Hyperforin

CAS Number	11079-53-1 (verified against PubChem CID 441298)
Molecular Formula / MW	C35H52O4 / 536.78 g/mol
Chemical Class	Prenylated phloroglucinol — a bicyclo[3.3.1]nonane-trione bearing four prenyl side chains
Botanical Source	Hypericum perforatum (St John’s wort) — flowering tops and buds
Typical Standardisation	Hyperforin by HPLC; 3% common. Note: hypericin is a separate marker, standardised independently
Primary Applications	Antidepressant formulation (mild-to-moderate depression); the principal driver of SJW’s drug interactions
Claim Strength (Overview)	High for CYP3A4/P-gp induction (well documented, dose-correlated) — this is a safety liability, not a benefit
Buy from Herbuno	Hyperforin 3% Powder (St John'S Wort Extract) | Standardized Hypericum perforatum → St John's wort Extract Powder (0.3 % Hypericin) - Hypericum perforatum →

Name origin: Hyperforin is named directly for the source genus Hypericum. Chemically it is a prenylated phloroglucinol built on a bicyclo[3.3.1]nonane-trione core decorated with four prenyl side chains — an unusually lipophilic and, as it turns out, unusually unstable architecture. The plant name perforatum refers to the translucent oil glands that make the leaves appear perforated when held to light. Traditional use: St John’s wort has a European medicinal record stretching to antiquity, with Dioscorides and Hippocrates citing it, and later folk use for wounds, burns, and conditions described as melancholy or nervous complaints — a traditional indication that maps onto its modern antidepressant application with unusual directness. The name references the plant’s flowering around the feast of St John the Baptist in late June. Safety context: This monograph leads with safety because hyperforin’s dominant clinical significance is not its antidepressant contribution but its status as the single most consequential herb–drug interaction agent in common use. Hyperforin is a potent activator of the pregnane X receptor (PXR) and thereby an inducer of CYP3A4 and P-glycoprotein, reducing plasma concentrations of a long list of prescription drugs — including immunosuppressants, HIV antiretrovirals, anticoagulants, and oral contraceptives. Any page on this compound that buried that fact would be indefensible. Commercial source: Hypericum perforatum extract standardised to hyperforin content; note that hyperforin and hypericin are separate markers standardised independently, and a "0.3% hypericin" extract tells a buyer nothing about its hyperforin load.

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Evidence for Hyperforin Applications

The drug-interaction liability is documented with rare precision and is directly proportional to hyperforin content. A review of the field found sufficient evidence from interaction studies and case reports that St John’s wort is a potent inducer of cytochrome P450 enzymes — particularly CYP3A4 — and/or P-glycoprotein, with co-medication resulting in decreased plasma concentrations of amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, simvastatin, and oral contraceptives, and with the degree of enzyme induction correlating strongly with the amount of hyperforin in the product (Müller 2006). Reduced efficacy of oral contraceptives is not a theoretical concern — it has produced case reports of unwanted pregnancy. Claim strength: High.

The mechanism is precisely identified. A review revisiting the clinical relevance of SJW interactions confirms these are caused by pregnane X receptor (PXR) activation: SJW preparations are potent PXR activators and hence inducers of CYP450 enzymes (most importantly CYP3A4) and P-glycoprotein, with the degree of CYP3A4 induction correlating significantly with the hyperforin content of the preparation (Nicolussi 2020 Br J Pharmacol). The EMA/HMPC position is that hyperforin is mainly responsible for these pharmacokinetic interactions and that the induction of CYP3A4, CYP2C9, CYP2C19 and P-gp is well documented and directly correlated with hyperforin content. Claim strength: High.

The corollary is commercially important and is the reason this compound is worth documenting properly rather than avoiding: because the interaction risk tracks hyperforin content, low-hyperforin SJW preparations substantially reduce it. Products delivering under roughly 1 mg/day of hyperforin have been reported as less likely to be associated with major interactions for CYP3A4 or P-glycoprotein substrates. Commercial SJW preparations have been found to vary in hyperforin content by more than sixty-fold, which means the risk profile of "St John’s wort" as a category is essentially meaningless without knowing the hyperforin figure. Claim strength: Moderate.

On the efficacy side, hyperforin is understood to contribute to SJW’s antidepressant activity through broad-spectrum inhibition of neurotransmitter reuptake — serotonin, dopamine, noradrenaline, glutamate, and GABA — but via an unusual mechanism: rather than binding transporters directly as conventional reuptake inhibitors do, hyperforin elevates intracellular sodium, which collapses the sodium gradient the transporters depend on. This is mechanistically distinctive but does not confer any regulatory advantage, and formulators should be clear that antidepressant claims are not permissible in most supplement contexts. Claim strength: Moderate (mechanistic).

