Research Status and Progress on the Anxiolytic and Antidepressant Effects of Tetrahydrocurcumin

1. Introduction

Anxiety and depression, as common mental health issues, have been on the rise in incidence year by year, severely impairing patients' quality of life. Existing treatment methods have limitations such as significant side effects and large individual differences in efficacy; therefore, the search for natural and safe alternative therapies has become a research focus. Tetrahydrocurcumin is a natural active component derived from the hydrogenation of curcumin extracted from the rhizomes of Curcuma longa (Zingiberaceae). With a molecular formula of C₂₁H₂₄O₆, its unsaturated double bonds are reduced in structure, endowing it with higher stability and bioavailability. In recent years, studies have found that it has potential value in the neuropsychiatric field, providing a new direction for the prevention and treatment of anxiety and depression.

2. In Vivo Metabolism of Tetrahydrocurcumin

Tetrahydrocurcumin is the primary bioactive metabolite of curcumin after oral administration. Curcumin is absorbed in the upper digestive tract and undergoes reduction and conjugation reactions to produce tetrahydrocurcumin and other metabolites. The unabsorbed portion enters the lower digestive tract, where it is further converted by gut microbiota enzymes such as reductases and hydrolases into highly active small-molecule metabolites. Compared to curcumin, tetrahydrocurcumin exhibits higher chemical stability due to the reduction of unsaturated C=C double bonds, resulting in superior oral bioavailability and pharmacokinetic profiles. Gut microbiota metabolism can also create a "slow-release effect," prolonging its duration of action in vivo. However, its hepatic metabolic mechanisms and the enzyme systems involved still require further in-depth study.

3. Mechanisms of Tetrahydrocurcumin in Antidepressant and Anxiolytic Effects

3.1 Neuroinflammatory Modulation Mechanism

Neuroinflammation is a key trigger of anxiety and depression. Chronic stress activates microglia, releasing pro-inflammatory cytokines such as TNF-α and IL-1β. Tetrahydrocurcumin (THC) can downregulate the expression of TLR-4, iNOS, and Iba1 proteins in the hippocampus, inhibit microglial overactivation, and reduce levels of IL-1β and TNF-α, thereby blocking the neuroinflammatory cascade.

3.2 Neuroplasticity and Neurotrophic Factor Regulation

Impaired neuroplasticity is closely associated with reduced BDNF levels. THC can reverse the low expression of BDNF in the hippocampus of depressed model mice. It also upregulates Gab2 and K-Ras, attenuates G1/S phase blockade via the Ras/ERK pathway, inhibits abnormal microglial cell cycle progression, and simultaneously downregulates TNF-α while upregulating TGF-β1, exerting anti-apoptotic effects.

3.3 Oxidative Stress and Neuroendocrine System Regulation

Oxidative stress exacerbates neural damage. THC can scavenge free radicals, reduce ROS levels, and inhibit caspase-3 and Bax protein activity. It also downregulates the ROS/p53 pathway, ameliorates high glucose-induced platelet abnormalities, and indirectly modulates the neuroendocrine system, contributing to mood improvement through multiple dimensions.

4. Pharmacological Studies on the Anxiolytic and Antidepressant Effects of Tetrahydrocurcumin

Animal experiments have provided important evidence for the anxiolytic and antidepressant activities of tetrahydrocurcumin. Studies have shown that in chronic restraint stress-induced depression models, tetrahydrocurcumin can improve behavioral indicators in mice and modulate the expression of related proteins in the hippocampus. Tetrahydrocurcumin can ameliorate anxiety- and depression-like behaviors in lipopolysaccharide-induced depressed mice, reduce the degree of demyelination in the prefrontal cortex, and nano-formulations demonstrate superior efficacy compared to conventional preparations. These studies suggest that it may exert its effects by improving neuroplasticity and reducing neuroinflammation. However, there is currently a lack of clinical trial data supporting its efficacy in humans.

5. Safety Assessment

The European Food Safety Authority (EFSA) considers tetrahydrocurcumin safe for target populations at a daily dose of 140 mg as a novel food, with no evidence of genotoxicity. Existing studies have not reported serious adverse reactions, but attention should be paid to its dose dependency. The proposed adult daily dose of 300 mg by the applicant is higher than the safe level recommended by EFSA. In the field of cosmetics, tetrahydrocurcumin is also widely used. In China, the maximum historical usage level of tetrahydrocurcumin as a cosmetic ingredient in leave-on products is 1%, and it is considered a safe component. Evaluation reports indicate that tetrahydrocurcumin is non-sensitizing, generally recognized as safe (GRAS), and has no genotoxicity concerns.

6. Summary and Outlook

As a natural active component, tetrahydrocurcumin shows great potential in the field of anxiety and depression treatment. Its multi-target mechanisms of action (anti-inflammatory, antioxidant, modulation of neuroglial function, etc.) and high safety profile give it unique advantages. However, current research has significant limitations: it primarily relies on animal models, lacking human clinical trial data; specific mechanisms such as metabolic pathways and neurotransmitter regulation are not fully elucidated; and the bioavailability of conventional preparations still has room for improvement. Future efforts should focus on clinical translation research, exploring optimal dosages and administration regimens; in-depth study of its interactions with the gut microbiota-brain axis; and developing novel delivery systems such as nano-formulations to enhance efficacy, promoting the application of this natural component in the field of mental health.

References

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