Depression and anxiety have become major public health concerns over the last two decades, significantly affecting millions of people globally. (Hamad et al., 2024, Limenih et al., 2024). These disorders lead to considerable impairment in daily functioning that hampers the quality of life (Terrell et al., 2024). As per the reports of World Health Organization (WHO), global count for the patients suffering from depression and anxiety are over 264 million, which negatively affects their work, relationships, and overall well-being (Voineskos et al., 2020). Moreover, 30–40 % of patients with depression experience treatment-resistant depression (TRD), even after undergoing standard antidepressant therapy (Bhattaccharjee et al., 2020). This highlights the limitations of existing therapeutic approaches, which often fail to provide rapid and effective outcomes (Sampogna et al., 2024).

Traditional treatment options for depression, such as fluoxetine and olanzapine, are associated with delayed onset of action and limited efficacy, particularly in preventing relapses (Ruberto et al., 2020). Current treatment, with Levosulpiride (Levo) which is a highly selective antagonist of dopamine D2 receptors, primarily targeting presynaptic membranes in dopaminergic pathways (Arif et al., 2022). Despite its potential, Levo, c under class IV of Biopharmaceutics Classification System (BCS), and shows low bioavailability, typically ranging between 20–30 % with several side effects (Baravkar et al., 2022, Fakhar-ud-Din and Khan, 2019). To address poor therapeutic issues, recent research efforts have shifted toward exploring combination therapies that pair synthetic drugs with herbal compounds, aiming to enhance therapeutic outcomes and minimize adverse effects (Sharma et al., 2023). Cannabidiol (CBD), is a naturally occurring compound gaining increasing recognition for its role in managing neurological disorders (Nelson et al., 2020). Various researchers have demonstrated effectiveness of CBD in terms of anti-inflammatory, neuroprotective, and psychoactive properties, making it a promising agent for addressing neuropsychiatric conditions (Florensa-Zanuy et al., 2021). Combining Levo with CBD offers a novel approach to optimizing efficacy while reducing the limitations associated with synthetic drugs.

The structure structure–activity relationship of Levo shows a benzamide derivative, exhibits its pharmacological activity primarily through selective antagonism of dopamine D2 receptors. The benzamide core structure is essential for receptor binding, while the para-substituted methoxy group enhances lipophilicity and CNS penetration. The amide linkage allows for key hydrogen bonding interactions within the receptor binding pocket, contributing to both selectivity and potency. The presence of a basic side chain further strengthens receptor binding through ionic interactions, improving oral bioavailability and systemic stability. These structural features make Levo effective in modulating dopaminergic pathways. While CBD, demonstrates a wide range of activities due to its phenolic hydroxyl groups and flexible cyclohexene ring. The hydroxyl groups are essential for anti-inflammatory and antioxidant activity, while the lipophilic pentyl side chain enhances membrane permeability and receptor interaction. CBD's structure enables modulation of the endocannabinoid system, TRPV1 channels, and 5-HT1A receptors, contributing to its anxiolytic and neuroprotective properties. When combined, Levo’s dopaminergic modulation and CBD’s influence on endocannabinoid and serotonergic systems result in a complementary mechanism. Structurally, this combination supports multi-target engagement that could enhance efficacy in managing anxiety and depression while minimizing side effects associated with monotherapy (Ali et al., 2022, Arif et al., 2025, Campos et al., 2016, Singh et al., 2023).

The combination of Levo and CBD offers a novel therapeutic strategy to address the multifactorial nature of depression and anxiety. While Levo acts on dopaminergic pathways to regulate mood and alleviate symptoms of functional dyspepsia commonly associated with mood disorders, CBD complements this action by targeting the endocannabinoid system and mitigating neuroinflammatory processes. Together, they may provide synergistic effects, ensuring rapid symptom relief, improved therapeutic outcomes, and better management of treatment-resistant cases.

