Hyperforin

Hyperforin at a Glance

Hyperforin is a prenylated acylphloroglucinol — a lipophilic, five-times-prenylated molecule built on a phloroglucinol core — and the constituent that carries most of what St John’s wort does, both good and bad ^{2,14Reference 2Beerhues L · 2006HyperforinView study →Reference 14Zanoli P · 2004Role of hyperforin in the pharmacological activities of StView study →}.

It is the extract’s principal antidepressant principle. But it inhibits neurotransmitter reuptake in a way no conventional antidepressant does: rather than binding and blocking the transporter, it dissipates the sodium gradient that every monoamine transporter runs on, producing broad, non-selective inhibition of serotonin, noradrenaline, dopamine, GABA and glutamate uptake at once ^{4,5,6Reference 4Singer A et al. · 1999Hyperforin, a major antidepressant constituent of StView study →Reference 5Müller WE et al. · 2001Hyperforin — antidepressant activity by a novel mechanism of actionView study →Reference 6Wonnemann M et al. · 2001Evaluation of synaptosomal uptake inhibition of most relevant constituents of StView study →}.

It is also the reason St John’s wort is the most interaction-prone herb in common use. Hyperforin is one of the most potent natural ligands of the pregnane X receptor (PXR), the master switch for drug-metabolising genes; PXR activation induces CYP3A4 and P-glycoprotein, and that single mechanism accounts for documented transplant rejections, contraceptive failures, and lost exposure to antiretrovirals and cancer drugs ^{15,16,19,23Reference 15Moore LB et al. · 2000Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA (2000). St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. PNAS. https://pubmed.ncbi.nlm.nih.gov/10852961/View study →Reference 16Watkins RE et al. · 2003Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR (2003). 2.1 Å crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry. https://pubmed.ncbi.nlm.nih.gov/12578355/View study →Reference 19Nicolussi S et al. · 2020Clinical relevance of StView study →Reference 23Ruschitzka F et al. · 2000Acute heart transplant rejection due to Saint John’s wortView study →}.

The third thing to know is that hyperforin is chemically unstable — it oxidises readily, which is why hyperforin content varies enormously between products, why some manufacturers deliberately make low-hyperforin extracts, and why “St John’s wort” is not one pharmacological entity ^{24,43Reference 24Orth HC et al. · 1999Isolation, purity analysis and stability of hyperforin as a standard material from Hypericum perforatum LView study →Reference 43Ang CY et al. · 2004Instability of StView study →}.

What It's Used For

The evidence on hyperforin is unusually lopsided. Its best-documented human effect is not a therapy at all — it is enzyme induction, established in dozens of controlled pharmacokinetic studies in people ^{20Reference 20Whitten DL et al. · 2006Systematic reviewThe effect of St John’s wort extracts on CYP3A: a systematic review of prospective clinical trialsView study →}. Its antidepressant credentials, by contrast, are real but extract-level: the isolate itself has never been given to depressed patients as a drug.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. The top row is deliberately included even though it is a hazard, not a use: it is where the strongest human evidence for this molecule sits, and hiding it would misrepresent the page.

01Drug-metabolism induction (a hazard, not a use)Promising78%PXR crystal structure + hepatocyte induction + dozens of controlled human PK studies, dose-scaling with hyperforin content ^{15,16,17,20,21,22,33Reference 15Moore LB et al. · 2000Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA (2000). St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. PNAS. https://pubmed.ncbi.nlm.nih.gov/10852961/View study →Reference 16Watkins RE et al. · 2003Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR (2003). 2.1 Å crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry. https://pubmed.ncbi.nlm.nih.gov/12578355/View study →Reference 17Komoroski BJ et al. · 2004Induction and inhibition of cytochromes P450 by the StView study →Reference 20Whitten DL et al. · 2006Systematic reviewThe effect of St John’s wort extracts on CYP3A: a systematic review of prospective clinical trialsView study →Reference 21Hohmann N et al. · 2024Dose-dependent induction of CYP3A activity by StView study →Reference 22Mai I et al. · 2004Hyperforin content determines the magnitude of the St John’s wort–cyclosporine drug interactionView study →Reference 33Mueller SC et al. · 2004Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxinView study →}

02Antidepressant (as the extract’s active principle)Promising52%Hyperforin-content-controlled RCT ^{37Reference 37Laakmann G et al. · 1998Laakmann G, Schüle C, Baghai T, Kieser M (1998). St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/9684948/View study →} + large extract meta-analyses ^{39,40Reference 39Linde K et al. · 2008Systematic reviewSt John’s wort for major depressionView study →Reference 40Ng QX et al. · 2017Meta-analysisClinical use of Hypericum perforatum (St John’s wort) in depression: a meta-analysisView study →} + rodent isolate work ^{12,13Reference 12Cervo L et al. · 2002Role of hyperforin in the antidepressant-like activity of Hypericum perforatum extractsView study →Reference 13Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →}; no isolate trial

03Anti-inflammatory (5-LOX / COX-1)Shaky34%Potent, mechanistically novel 5-LOX inhibition in enzyme and cell assays, plus a rat in-vivo model ^{46,47Reference 46Albert D et al. · 2002Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenaseView study →Reference 47Feisst C et al. · 2009AnimalHyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivoView study →}

