Physiological Activity and Mechanism of Curcumin in Antidepressant Effects and Neuroprotection

Depression, a highly prevalent psychiatric disorder, is marked by persistent low mood, reduced interest, and impaired cognitive function. Its pathogenesis involves multiple factors, including neuroendocrine dysregulation, oxidative stress imbalance, and excessive inflammatory responses. In recent years, curcumin, a natural product, has drawn significant interest in research on mood regulation and antidepressant effects, thanks to its notable antioxidant, anti-inflammatory, and neuroprotective properties. Based on existing research, this article systematically reviews curcumin’s physiological activities, mechanisms of action, experimental evidence, and clinical application prospects in exerting antidepressant effects and improving mood, aiming to provide a theoretical foundation for its development as a natural antidepressant.

Keywords: curcumin, neurological disorders, oxidative stress, antioxidant properties, molecular mechanism

1. Introduction

With global population aging and mounting social pressure, depression has emerged as a major psychiatric disorder impacting human health. Its incidence continues to rise annually, placing a heavy burden on both individuals and society. Currently, commonly used clinical antidepressants are limited by significant side effects, large individual differences in efficacy, and a tendency to induce drug resistance. Thus, exploring safe and effective natural antidepressant substances has become a research focus. Curcumin, a natural polyphenolic compound extracted from Curcuma longa, has gained attention in the field of neurological diseases due to its prominent antioxidant, anti-inflammatory, and neuroprotective effects. Studies indicate that oxidative stress imbalance is one of the key mechanisms driving depression. Through pathways such as regulating oxidative stress, mitigating neuroinflammation, and repairing synaptic function, curcumin demonstrates potential antidepressant and mood-regulating activities.

2. Physicochemical Properties and Metabolism of Curcumin

2.1 Chemical Composition and Physicochemical Properties

Curcumin (CU) is a natural polyphenolic compound extracted from the rhizomes of Curcuma longa. Its unique chemical structure endows it with significant biological activity. Its antioxidant properties help scavenge harmful free radicals in the body, thereby protecting neuronal cells from damage and potentially benefiting brain function and mood regulation. Curcumin is lipid-soluble but poorly soluble in water, which limits its absorption efficiency in vivo. Its structure undergoes changes under different acid-base conditions, affecting not only its stability but also potentially altering its bioactivity. Studies have shown that different administration routes (e.g., oral or injectable) significantly influence the absorption and utilization of curcumin in the body. Furthermore, to enhance its bioavailability, researchers have recently explored strategies such as nanonization, lipid carriers, and combination with adjuvants, broadening its application prospects in neuroprotection, antidepressant effects, and mood improvement.

2.2 In Vivo Metabolic Processes

Curcumin is primarily metabolized in the liver, undergoing two key types of reactions: conjugation with endogenous chemicals to form excretable products, and progressive reduction and structural modification of the molecule. In the first type of reaction, the hydroxyl groups of curcumin conjugate with glucuronic acid or sulfuric acid, facilitating excretion via bile or feces. In the second type, curcumin undergoes stepwise reduction under the action of endogenous enzymes, forming a series of derivatives. When administered orally, curcumin is mainly excreted in feces; when delivered via injection, its metabolites are more frequently excreted through bile, with only metabolized forms detectable in urine (parent curcumin is barely present). Studies also indicate that curcumin can cross the blood-brain barrier. Although its concentration in brain tissues is not high, it is sufficient to support its role in regulating neural function and mood.

3. Antidepressant Physiological Activities and Experimental Evidence of Curcumin

3.1 Antidepressant Effects in Animal Models

Curcumin has demonstrated clear ameliorative effects in various animal models of depression. Studies have shown that it can significantly alleviate symptoms resembling anhedonia and behavioral despair, leading to more positive behaviors in animals during tests such as the sucrose preference test, forced swimming test, and novelty-induced feeding test. These findings suggest that curcumin has the potential to improve core depressive symptoms. In terms of mechanisms, curcumin can enhance antioxidant defense in hippocampal tissue—for instance, by increasing the activity of protective enzymes, reducing levels of oxidative damage, and reversing stress-induced inhibition of key proteins. This activates antioxidant-related signaling pathways, promotes the expression of multiple protective enzymes, and mitigates neuronal damage. In depression models induced by Toxoplasma gondii infection, curcumin also ameliorates anxiety- and depression-like behaviors, an effect closely linked to enhanced antioxidant capacity and reduced neuro-oxidative damage.

3.2 Formulation Optimization to Enhance Antidepressant Activity

Addressing curcumin’s limitations of in vivo instability and low absorption, the development of novel formulations in recent years has opened new avenues for improving its efficacy. Research indicates that when curcumin is formulated into nanocapsules, it more effectively increases brain SOD activity in experimental depression models compared to conventional curcumin, thereby improving cerebral antioxidant status and enhancing neuroprotective effects. Another formulation—curcumin-zinc oxide composite nanoparticles—has also shown stronger efficacy than free curcumin. It significantly elevates GSH levels in the cerebral cortex, hippocampus, and striatum, while reducing MDA levels more markedly. These improvements are thought to be closely related to the ability of nanocarriers to enhance curcumin’s penetration across the blood-brain barrier. Beyond antidepressant effects, such novel formulations may also hold greater potential in treating neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease, making them an increasingly prominent area of research.

