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HISTIDINA

Also known as: Histidine, L-histidine, Histidine-containing dipeptides (HCDs), Carnosine (β-alanyl-L-histidine), Anserine

Overview

Histidine is an essential amino acid found in protein-rich foods like meat, fish, and dairy. It serves as a precursor to histidine-containing dipeptides (HCDs) such as carnosine and anserine, which are concentrated in muscle and brain tissues. Supplementation with histidine or HCDs is explored for cognitive enhancement, neuroprotection, antioxidant effects, and potential benefits in mood disorders and age-related conditions. Histidine is involved in protein synthesis, acts as a precursor for histamine, and contributes to antioxidant defense through carnosine. Carnosine and related dipeptides have buffering capacity and may protect tissues from oxidative stress. Research on HCDs, particularly carnosine and anserine, is moderately to advanced, with multiple randomized controlled trials (RCTs) and systematic reviews/meta-analyses available, showing statistically significant effects on cognition and depression-related outcomes.

Benefits

Supplementation with histidine-containing dipeptides (mainly carnosine/anserine) has been shown to improve cognitive performance, specifically delayed recall, with meta-analytic evidence supporting a positive effect size in human RCTs. Improvements in depression symptoms and quality of life have also been reported in a systematic review and meta-analysis of HCD supplementation. Older adults and individuals with mild cognitive impairment or depressive symptoms appear to benefit most from HCD supplementation. Meta-analyses report statistically significant improvements in cognitive recall and depression scores, though exact effect sizes vary by study; benefits are clinically relevant in populations with cognitive decline or mood disorders. Benefits observed in RCTs typically emerge over weeks to months of supplementation, consistent with the time needed for cognitive or mood improvements. Animal studies suggest antioxidant effects in tissues such as the retina, potentially mitigating oxidative stress associated with age-related macular degeneration.

How it works

Histidine is a precursor to carnosine, which acts as an antioxidant, metal ion chelator, and pH buffer in tissues. Carnosine and related dipeptides may modulate neurotransmission, reduce oxidative stress, and improve mitochondrial function. Effects are prominent in the central nervous system (cognition, mood) and muscular system (buffering capacity). Antioxidant properties protect retinal and neural tissues from oxidative damage. Reactive oxygen species (ROS), metal ions (e.g., zinc, copper), and neurotransmitter systems are influenced indirectly by histidine metabolites. Histidine is absorbed as an amino acid; carnosine and anserine are absorbed as dipeptides but may be hydrolyzed by carnosinase enzymes in plasma, affecting bioavailability.

Side effects

Histidine and histidine-containing dipeptides are generally safe when consumed at typical supplemental doses. Rare side effects include mild gastrointestinal discomfort. No significant rare adverse events have been documented in high-quality RCTs. No major drug interactions have been identified, but caution is advised in individuals on histamine-related medications due to histidine’s role as a histamine precursor. There are no established contraindications, but caution is advised in individuals with histamine intolerance or those who are allergy-prone. Pregnant and breastfeeding women should consult healthcare providers. Elderly populations may benefit but require monitoring.

Dosage

Effective doses in studies vary; carnosine/HCD supplementation typically ranges from 500 mg to 1,000 mg daily. Meta-analyses include studies with doses around 500–1,000 mg/day of carnosine or equivalent HCDs. There is no established toxic dose; doses up to 2,000 mg/day of carnosine have been used safely in trials. Daily dosing with meals may improve absorption and reduce gastrointestinal discomfort. Carnosine or anserine supplements are preferred for cognitive benefits rather than free histidine alone. The presence of carnosinase enzyme affects bioavailability; co-supplementation with beta-alanine may increase muscle carnosine levels. Adequate protein intake supports endogenous histidine availability.

FAQs

Is histidine supplementation necessary?

Generally not required with adequate dietary protein; supplementation mainly considered for cognitive or mood support via HCDs.

Is it safe long-term?

Yes, current evidence supports safety in long-term use at studied doses.

When are benefits expected?

Cognitive and mood improvements typically appear after several weeks of consistent supplementation.

Can histidine alone improve cognition?

Evidence favors histidine-containing dipeptides (carnosine/anserine) rather than free histidine for cognitive benefits.

Does it interact with medications?

No significant interactions, but caution with histamine-related drugs.

Research Sources

https://pubmed.ncbi.nlm.nih.gov/38545720/ – This systematic review and meta-analysis analyzed RCTs on carnosine/histidine-containing dipeptide supplementation effects on depression and quality of life. The study included multiple RCTs with adequate sample sizes, showing statistically significant improvements in depression scores and life quality metrics, suggesting mood benefits. Limitations include heterogeneity in study populations and dosages.
https://pubmed.ncbi.nlm.nih.gov/38013229/ – This systematic review reviewed RCTs on HCD supplementation and cognitive performance, focusing on delayed recall. The review included 10 RCTs with rigorous methodology and adequate sample sizes and found significant cognitive improvements with HCD supplementation versus placebo, with consistent effect sizes, indicating cognitive benefits. Limitations include variability in cognitive assessment tools.
https://www.mdpi.com/2072-6643/12/5/1414 – This review provides a comprehensive overview of histidine metabolism and physiological effects in humans and animals. It summarizes biochemical pathways and potential health impacts, supporting mechanistic understanding of histidine and its dipeptides. It is a high-quality review with extensive literature coverage.
https://scispace.com/pdf/carnosine-supplementation-and-retina-oxidative-parameters-in-1grijju8.pdf – This animal study investigated carnosine supplementation effects on oxidative stress in rat retina under hypercaloric diet conditions. The study found carnosine reduced oxidative markers, suggesting protective effects relevant to age-related macular degeneration, supporting antioxidant mechanisms relevant to human health.