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Tetrahydroberberine combined with protopanaxadiol synergistically improves sleep in PCPA-induced insomnia in rats

The combination of tetrahydroberberine (THB) and protopanaxadiol (PPD) showed synergistic effects in rats with PCPA-induced insomnia, shortening sleep latency by 56.2% and prolonging sleep duration by 112.8% compared to the model group, outperforming either monotherapy. The treatment also restored body weight, reduced hippocampal damage, balanced neurotransmitters, and modulated the microbiota-gut-brain axis and PI3K/AKT/AGE-RAGE pathways.

Last updated: Aug 25, 2026•0 RCTs•📖 Read as article →

Evidence Score

Evidence Score26/100
Human RCT☆☆☆☆☆
Meta-analysis☆☆☆☆☆
Mechanism★★★★★
Safety★★★★☆
Confidencelow

Study Evidence

Study 1. Synergistic Therapeutic Effects of Tetrahydroberberine Combined with Protopanaxadiol on PCPA-Induced Insomnia in Rats: Involvement of the Microbiota-Gut-Brain Axis and Regulation of PI3K/AKT/AGE-RAGE Pathways.

observational

Li M, Wang Y, Liang Z, Li H, Zhao Y, Kong L, Guo N, Dai G, Zhang G, Lu X, Yao J · Pharmaceuticals (Basel, Switzerland) (2026)

Participants: N/A
Duration: Not specified in abstract
Intervention: Combined oral administration of tetrahydroberberine (THB) and protopanaxadiol (PPD)
Outcome: Sleep latency, sleep duration, body weight gain, hippocampal neuronal damage, neurotransmitter levels (serotonin, dopamine, glutamate), HPA axis markers (CRH, corticosterone), inflammatory cytokines, gut microbiota composition, and PI3K/AKT/AGE-RAGE pathway protein expression
Effect Size: Sleep latency reduced by 56.2% (combination) vs 44.2% (THB alone) and 20.7% (PPD alone); sleep duration increased by 112.8% (combination) vs 70.2% (THB) and 59.6% (PPD); p-PI3K increased 1.9-fold, p-AKT increased 2.5-fold; RAGE decreased 31.8%
Population: PCPA-induced insomnia rat model (Sprague-Dawley rats)

Result:

PubMed: 41901236DOI: 10.3390/ph19030390

Mechanism Graph

Combined THB+PPD restores gut microbial homeostasis (increases beneficial Lactobacillus)
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Modulates glycine-serine-threonine metabolic pathway
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Activates PI3K/AKT neurotrophic pathway (upregulates p-PI3K and p-AKT)
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Inhibits AGE/RAGE pro-inflammatory axis (downregulates RAGE)
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Upregulates tight junction proteins (ZO-1, Occludin) enhancing blood-brain barrier integrity
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Result: Reduced HPA axis overactivation, balanced neurotransmitters, decreased inflammation, and improved sleep

Limitations

  • ⚠Animal model (rats) limits direct generalizability to humans
  • ⚠Dose and administration details not provided in abstract, preventing clinical translation

Frequently Asked Questions

What is tetrahydroberberine (THB)?▼

Tetrahydroberberine is a natural alkaloid derived from plants like Coptis chinensis, known for sedative and neuroprotective properties.

How does the THB+PPD combination compare to diazepam in this study?▼

The abstract mentions a diazepam group but does not provide direct comparative effect sizes; however, the combination showed synergistic effects superior to either THB or PPD alone.

What is the microbiota-gut-brain axis?▼

It is a bidirectional communication system between the gut microbiome and the brain, involving neural, endocrine, and immune pathways, which this study suggests is modulated by THB+PPD to improve sleep.

Could this combination be used for human insomnia?▼

This is a preclinical animal study; human trials are needed to confirm safety and efficacy before any clinical use.

Products

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References

  1. 1.Li M, Wang Y, Liang Z, Li H, Zhao Y, Kong L, Guo N, Dai G, Zhang G, Lu X, Yao J. "Synergistic Therapeutic Effects of Tetrahydroberberine Combined with Protopanaxadiol on PCPA-Induced Insomnia in Rats: Involvement of the Microbiota-Gut-Brain Axis and Regulation of PI3K/AKT/AGE-RAGE Pathways.." Pharmaceuticals (Basel, Switzerland), 2026. PMID: 41901236 DOI: 10.3390/ph19030390
Disclaimer: This content is for educational purposes only and is not medical advice. Evidence scores reflect the quality and quantity of available research, not clinical recommendations. Always consult a healthcare professional before starting any supplement or intervention.