04Antibacterial (gram-positive)Shaky30%Isolate active against multiresistant S. aureus and other gram-positives in vitro ^{44Reference 44Schempp CM et al. · 1999Antibacterial activity of hyperforin from St John’s wort, against multiresistant Staphylococcus aureus and gram-positive bacteriaView study →}

05Antitumour / pro-apoptoticShaky26%Cell lines (IC₅₀ 3–15 µM) + one rat mammary-carcinoma model ^{45Reference 45Schempp CM et al. · 2002Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from StView study →}

06Neuroprotective / anti-amyloidShaky22%Rodent amyloid models and TRPC6-driven neurotrophic effects; no human data ^{10,48,49Reference 10Leuner K et al. · 2013Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca2+-permeable TRPC6 channelsView study →Reference 48Dinamarca MC et al. · 2006Hyperforin prevents beta-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer’s amyloid-beta-depositsView study →Reference 49Griffith TN et al. · 2010Neurobiological effects of hyperforin and its potential in Alzheimer’s disease therapyView study →}

Mechanisms

The load-bearing point is that one physical property — hyperforin’s protonophore/ionophore behaviour — plausibly explains most of the neuropharmacology, and a completely separate property (high-affinity PXR binding) explains all of the danger. They are not the same mechanism, and a low-hyperforin extract turns down both at once ^{8,16,22Reference 8Sell TS et al. · 2014Protonophore properties of hyperforin are essential for its pharmacological activityView study →Reference 16Watkins RE et al. · 2003Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR (2003). 2.1 Å crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry. https://pubmed.ncbi.nlm.nih.gov/12578355/View study →Reference 22Mai I et al. · 2004Hyperforin content determines the magnitude of the St John’s wort–cyclosporine drug interactionView study →}.

Pharmacokinetics

Hyperforin is absorbed and measurable in humans, which is more than can be said for many plant constituents. After a single 300 mg tablet of a hyperforin-standardised extract (14.8 mg hyperforin), peak plasma levels of about 150 ng/mL (~280 nM) were reached at 3.5 hours, with a half-life of ~9 h and mean residence time ~12 h; kinetics were linear up to 600 mg of extract but sub-proportional at 900–1200 mg. On the standard 3 × 300 mg/day regimen, estimated steady-state plasma concentration is ~100 ng/mL (~180 nM), and repeated dosing produced no accumulation ^{42Reference 42Biber A et al. · 1998Clinical trialOral bioavailability of hyperforin from hypericum extracts in rats and human volunteersView study →}. Multiple-dose human data from a different hypericum tablet agree on the general picture ^{54Reference 54Schulz HU et al. · 2005Investigation of pharmacokinetic data of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin revealed from single and multiple oral dose studies with a hypericum extract containing tablet in healthy male volunteersView study →}.

Two features matter more than the numbers. First, brain penetration appears poor — hyperforin was undetectable in rat brain at doses that produced antidepressant-like behaviour, and the reviewers who noted this treat it as the central unresolved objection to the in-vitro mechanism ^{12,13Reference 12Cervo L et al. · 2002Role of hyperforin in the antidepressant-like activity of Hypericum perforatum extractsView study →Reference 13Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →}. Second, hyperforin’s own induction of CYP3A4 and P-gp makes it a perpetrator whose effect builds over roughly a week and persists after stopping, which is why interaction management is about timing as well as avoidance ^{19Reference 19Nicolussi S et al. · 2020Clinical relevance of StView study →}.

Clinical Trials

There are no clinical trials of isolated hyperforin. The human trial literature is entirely about extracts, and it splits along hyperforin content:

• Hyperforin-content-controlled antidepressant trial: WS 5572 (5% hyperforin) beat placebo; the otherwise-identical WS 5573 (0.5%) did not ^{37Reference 37Laakmann G et al. · 1998Laakmann G, Schüle C, Baghai T, Kieser M (1998). St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/9684948/View study →}.
• Low-hyperforin extract vs. an SSRI: Ze 117 (a deliberately low-hyperforin extract) was equipotent with fluoxetine in mild-moderate depression with markedly fewer adverse events ^{38Reference 38Schrader E · 2000RCTEquivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depressionView study →}.
• Extract-level meta-analysis: Cochrane, 29 trials, 5,489 patients — superior to placebo, comparable to standard antidepressants, fewer dropouts ^{39Reference 39Linde K et al. · 2008Systematic reviewSt John’s wort for major depressionView study →}; a 2017 meta-analysis agreed ^{40Reference 40Ng QX et al. · 2017Meta-analysisClinical use of Hypericum perforatum (St John’s wort) in depression: a meta-analysisView study →}. But a large US RCT in more severe major depression was null ^{41Reference 41Shelton RC et al. · 2001RCTEffectiveness of St John’s wort in major depression: a randomized controlled trialView study →}.
• Interaction pharmacokinetics — the largest body of human work: dozens of controlled studies on midazolam, ciclosporin, tacrolimus, digoxin, warfarin, oral contraceptives, indinavir, nevirapine, irinotecan and imatinib ^{20,21,22,25,26,27,28,29,30,31,32,33Reference 20Whitten DL et al. · 2006Systematic reviewThe effect of St John’s wort extracts on CYP3A: a systematic review of prospective clinical trialsView study →Reference 21Hohmann N et al. · 2024Dose-dependent induction of CYP3A activity by StView study →Reference 22Mai I et al. · 2004Hyperforin content determines the magnitude of the St John’s wort–cyclosporine drug interactionView study →Reference 25Piscitelli SC et al. · 2000Indinavir concentrations and St John’s wortView study →Reference 26de Maat MM et al. · 2001Drug interaction between St John’s wort and nevirapineView study →Reference 27Mathijssen RH et al. · 2002Effects of StView study →Reference 28Frye RF et al. · 2004Effect of St John’s wort on imatinib mesylate pharmacokineticsView study →Reference 29Hall SD et al. · 2003The interaction between St John’s wort and an oral contraceptiveView study →Reference 30Murphy PA et al. · 2005Interaction of StView study →Reference 31Jiang X et al. · 2004Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjectsView study →Reference 32Mai I et al. · 2003Impact of St John’s wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patientsView study →Reference 33Mueller SC et al. · 2004Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxinView study →}.

