Hyperforin
The main antidepressant constituent of St. John's Wort; activates TRPC6 to indirectly inhibit monoamine reuptake.
Pharmacology
Contents
WHAT IS HYPERFORIN?
Detailed overview
Hyperforin is a lipophilic phloroglucinol and one of the main active constituents of St. John's Wort (Hypericum perforatum), regarded as a key carrier of the plant's antidepressant activity. Unlike classic SSRIs it does not block transporters directly; instead it activates the TRPC6 cation channel, and the resulting sodium (and calcium) influx raises intracellular sodium, which lowers the driving force for reuptake of serotonin, dopamine and norepinephrine. It also promotes neurite outgrowth and BDNF signaling, but as a strong PXR agonist it induces the CYP3A4 enzyme, creating a significant drug-interaction risk. Most evidence for the isolated compound is preclinical and mechanistic, while clinical antidepressant efficacy has mainly been shown for standardized St. John's Wort extracts that contain hyperforin.
Mechanism
TRPC6 activation, indirect monoamine reuptake inhibition
Half-life
Approximately 9-12 hours
Legal status
Herbal constituent (in St. John's Wort extract)
Receptor profile
- TRPC6 channel / sodium influxStrong
- Monoamine reuptake (serotonin/dopamine/norepinephrine)Moderate
- Pregnane X receptor (CYP3A4 induction)Strong
- BDNFWeak
Safety
Side effects, stop signs, contraindications
Side effects · 6
- Photosensitivity (phototoxic skin reactions), especially in fair-skinned people and strong sunlight
- Mild gastrointestinal upset, nausea, appetite changes
- Restlessness, sleep changes and headache
- Risk of serotonin syndrome when combined with other serotonergic drugs
- Major drug interactions due to CYP3A4 and P-glycoprotein induction
- Dry mouth, dizziness, occasionally skin itching
Contraindications · 5
- Concurrent SSRI, SNRI, MAO inhibitor or triptan therapy: risk of serotonin syndrome
- Pregnancy and breastfeeding: safety not well established, avoid
- Patients on critical medications (contraceptives, warfarin, ciclosporin/tacrolimus, antiretroviral and anticancer drugs): enzyme induction can cause loss of efficacy
- Before planned surgery or anesthesia: enzyme induction can alter drug metabolism
- Known photosensitivity or concurrent photosensitizing therapy
Related Nootropics
Same therapeutic category
Studies
Related research and clinical findings
Hyperforin, a major antidepressant constituent of St. John's Wort, inhibits serotonin uptake by elevating free intracellular Na+
Singer A, Wonnemann M, Müller WE
Hyperforin: antidepressant activity by a novel mechanism of action
Müller WE, Singer A, Wonnemann M
Hyperforin, a key constituent of St. John's wort specifically activates TRPC6 channels
Leuner K, Kazanski V, Müller M, et al.
Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca(2+)-permeable TRPC6 channels
Leuner K, Li W, Amaral MD, et al.
Hyperforin: To Be or Not to Be an Activator of TRPC(6)
Friedland K, Harteneck C
Hypericum perforatum in the treatment of psychiatric and neurodegenerative disorders: Current evidence and potential mechanisms of action
Zirak N, Shafiee M, Soltani G, et al.
FAQ
FAQ
The main antidepressant constituent of St. John's Wort; activates TRPC6 to indirectly inhibit monoamine reuptake.
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Structure & chemistry
The information here is strictly for educational and scientific purposes. It does not replace medical advice or clinical consultation, and it does not encourage illegal substance or pharmaceutical use. Data is sourced. When in doubt, consult your doctor.