRISMA-based systematic review by searching PubMed, CINAHL, and Web of Science using MeSH search terms. Articles were independently reviewed by two researchers (with a third resolving conflicts) during title/abstract screening and full-text review. Data were extracted in the same approach, with a quality assessment of included articles. Results: Out of 1881 non-duplicated studies, 36 were included in the review focusing on CNS signs (mood, behavior, sleep). Most studies (n = 32) achieved a 4 or 5 out of 5 points, indicating high study quality. Overall, SAMe was effective in 24 of 36 studies, with adverse events mostly consisting of mild, transient gastrointestinal disturbances. Conclusions: Many patients in these studies did experience improvements in CNS signs from using SAMe alone or in combination with existing therapy. However, future studies are needed to further understand the long-term effects of SAMe in the CNS.