Last checked: July 2026.

How Hyperforin Works

The Sodium-Gradient Mechanism

This is the part most often described wrongly. Monoamine transporters are secondary active transporters: they haul serotonin, noradrenaline or dopamine into the neuron by riding the inward electrochemical gradient of sodium. Remove the gradient and the transporter stops, no matter how intact it is.

Kinetic analysis in mouse-brain synaptosomes showed exactly this signature. Hyperforin at 2 µM cut V(max) by more than half while barely changing K(m) — non-competitive inhibition. Citalopram did the opposite: raised K(m), left V(max) alone. Hyperforin is also only a weak inhibitor of [³H]paroxetine binding relative to its effect on serotonin uptake — i.e. it does not occupy the transporter’s substrate site. Measuring free intracellular sodium directly confirmed the cause: hyperforin raised [Na⁺]ᵢ substantially, as the Na⁺/H⁺ ionophore monensin does, while citalopram did not move it at all ^{4Reference 4Singer A et al. · 1999Hyperforin, a major antidepressant constituent of StView study →}.

Why This Is Not “SSRI-Like”

Two consequences follow, and both distinguish hyperforin sharply from conventional antidepressants:

• It is not selective, and cannot be. A collapsed sodium gradient disables every Na⁺-coupled transporter in reach. Hyperforin therefore inhibits uptake of serotonin, noradrenaline, dopamine, GABA and L-glutamate simultaneously — a profile no SSRI, SNRI or tricyclic produces ^{5,6Reference 5Müller WE et al. · 2001Hyperforin — antidepressant activity by a novel mechanism of actionView study →Reference 6Wonnemann M et al. · 2001Evaluation of synaptosomal uptake inhibition of most relevant constituents of StView study →}.
• It does not bind the transporter. Describing hyperforin as “a natural SSRI” inverts the pharmacology: SSRIs work because they occupy a specific site on SERT; hyperforin works despite not occupying it ^{4,5Reference 4Singer A et al. · 1999Hyperforin, a major antidepressant constituent of StView study →Reference 5Müller WE et al. · 2001Hyperforin — antidepressant activity by a novel mechanism of actionView study →}.

Adhyperforin, the closely related homologue that co-occurs in the plant, shows the same strong inhibition across all uptake systems tested; the oligomeric procyanidin fraction shows a weak-to-moderate one ^{6Reference 6Wonnemann M et al. · 2001Evaluation of synaptosomal uptake inhibition of most relevant constituents of StView study →}. Binding studies across 5-HT₆, 5-HT₇, GABA(A)/benzodiazepine, sigma, NPY-Y1/Y2 receptors and the dopamine transporter found no conventional receptor mechanism that would explain the extract’s activity ^{11Reference 11Gobbi M et al. · 2001In vitroIn vitro binding studies with two hypericum perforatum extracts — hyperforin, hypericin and biapigenin — on 5-HT6, 5-HT7, GABA(A)/benzodiazepine, sigma, NPY-Y1/Y2 receptors and dopamine transportersView study →}.

TRPC6 & the Protonophore Question

How hyperforin raises intracellular sodium has two competing (and probably complementary) answers.

The first is TRPC6. Hyperforin selectively activates TRPC6 channels — inducing Na⁺ and Ca²⁺ entry and currents in TRPC6-expressing cells, suppressed by a dominant-negative TRPC6 mutant and absent in the phylogenetically related TRPC3 — making it the first selective pharmacological tool for studying TRPC6 ^{7Reference 7Leuner K et al. · 2007Hyperforin — a key constituent of StView study →}. The same channel activity produces the neurotrophic effects (axonal sprouting, dendritic-spine remodelling) ^{7,10Reference 7Leuner K et al. · 2007Hyperforin — a key constituent of StView study →Reference 10Leuner K et al. · 2013Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca2+-permeable TRPC6 channelsView study →}.