A formulation constraint that buyers routinely underestimate: hyperforin is very unstable, decomposing rapidly in the presence of oxygen and light, and is reported to be more stable in ethanol or methanol solution than as a solid. This has three consequences. Assayed hyperforin content at manufacture may not reflect content at point of consumption. Product-to-product and batch-to-batch variability is partly a degradation artefact rather than a raw-material one. And — a genuinely counterintuitive point — a poorly stored high-hyperforin extract may degrade toward a lower-interaction-risk profile, which is not a quality outcome anyone should rely on. Claim strength: High (established instability).

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Dosage & Formulator Specification

Herbuno carries Hypericum perforatum extract standardized to 3% hyperforin, alongside St John’s wort extract standardized to 0.3% hypericin, unstandardized extract powder, and a water-soluble liquid extract. Buyers must understand that hyperforin and hypericin are independent markers: a 0.3% hypericin specification conveys nothing about hyperforin load, and therefore nothing about the product’s drug-interaction risk profile.

Dosing guidance for this compound cannot responsibly be given as a simple figure, because the hyperforin content is simultaneously the presumed active driver and the primary safety liability. Clinical SJW research has used extract doses around 900 mg/day, with one interaction study using a 300 mg/day preparation containing 7.48 mg hyperforin as its low dose. Formulators must decide deliberately which side of the trade-off they are on: a high-hyperforin extract carries the interaction burden, while a low-hyperforin extract (under roughly 1 mg/day) substantially reduces that burden but departs from the material used in much of the efficacy literature.

Analytical verification must specify hyperforin content by HPLC separately from hypericin, with adhyperforin quantified where relevant (commercial hyperforin reference material commonly specifies under 10% adhyperforin). Given the compound’s marked instability, the certificate of analysis date and storage history are unusually material: light-protected, oxygen-excluded, cold storage should be specified and documented. Stability data across the intended shelf life — not merely a release assay — is a reasonable demand for any hyperforin-standardized material.

Any product containing meaningful hyperforin requires prominent drug-interaction warning language — this is not optional risk-management boilerplate but the central safety fact about the ingredient. Documented consequences of co-administration include loss of efficacy of immunosuppressants (ciclosporin, tacrolimus), HIV protease and non-nucleoside reverse transcriptase inhibitors, the antineoplastics irinotecan and imatinib, anticoagulants, and hormonal contraceptives, with case reports of irregular bleeding and unwanted pregnancy. Induction begins within about three days, peaks at one to two weeks, and persists for a comparable period after discontinuation — so the risk window extends beyond the dosing period. Concurrent use with serotonergic antidepressants also raises serotonin-syndrome concern. Photosensitivity is a separate, hypericin-associated caution.

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Frequently Asked Questions — Hyperforin

Why is hyperforin considered a safety problem rather than a benefit?
Because it is a potent activator of the pregnane X receptor, and thereby an inducer of CYP3A4 and P-glycoprotein. This reduces plasma levels of a long list of prescription drugs — immunosuppressants, HIV antiretrovirals, anticoagulants, statins, and oral contraceptives among them, with documented cases of unwanted pregnancy. The degree of induction correlates directly with hyperforin content.

Does a '0.3% hypericin' label tell you the interaction risk?
No — and this is a consequential misunderstanding. Hyperforin and hypericin are separate markers standardised independently. A hypericin figure conveys nothing about hyperforin load, and therefore nothing about the drug-interaction risk. Commercial SJW products have been found to vary in hyperforin content by more than sixtyfold.

Can low-hyperforin St John's wort reduce the interaction risk?
Yes, substantially. Because the risk tracks hyperforin content, products delivering under roughly 1 mg/day of hyperforin have been reported as less likely to cause major interactions with CYP3A4 or P-glycoprotein substrates. This is the main reason the hyperforin figure — not the hypericin one — is the number that matters.

Why is hyperforin so unstable?
It is a highly lipophilic prenylated phloroglucinol that decomposes rapidly on exposure to oxygen and light, and is more stable in ethanol or methanol solution than as a solid. This means assayed content at manufacture may not reflect content at consumption, and stability data across shelf life — not just a release assay — is a reasonable demand.

Related compounds: Quercetin, Rutin, Chlorogenic Acid, Apigenin

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Claim-strength scale – High = multiple human RCTs; Moderate = limited trials or strong preclinical convergence; Emerging = early-stage lab or animal data.

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