Furthermore, poor drug bioavailability and the challenge of targeting and passing of therapeutic agents across the blood–brain barrier (BBB) exacerbate the problem (Qiao et al., 2024, Zheng et al., 2024). The BBB consists of tightly joined endothelial cells, astrocyte end-feet, and a basement membrane. It protects the brain while also restricting drug entry due to its tight junctions, efflux transporters, and enzymatic barriers (Abbott, 2013). These limitations underscore the urgent need to explore innovative pharmacological approaches and advanced delivery systems to achieve rapid and sustained therapeutic effects. In this regard, Cyclodextrins and phospholipids, two components that have shown potential in enhancing drug solubility and bioavailability, respectively. Cyclodextrins are cyclic oligosaccharides known for their ability to enhance the solubility, bioavailability, and stability of drugs by forming inclusion complexes. As cyclic oligosaccharides, cyclodextrins enhance drug solubility, bioavailability, and stability by forming inclusion complexes, improving their aqueous solubility by interacting with lipid membranes and causing transient disruptions that improve passive diffusion across the blood brain barrier. (Losada-Barreiro et al., 2024, Semalty, 2014). Cyclodextrins may regulate P-glycoprotein function, lowering drug efflux from endothelial cells. The potency of Cyclodextrin as a drug carrier is dependent on the type of Cyclodextrin used in formulation development. Consequently, Cyclodextrin derivatizations produce amorphous and nanocrystalline forms that are physically and microbiologically stable over prolonged periods of time and enhance drug delivery through biological membranes. With several free hydroxyl groups, the cyclodextrin structure allows substituents to construct functionalized molecules. The derivatization of cyclodextrin by reacting with its primary and secondary hydroxyl groups can have a significant influence on its ability to form complexes with specific molecules, thereby increasing its solubility potential. As a result of these substituents being attached, the natural hydrogen bonding network within Cyclodextrins molecules becomes disrupted, which enhances the ability of Cyclodextrins molecules to interact with water molecules around them. This increases their aqueous solubility up to 100-folds (Loftsson, 2012, Loftsson et al., 2007, Másson et al., 1999). While phospholipids form liposomal or micellar structures that mimic cellular membranes, they improve drug absorption by bypassing efflux systems and promoting cellular uptake via endocytic pathways. These properties make them promising carriers for CNS drug delivery. (Kaur et al., 2024, Sánchez-Dengra et al., 2023, Zhang et al., 2023). Additionally, Electrospun nanofibers are gaining considerable attention as an innovative platform for oral drug delivery, offering unique benefits in enhancing drug solubility, stability, and controlled release. Nanofibers possess several advantageous properties, which includes tunable porosity, capacity to encapsulate a broad spectrum of drugs and their high surface area-to-volume ratio make them highly effective for oral drug delivery applications (Ghasemiyeh et al., 2024, Muratoglu et al., 2024a), [22], [23]. Additionally, Electrospun nanofibers can notably enhance the solubility of such drugs, thereby improving their dissolution rate in the gastrointestinal tract (Arif Nadaf et al., 2022, Kajdič et al., 2020).

Considering all above points the integration of Levo and CBD loaded cyclodextrin-phospholipid inclusion complexes within nanofibers enables the creation of a multi-functional drug delivery system that offers both immediate and sustained drug release profiles. By carefully designing the polymer composition of the nanofibers, the release pattern could be controlled, allowing for the creation of formulations that provide a rapid onset of action followed by sustained release to maintain therapeutic levels over an extended period (Cid-Samamed et al., 2022, Li et al., 2021, Pires et al., 2019).

The current investigation aims to design and develop a novel drug delivery system combining cyclodextrin-phospholipid complexes loaded with Levo and CBD and further incorporating them into nanofibers. This integrated approach is expected to enhance drug solubility, permeability, and overall efficacy for treating depression and anxiety. The prepared formulation will be prepared and characterized followed by the comparative efficacy and pharmacodynamic evaluations. The overall aim of the investigation was to develop and explore the efficacy and safety of this innovative combination, offering a promising avenue for improved efficacy and management of anxiety and depression.