The second is simpler and more physical: hyperforin is itself a protonophore. It induces TRPC6-independent H⁺ currents in HEK-293 cells, cortical microglia, chromaffin cells — and in pure lipid bilayers, where no protein exists to mediate them. The resulting cytosolic acidification fuels the plasma-membrane sodium–proton exchanger, which is what actually raises free intracellular Na⁺ and inhibits Na⁺-cotransported neurotransmitter uptake ^{8Reference 8Sell TS et al. · 2014Protonophore properties of hyperforin are essential for its pharmacological activityView study →}. The same proton-carrying property explains a distinct downstream effect: hyperforin dissipates the pH gradient across synaptic-vesicle membranes, on which vesicular monoamine loading depends, depleting vesicle content and redistributing nerve-ending monoamines ^{9Reference 9Roz N · 2003Hyperforin inhibits vesicular uptake of monoamines by dissipating pH gradient across synaptic vesicle membraneView study →}.

The honest summary is that TRPC6 activation is well demonstrated but may be one manifestation of a more general membrane effect rather than the root cause ^{8Reference 8Sell TS et al. · 2014Protonophore properties of hyperforin are essential for its pharmacological activityView study →}.

Beyond Monoamines

The reuptake story does not exhaust the molecule. Hyperforin’s inhibition of GABA and L-glutamate uptake is pharmacologically unusual in its own right ^{5,6Reference 5Müller WE et al. · 2001Hyperforin — antidepressant activity by a novel mechanism of actionView study →Reference 6Wonnemann M et al. · 2001Evaluation of synaptosomal uptake inhibition of most relevant constituents of StView study →}; its 5-LOX/COX-1 inhibition is potent and mechanistically novel ^{46,47Reference 46Albert D et al. · 2002Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenaseView study →Reference 47Feisst C et al. · 2009AnimalHyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivoView study →}; its TRPC6-driven neurotrophic signalling resembles BDNF rather than a monoamine drug ^{10Reference 10Leuner K et al. · 2013Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca2+-permeable TRPC6 channelsView study →}; and reviews have proposed that the sigma system may be indirectly engaged in vivo via an unidentified metabolite ^{13,14Reference 13Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →Reference 14Zanoli P · 2004Role of hyperforin in the pharmacological activities of StView study →}.

The Interaction Story: PXR, CYP3A4 and P-Glycoprotein

This is the single most clinically consequential fact about any compound here, and it is worth following the chain link by link rather than summarising it as “St John’s wort interacts with drugs.”

The Mechanism Chain

1. Hyperforin binds and activates PXR. The pregnane X receptor is a nuclear xenobiotic receptor that acts as the master regulator of drug-metabolism and excretion genes. St John’s wort’s induction of hepatic drug metabolism was traced to PXR activation in 2000 ^{15Reference 15Moore LB et al. · 2000Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA (2000). St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. PNAS. https://pubmed.ncbi.nlm.nih.gov/10852961/View study →}, and in 2003 hyperforin was crystallised inside the human PXR ligand-binding domain at 2.1 Å — where it forces conformational changes that enlarge the binding pocket by about 250 ų ^{16Reference 16Watkins RE et al. · 2003Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR (2003). 2.1 Å crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry. https://pubmed.ncbi.nlm.nih.gov/12578355/View study →}.
2. Activated PXR turns on CYP3A4 and P-glycoprotein. In primary human hepatocytes, hyperforin significantly increased CYP3A4 mRNA, protein and enzyme activity (and CYP2C9), while leaving CYP1A2 and CYP2D6 alone; hypericin did nothing to any of them ^{17Reference 17Komoroski BJ et al. · 2004Induction and inhibition of cytochromes P450 by the StView study →}. In intestinal (LS180) cells, hyperforin-containing extracts induced MDR1/P-glycoprotein expression ^{18Reference 18Gutmann H et al. · 2006Hypericum perforatum: which constituents may induce intestinal MDR1 and CYP3A4 mRNA expression? Planta Medica. https://pubmed.ncbi.nlm.nih.gov/16755466/View study →}.
3. CYP3A4 metabolises over half of all prescription drugs; P-gp pumps many of the same drugs back out of the gut. Inducing both at once attacks a drug’s exposure from two directions — the reason the effect is largest in the gut rather than the liver ^{21Reference 21Hohmann N et al. · 2024Dose-dependent induction of CYP3A activity by StView study →}.
4. Blood levels of the co-administered drug fall — sometimes below the therapeutic threshold. The failure mode is silent: nothing feels wrong until the transplant rejects, the pregnancy occurs, or the viral load rebounds.

What Actually Fails in People

Every item below is a documented human finding, not an extrapolation:

Co-administered drug	Documented consequence	Ref
Ciclosporin (transplant)	Acute heart-transplant rejection in two patients; 45–52% fall in ciclosporin AUC with a high-hyperforin extract, requiring a 65% dose increase	22,23Reference 22Mai I et al. · 2004Hyperforin content determines the magnitude of the St John’s wort–cyclosporine drug interactionView study →Reference 23Ruschitzka F et al. · 2000Acute heart transplant rejection due to Saint John’s wortView study →
Tacrolimus / mycophenolic acid	Reduced tacrolimus exposure in renal transplant patients	32Reference 32Mai I et al. · 2003Impact of St John’s wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patientsView study →
Indinavir (HIV protease inhibitor)	Substantially reduced indinavir plasma concentrations	25Reference 25Piscitelli SC et al. · 2000Indinavir concentrations and St John’s wortView study →
Nevirapine (NNRTI)	Increased nevirapine clearance	26Reference 26de Maat MM et al. · 2001Drug interaction between St John’s wort and nevirapineView study →
Combined oral contraceptives	Faster ethinylestradiol/norethindrone metabolism; breakthrough bleeding in 7 of 12 women (vs 2 of 12 control); in a second study, follicle growth and probable ovulation	29,30Reference 29Hall SD et al. · 2003The interaction between St John’s wort and an oral contraceptiveView study →Reference 30Murphy PA et al. · 2005Interaction of StView study →
Irinotecan (chemotherapy)	Plasma levels of the active metabolite SN-38 fell 42%, with correspondingly less myelosuppression	27Reference 27Mathijssen RH et al. · 2002Effects of StView study →
Imatinib (targeted oncology)	Reduced imatinib exposure	28Reference 28Frye RF et al. · 2004Effect of St John’s wort on imatinib mesylate pharmacokineticsView study →
Warfarin	Apparent clearance of both S- and R-warfarin significantly induced, with a measurable loss of anticoagulant effect (INR AUC ratio 0.79)	31Reference 31Jiang X et al. · 2004Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjectsView study →
Digoxin (P-gp substrate)	AUC down ~25% with a high-hyperforin extract; no significant change with hyperforin-free preparations, tea, juice or oil extract	33Reference 33Mueller SC et al. · 2004Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxinView study →
Midazolam (CYP3A probe)	Oral clearance up 1.96×, 3.86× and 5.62× at 300, 900 and 1800 mg/day of extract	21Reference 21Hohmann N et al. · 2024Dose-dependent induction of CYP3A activity by StView study →

The 2020 review that revisited twenty years of this literature is unambiguous about the driver: the degree of CYP3A4 induction correlates significantly with the hyperforin content of the preparation ^{19Reference 19Nicolussi S et al. · 2020Clinical relevance of StView study →}.

Dose- and Content-Dependence

This is the part that turns a scary list into something actionable. The interaction is not a fixed property of “St John’s wort” — it scales with how much hyperforin is in the bottle:

• Across 31 prospective trials, every one of the 19 high-hyperforin studies (>10 mg/day) showed CYP3A induction; none of the three low-hyperforin studies (<4 mg/day) did ^{20Reference 20Whitten DL et al. · 2006Systematic reviewThe effect of St John’s wort extracts on CYP3A: a systematic review of prospective clinical trialsView study →}.
• A crossover study in renal transplant patients found a high-hyperforin extract cut ciclosporin AUC by 52% while a low-hyperforin extract produced no significant change and needed no dose adjustment ^{22Reference 22Mai I et al. · 2004Hyperforin content determines the magnitude of the St John’s wort–cyclosporine drug interactionView study →}.
• A low-hyperforin St John’s wort powder produced only an 11.3% fall in midazolam AUC in healthy volunteers — within no-effect boundaries and judged not clinically relevant ^{34Reference 34Mueller SC et al. · 2009No clinically relevant CYP3A induction after StView study →}; a low-hyperforin extract showed no relevant interaction with alprazolam, caffeine, tolbutamide or digoxin ^{35Reference 35Arold G et al. · 2005No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John’s wort extractView study →}.
• Even within hyperforin-containing products, digoxin exposure fell in proportion to hyperforin dose, and hyperforin-free preparations, tea, juice and oil extract produced no significant interaction at all ^{33Reference 33Mueller SC et al. · 2004Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxinView study →}.

Two cautions before anyone reads that as reassurance. Low-hyperforin does not mean no PXR ligand — hypericin and quercitrin showed some induction of MDR1/CYP3A4 mRNA in intestinal cells ^{18Reference 18Gutmann H et al. · 2006Hypericum perforatum: which constituents may induce intestinal MDR1 and CYP3A4 mRNA expression? Planta Medica. https://pubmed.ncbi.nlm.nih.gov/16755466/View study →} — and, more importantly, the hyperforin content of a given commercial product is often unknown, unlabelled and unstable (see below). Assuming a product is low-hyperforin because it is “gentle” is not a safe inference.

Timing

Induction is transcriptional, so it is slow in both directions: the effect builds over roughly a week of dosing and persists for a week or more after the herb is stopped ^{19Reference 19Nicolussi S et al. · 2020Clinical relevance of StView study →}. That matters when a new prescription, a surgery or a transplant work-up is being scheduled — stopping St John’s wort the day before is not enough. Induction also stacks: adding rifampicin to St John’s wort raised oral midazolam clearance 17.5-fold ^{21Reference 21Hohmann N et al. · 2024Dose-dependent induction of CYP3A activity by StView study →}.

Serotonin Syndrome: A Different Kind of Interaction

The induction story is pharmacokinetic — it makes other drugs disappear. There is a second, entirely separate interaction that is pharmacodynamic, and it runs the other way: too much serotonergic activity at once.

