Does St. John's Wort (Hypericum perforatum) affect Gamma-Aminobutyric Acid (GABA) levels?

St. John's Wort's Effects on GABA

St. John's Wort (Hypericum perforatum) does affect GABA receptors, with studies showing it can interact with both GABA(A) and GABA(B) receptors, though this is not its primary mechanism of action for antidepressant effects.

Mechanism of Action on GABA

St. John's Wort has been found to interact with the GABAergic system in several ways:

• In vitro studies demonstrate that hydromethanolic extracts of St. John's Wort interact with GABA(A) receptors with an IC50 of 5.5 μg/ml 1
• St. John's Wort extracts show significant affinity for both GABA(A) and GABA(B) receptors in receptor binding assays 2, 1
• The herb inhibits synaptosomal uptake of several neurotransmitters, including GABA 2, 3

Primary Active Constituents

The effects of St. John's Wort on neurotransmitter systems, including GABA, appear to be mediated by several constituents:

• Hyperforin: The primary active constituent that inhibits synaptosomal uptake of multiple neurotransmitters including GABA 2, 3
• Adhyperforin: Shows a similar inhibitory profile to hyperforin on neurotransmitter uptake systems including GABA 3
• Oligomeric procyanidins fraction (OPC): Demonstrates weak to moderate inhibition of neurotransmitter uptake 3

Clinical Relevance

While St. John's Wort does affect GABA systems, this is important to understand in the context of:

1. Drug interactions: St. John's Wort is a known inducer of cytochrome P450 3A4 (CYP3A4), which can decrease plasma concentrations of many medications 4

2. Perioperative considerations: The Society for Perioperative Assessment and Quality Improvement (SPAQI) recommends discontinuing St. John's Wort for 2 weeks before surgery due to its multiple effects on neurotransmitter systems and drug metabolism 4

3. Antidepressant effects: While St. John's Wort affects multiple neurotransmitter systems including GABA, its antidepressant effects are likely due to the combined action on several systems rather than GABA alone 2

Important Caveats

• The concentrations of St. John's Wort extract required for significant GABA receptor activity in vitro may be difficult to achieve after oral administration in humans 1
• St. John's Wort is not regulated by the FDA, and there is no standard regarding contents and potency of commercially available preparations 4
• St. John's Wort can significantly reduce the efficacy of many medications through its induction of CYP3A4 4

Clinical Implications

For patients taking medications that interact with St. John's Wort:

• Monitor for reduced efficacy of medications metabolized by CYP3A4
• Consider that an increase in medication dose may be necessary in patients receiving St. John's Wort 4
• Be particularly cautious with medications that have narrow therapeutic windows 4

For patients considering St. John's Wort for depression:

• While it may be effective for mild to moderate depression, its effects on multiple neurotransmitter systems (including GABA) and potential for drug interactions must be considered 4, 5
• It is contraindicated in patients receiving monoamine oxidase or serotonin reuptake inhibitors 4

In summary, while St. John's Wort does affect GABA receptors and uptake, this is part of a broader pharmacological profile that includes effects on multiple neurotransmitter systems and drug-metabolizing enzymes.