4. Mechanisms of Curcumin’s Antidepressant Action

4.1 Multidimensional Regulation of Oxidative Stress

A key mechanism underlying curcumin’s antidepressant effects is its multidimensional regulation of oxidative stress. Unlike drugs that act via a single signaling pathway, curcumin exerts protective effects through both direct and indirect mechanisms. First, its unique molecular structure enables it to directly scavenge excessive reactive oxygen species (ROS) and free radicals, thereby blocking destructive reactions such as lipid peroxidation. Second, it can activate intracellular antioxidant signaling pathways, inducing the body’s intrinsic defense system to promote the expression of various antioxidant enzymes and enhance the tolerance of neurons to damage.  Notably, curcumin not only alleviates oxidative stress but also indirectly improves inflammatory responses and neuronal function. For example, under conditions of stress or inflammation, it can restore suppressed key signaling pathways, thereby protecting brain regions closely associated with mood (such as the hippocampus) and maintaining synaptic plasticity and the stability of neural circuits. This dual mode—combining "scavenging harmful molecules" and "enhancing intrinsic defense"—provides a solid molecular basis for curcumin’s antidepressant effects and highlights its unique advantage in multi-target regulation.

4.2 Regulation of Neuroinflammation and Synaptic Plasticity

Curcumin can inhibit excessive activation of microglia, reduce the release of proinflammatory cytokines (e.g., TNF-α, IL-6), and alleviate neuroinflammation by regulating the TLR4/NF-κB pathway, which helps maintain the stability of the neural environment. Meanwhile, curcumin promotes the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus and increases the levels of synapse-related proteins, including postsynaptic density proteins and synaptic vesicle proteins, thereby ameliorating synaptic structural damage and reduced neuroplasticity in depressive states. These integrated effects not only help restore neural circuit function but also provide mechanistic support for its potential application in mood regulation and antidepressant interventions.

5. Safety Evaluation and Side Effects

Curcumin is generally well-tolerated at conventional doses. Clinical studies have shown that when the daily intake is within 1 gram, only a small number of subjects may experience side effects such as dry mouth, mild gastrointestinal discomfort, or transient digestive tract reactions, which generally require no special treatment, and no serious adverse events have been reported. Animal experiments suggest that long-term use of high doses (for more than several months) may impose a certain burden on the liver and kidneys; therefore, attention should be paid to controlling the treatment course and dosage in clinical applications. In addition, moderate attention should be paid to drug interactions involving curcumin. Studies indicate that it may affect the efficacy of certain immunosuppressants, and coagulation function should be monitored when used in combination with anticoagulants. However, no significant drug interactions or safety risks have been identified in antidepressant therapy to date. Overall, as a natural active ingredient, curcumin has relatively high safety and is suitable for adjuvant intervention and long-term health management under the guidance of physicians. Meanwhile, further long-term, multi-center clinical studies are still needed to verify its safety and tolerability.

6. Clinical Research Progress and Application Prospects

Clinical studies have provided preliminary evidence for curcumin’s antidepressant effects. A randomized double-blind controlled trial demonstrated that after 6 weeks of treatment, 1000 mg/day of curcumin improved depressive symptoms in patients with major depressive disorder (MDD) to a similar degree as 20 mg/day of fluoxetine, with response rates in both groups significantly higher than that in the placebo group. Meanwhile, the incidence of adverse reactions in the curcumin group was lower, including dry mouth and mild insomnia. Notably, when curcumin was combined with fluoxetine, the improvement in depression scores was further enhanced, suggesting a potential synergistic effect. Curcumin has also shown positive effects in patients with comorbid depression. For example, in diabetic patients with peripheral neuropathy, daily supplementation with nano-curcumin for several weeks significantly alleviated depressive and anxiety symptoms. In obese individuals with long-term exposure to environmental pollutants, curcumin intervention reduced anxiety scores and improved systemic oxidative stress levels, indicating its potential value in environment- or disease-related mood disorders. Additionally, in healthy perimenopausal women, curcumin supplementation for several weeks reduced depressive symptoms, accompanied by decreased inflammatory and oxidative stress markers—further supporting its mechanism of regulating mood through antioxidant and anti-inflammatory pathways. However, curcumin still faces challenges in clinical application. Its poor water solubility, limited oral absorption, low bioavailability, and rapid in vivo metabolism restrict its therapeutic efficacy. To address these issues, the development of novel formulations has become a research focus, including carriers such as nanoparticles, liposomes, and polymeric micelles, which enhance curcumin’s solubility and stability. Furthermore, structural modifications of curcumin (e.g., developing analogues) can improve its ability to cross the blood-brain barrier and enhance targeting affinity. In the future, through formulation optimization and dosage adjustment, it is expected that curcumin’s pharmacokinetic limitations will be overcome, enabling more stable clinical efficacy.

7. Conclusion and Outlook

Curcumin exerts antidepressant effects through multiple mechanisms, including regulating oxidative stress, inhibiting neuroinflammation, and improving neuroplasticity. Both animal models and clinical studies have demonstrated its significant mood-regulating effects, making it a promising natural antidepressant. However, current research still has limitations: first, clinical trials generally have small sample sizes (most with fewer than 50 participants) and lack long-term efficacy and safety evaluations; second, the differences in its mechanisms of action across various cell types (e.g., astrocytes and neurons) have not been fully elucidated; third, the optimal dosage and formulation selection require systematic investigation. Future research could focus on three directions: first, using single-cell sequencing and spatial transcriptomics to dissect the targeted regulatory mechanisms of curcumin on cell subtypes in different brain regions under depressive states; second, conducting multi-center, large-sample, long-term follow-up clinical trials to clarify its efficacy and dose-response relationships across different depression subtypes; third, developing brain-targeted novel curcumin formulations through medicinal chemistry and material engineering approaches to enhance bioavailability and therapeutic specificity. With the deepening of research, curcumin is expected to emerge as a natural drug for the prevention and treatment of depression, providing new strategies and insights for the comprehensive management of mood disorders.

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