Because hyperforin raises synaptic serotonin (by the sodium-gradient route described above), combining St John’s wort with SSRIs, SNRIs, triptans, tramadol, MAOIs or other serotonergic agents can precipitate serotonin syndrome — agitation, tremor, clonus, hyperthermia, autonomic instability, and in severe cases rhabdomyolysis. A published case describes serotonin syndrome with rhabdomyolysis in a patient taking triptans, fluoxetine and hypericum together ^{36Reference 36Bonetto N et al. · 2007Serotonin syndrome and rhabdomyolysis induced by concomitant use of triptans, fluoxetine and hypericumView study →}.

Three points worth holding separate:

• The two interaction types have opposite logic. Enzyme induction makes co-administered drugs less effective; serotonergic additivity makes them more dangerous. The same herb does both, for different reasons.
• Low-hyperforin extracts do not reliably solve this one. Reducing hyperforin content reduces PXR induction — but hyperforin is also the serotonergic principle, and other constituents contribute; a low-hyperforin product is not automatically safe to stack with an SSRI.
• This is a clinical judgement, not a self-management problem. Anyone considering St John’s wort alongside a prescribed antidepressant needs a clinician, not a checklist.

High- Versus Low-Hyperforin Extracts

This is the industry’s response to everything above, and it creates a genuine scientific tension worth stating plainly.

The case for low-hyperforin extracts is straightforward: hyperforin is the PXR ligand, so removing it removes the interaction risk. Ze 117 — a deliberately low-hyperforin extract — was equipotent with fluoxetine on all main outcome measures in a 240-patient randomised comparison in mild-moderate depression, with adverse events in 8% versus fluoxetine’s 23% ^{38Reference 38Schrader E · 2000RCTEquivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depressionView study →}. Low-hyperforin products show no clinically relevant CYP3A induction ^{34,35Reference 34Mueller SC et al. · 2009No clinically relevant CYP3A induction after StView study →Reference 35Arold G et al. · 2005No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John’s wort extractView study →}, and hyperforin-free preparations do not touch digoxin ^{33Reference 33Mueller SC et al. · 2004Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxinView study →}.

The case against is equally direct: the only trial that held everything else constant and varied hyperforin alone found that the 0.5% extract performed like placebo while the 5% extract did not ^{37Reference 37Laakmann G et al. · 1998Laakmann G, Schüle C, Baghai T, Kieser M (1998). St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/9684948/View study →}, and hyperforin-free extracts lose antidepressant-like activity in rodents ^{13Reference 13Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →}.

Both cannot be fully right, and the reconciliation is not settled. Possibilities include: the Ze 117 comparison lacked a placebo arm (an equipotency finding against fluoxetine in mild depression is weaker evidence than it looks); other constituents (hypericin, the flavonoid and biflavone fraction, oligomeric procyanidins) contribute more than the hyperforin-centric model allows ^{6,11Reference 6Wonnemann M et al. · 2001Evaluation of synaptosomal uptake inhibition of most relevant constituents of StView study →Reference 11Gobbi M et al. · 2001In vitroIn vitro binding studies with two hypericum perforatum extracts — hyperforin, hypericin and biapigenin — on 5-HT6, 5-HT7, GABA(A)/benzodiazepine, sigma, NPY-Y1/Y2 receptors and dopamine transportersView study →}; or hyperforin’s contribution is real but smaller than the 1998 trial’s single result implies.

The practical reading for a reader, rather than a researcher: “St John’s wort” is not one product. A hyperforin-rich extract is the one the antidepressant trials most cleanly support and the one that causes drug failures; a low-hyperforin extract is safer to combine and has decent but less decisive efficacy evidence. Which one is in a given bottle is frequently not stated.

Instability & Degradation

Hyperforin’s chemistry is inconvenient in a way that propagates all the way to the clinic. It is highly sensitive to oxidation. Isolating it as a reference standard required protecting every step from oxygen — ascorbic acid in the mobile phases, evaporation and freeze-drying under nitrogen, helium sparging — and even then long-term storage at −70 °C under nitrogen is recommended ^{24Reference 24Orth HC et al. · 1999Isolation, purity analysis and stability of hyperforin as a standard material from Hypericum perforatum LView study →}.

In products, the same lability shows up as degradation. In acidic aqueous solutions and a St John’s wort functional beverage, hyperforin and adhyperforin decreased the most of all marker constituents, particularly under light exposure; the major degradation products were identified as furohyperforin, furohyperforin hydroperoxide and a furohyperforin isomer, the last of which was also found in the commercial drink ^{43Reference 43Ang CY et al. · 2004Instability of StView study →}.

Three consequences follow:

• Product variability is chemical, not just agricultural. Content depends on chemotype and harvest, then falls further with drying, light, acidity and storage time ^{24,43Reference 24Orth HC et al. · 1999Isolation, purity analysis and stability of hyperforin as a standard material from Hypericum perforatum LView study →Reference 43Ang CY et al. · 2004Instability of StView study →}.
• A stated hyperforin percentage is a claim about the day of manufacture. This is why research uses the stabilised dicyclohexylammonium (DCHA) salt rather than free hyperforin ^{12Reference 12Cervo L et al. · 2002Role of hyperforin in the antidepressant-like activity of Hypericum perforatum extractsView study →}.
• Old or poorly stored product is a different drug. Degradation reduces the antidepressant principle and, by the same token, the interaction risk — unpredictably, in both directions.

