Does St. John's Wort increase noradrenaline levels?

Does St. John's Wort Increase Noradrenaline?

Yes, St. John's Wort inhibits the synaptosomal uptake of noradrenaline (norepinephrine), effectively increasing its availability in the synaptic cleft. 1, 2

Mechanism of Action

St. John's Wort affects multiple neurotransmitter systems simultaneously, which distinguishes it from many conventional antidepressants:

• It inhibits the neuronal uptake of several neurotransmitters:
  • Serotonin
  • Noradrenaline (norepinephrine)
  • Dopamine
  • GABA
  • L-glutamate 1

Active Components

The primary constituent responsible for noradrenaline reuptake inhibition is hyperforin:

• Hyperforin and its analog adhyperforin are the main components that inhibit neurotransmitter reuptake 1
• Unlike conventional antidepressants, hyperforin does not competitively inhibit the binding sites on transporter proteins
• Instead, it affects the sodium gradient, which indirectly leads to uptake inhibition 1

Clinical Evidence

Research demonstrates that St. John's Wort has a unique pharmacological profile:

• It is the only antidepressant known to inhibit the reuptake of serotonin, noradrenaline, and dopamine with similar potencies 3
• In vivo studies show that St. John's Wort extract causes changes in neurotransmitter concentrations in brain areas implicated in depression 4
• It leads to downregulation of beta-adrenergic receptors and upregulation of serotonin 5-HT2 receptors in the rat frontal cortex 4

Important Clinical Considerations

Despite its effects on noradrenaline reuptake, St. John's Wort has some important clinical distinctions:

• Unlike conventional noradrenaline reuptake inhibitors like imipramine, St. John's Wort does not significantly affect cardiovascular parameters:

  • No effect on blood pressure
  • No effect on heart rate
  • No effect on heart rate variability
  • No effect on blood pressure variability 5

• However, it does consistently increase plasma DOPAC (dopamine metabolite) concentrations 5

Drug Interactions and Precautions

St. John's Wort has significant drug interaction potential that must be considered:

• It induces cytochrome P450 isoenzyme 3A4 (CYP3A4), which can reduce plasma concentrations of many medications 6
• It should be held for 2 weeks before surgery due to multiple constituents with long half-lives 6
• It is contraindicated in patients receiving monoamine oxidase inhibitors or serotonin reuptake inhibitors due to risk of serotonin syndrome 6
• It may reduce the effectiveness of oral contraceptives 6

Clinical Applications

For patients with major depressive disorder:

• Low-quality evidence suggests St. John's Wort may be as effective as second-generation antidepressants (SGAs) 6
• Moderate-quality evidence indicates it may be better tolerated than SGAs 6
• However, the American College of Physicians recommends either cognitive behavioral therapy or second-generation antidepressants as first-line treatments for major depressive disorder 6

Important Caveats

1. Quality control is a major issue:

   • St. John's Wort is not regulated by the FDA
   • No standard exists for contents and potency
   • Patients may not reliably obtain preparations with similar effectiveness to those used in studies 6

2. Common adverse effects include:

   • Gastrointestinal symptoms
   • Skin reactions
   • Fatigue
   • Sedation
   • Restlessness
   • Dizziness
   • Headache
   • Dry mouth 6

3. St. John's Wort has photosensitizing effects when administered topically and orally, requiring caution in patients undergoing phototherapy or with significant sun exposure 6