Isolate Versus Plant Studies

Hyperforin is an unusually clean case for this distinction, because the two evidence layers point in different directions on how confident to be.

The isolate evidence is strong on mechanism. Purified hyperforin has been characterised in synaptosomes, in TRPC6-expressing cells, in lipid bilayers, in human hepatocytes and in a PXR co-crystal ^{4,7,8,16,17Reference 4Singer A et al. · 1999Hyperforin, a major antidepressant constituent of StView study →Reference 7Leuner K et al. · 2007Hyperforin — a key constituent of StView study →Reference 8Sell TS et al. · 2014Protonophore properties of hyperforin are essential for its pharmacological activityView study →Reference 16Watkins RE et al. · 2003Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR (2003). 2.1 Å crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry. https://pubmed.ncbi.nlm.nih.gov/12578355/View study →Reference 17Komoroski BJ et al. · 2004Induction and inhibition of cytochromes P450 by the StView study →}. There is very little hand-waving here: these are studies of this molecule.

The human evidence is entirely plant-level. Every clinical result — antidepressant efficacy and drug interactions alike — comes from standardised hydroalcoholic extracts (WS 5570, WS 5572, WS 5573, LI 160, Ze 117), never the isolate ^{37,38,39Reference 37Laakmann G et al. · 1998Laakmann G, Schüle C, Baghai T, Kieser M (1998). St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/9684948/View study →Reference 38Schrader E · 2000RCTEquivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depressionView study →Reference 39Linde K et al. · 2008Systematic reviewSt John’s wort for major depressionView study →}. What redeems the attribution is that several of those extract studies were designed to vary hyperforin content specifically, which is a far stronger form of extract evidence than the usual “the extract worked, therefore compound X works” ^{20,22,33,37Reference 20Whitten DL et al. · 2006Systematic reviewThe effect of St John’s wort extracts on CYP3A: a systematic review of prospective clinical trialsView study →Reference 22Mai I et al. · 2004Hyperforin content determines the magnitude of the St John’s wort–cyclosporine drug interactionView study →Reference 33Mueller SC et al. · 2004Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxinView study →Reference 37Laakmann G et al. · 1998Laakmann G, Schüle C, Baghai T, Kieser M (1998). St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/9684948/View study →}.

The unresolved seam is pharmacokinetic. Isolate mechanisms operate at 0.1–1 µM; therapeutic dosing produces ~180 nM in plasma and hyperforin was undetectable in rat brain ^{12,13,42Reference 12Cervo L et al. · 2002Role of hyperforin in the antidepressant-like activity of Hypericum perforatum extractsView study →Reference 13Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →Reference 42Biber A et al. · 1998Clinical trialOral bioavailability of hyperforin from hypericum extracts in rats and human volunteersView study →}. For the interaction effects this hardly matters — PXR sits in gut and liver, exactly where hyperforin concentrations are highest ^{21Reference 21Hohmann N et al. · 2024Dose-dependent induction of CYP3A activity by StView study →}. For the antidepressant effects it matters a great deal, and it is the main reason to treat the mechanism as well-supported but not closed ^{13Reference 13Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →}.

Its Role in Plants

Hyperforin is not made for people. Its skeleton is assembled by isobutyrophenone synthase from isobutyryl-CoA and three molecules of malonyl-CoA — a polyketide-type mechanism — and the first prenylation is carried out by a soluble, ion-dependent dimethylallyltransferase ^{2Reference 2Beerhues L · 2006HyperforinView study →}. Isotope-labelling of cut H. perforatum sprouts showed that the five isoprenoid units come essentially entirely (>98%) from the deoxyxylulose phosphate (MEP) pathway, not the mevalonate pathway ^{51Reference 51Adam P et al. · 2002Biosynthesis of hyperforin in Hypericum perforatumView study →}.

It accumulates chiefly in the pistils and immature fruits, where it most likely acts as a defensive compound — consistent with its original identification as an antibiotic and its potent gram-positive activity ^{1,2,44Reference 1Gurevich AI et al. · 1971Gurevich AI, Dobrynin VN, Kolosov MN, Popravko SA, Riabova ID (1971). [Antibiotic hyperforin from Hypericum perforatum L]. Antibiotiki. https://pubmed.ncbi.nlm.nih.gov/5000144/View study →Reference 2Beerhues L · 2006HyperforinView study →Reference 44Schempp CM et al. · 1999Antibacterial activity of hyperforin from St John’s wort, against multiresistant Staphylococcus aureus and gram-positive bacteriaView study →}. This is a plant-defence function, and it should not be read as human pharmacology; the fact that a molecule protects reproductive tissue from bacteria says nothing about what it does in a brain.

Major Natural Sources

Hyperforin is effectively a single-species molecule in any practical sense.

Source	Part	Hyperforin content
St John’s wort (Hypericum perforatum)	Dried flowering herb	~2–4% 24Reference 24Orth HC et al. · 1999Isolation, purity analysis and stability of hyperforin as a standard material from Hypericum perforatum LView study →
St John’s wort	Pistils and immature fruits	Site of greatest accumulation (qualitative) 2Reference 2Beerhues L · 2006HyperforinView study →
High-hyperforin research extracts (WS 5572, LI 160)	Hydroalcoholic extract	~5% of extract 37,42Reference 37Laakmann G et al. · 1998Laakmann G, Schüle C, Baghai T, Kieser M (1998). St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/9684948/View study →Reference 42Biber A et al. · 1998Clinical trialOral bioavailability of hyperforin from hypericum extracts in rats and human volunteersView study →
Low-hyperforin research extracts (WS 5573, Ze 117)	Hydroalcoholic extract	~0.5% or less 37,38Reference 37Laakmann G et al. · 1998Laakmann G, Schüle C, Baghai T, Kieser M (1998). St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/9684948/View study →Reference 38Schrader E · 2000RCTEquivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depressionView study →

Within the plant it sits alongside its homologue adhyperforin (pharmacologically similar in uptake assays ^{6Reference 6Wonnemann M et al. · 2001Evaluation of synaptosomal uptake inhibition of most relevant constituents of StView study →}), the naphthodianthrone pigments hypericin and pseudohypericin, the biflavones amentoflavone and biapigenin, and the flavonoids hyperoside, quercetin, rutin and kaempferol. Of these, only hyperforin (and adhyperforin) carry the potent uptake-inhibiting and PXR-activating profile ^{6,11,17Reference 6Wonnemann M et al. · 2001Evaluation of synaptosomal uptake inhibition of most relevant constituents of StView study →Reference 11Gobbi M et al. · 2001In vitroIn vitro binding studies with two hypericum perforatum extracts — hyperforin, hypericin and biapigenin — on 5-HT6, 5-HT7, GABA(A)/benzodiazepine, sigma, NPY-Y1/Y2 receptors and dopamine transportersView study →Reference 17Komoroski BJ et al. · 2004Induction and inhibition of cytochromes P450 by the StView study →}.

Discovery & Synthesis

Hyperforin was isolated in 1971 by Gurevich, Dobrynin, Kolosov, Popravko and Riabova in Moscow, and reported in the Soviet journal Antibiotiki — as an antibiotic, not an antidepressant ^{1Reference 1Gurevich AI et al. · 1971Gurevich AI, Dobrynin VN, Kolosov MN, Popravko SA, Riabova ID (1971). [Antibiotic hyperforin from Hypericum perforatum L]. Antibiotiki. https://pubmed.ncbi.nlm.nih.gov/5000144/View study →}. The molecule’s second career began nearly three decades later: Chatterjee and colleagues proposed in 1998 that it was the antidepressant component of hypericum extracts ^{3Reference 3Chatterjee SS et al. · 1998Hyperforin as a possible antidepressant component of hypericum extractsView study →}, Singer and Müller worked out the sodium-gradient mechanism in 1999 ^{4Reference 4Singer A et al. · 1999Hyperforin, a major antidepressant constituent of StView study →}, and Laakmann’s hyperforin-content-controlled clinical trial appeared the same year ^{37Reference 37Laakmann G et al. · 1998Laakmann G, Schüle C, Baghai T, Kieser M (1998). St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/9684948/View study →}. Its third identity — the cause of the herb’s drug interactions — arrived in 2000 with the PXR papers ^{15Reference 15Moore LB et al. · 2000Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA (2000). St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. PNAS. https://pubmed.ncbi.nlm.nih.gov/10852961/View study →}.

Synthesis took much longer. As late as 2006 a dedicated review could state flatly that no total synthesis had been described ^{2Reference 2Beerhues L · 2006HyperforinView study →}. Two independent routes then landed: a catalytic asymmetric total synthesis of ent-hyperforin by Shimizu and Shibasaki’s group in 2010 ^{52Reference 52Shimizu Y et al. · 2010Catalytic asymmetric total synthesis of ent-hyperforinView study →}, and an enantioselective total synthesis of hyperforin by Sparling, Moebius and Shair in 2013 ^{53Reference 53Sparling BA et al. · 2013Enantioselective total synthesis of hyperforinView study →}. These are landmark syntheses of a densely functionalised, oxidation-prone bicyclic polyprenylated acylphloroglucinol — but they are laboratory achievements, not a commercial supply route. All practical hyperforin still comes from the plant, and its instability means it is handled as the DCHA salt or as a stabilised extract rather than as free material ^{12,24Reference 12Cervo L et al. · 2002Role of hyperforin in the antidepressant-like activity of Hypericum perforatum extractsView study →Reference 24Orth HC et al. · 1999Isolation, purity analysis and stability of hyperforin as a standard material from Hypericum perforatum LView study →}.

Patents: not yet researched.

Toxicity & Safety

Hyperforin’s moderate flag is not about organ toxicity. Direct toxicity looks low — the isolate suppressed rat tumours at effective doses “without any signs of acute toxicity” ^{45Reference 45Schempp CM et al. · 2002Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from StView study →}, and the herb itself is among the better-tolerated antidepressant options in head-to-head trials ^{38Reference 38Schrader E · 2000RCTEquivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depressionView study →}. The flag is for the harm it causes to other drugs, which is documented, mechanistically explained, and has produced transplant rejections in real patients ^{23Reference 23Ruschitzka F et al. · 2000Acute heart transplant rejection due to Saint John’s wortView study →}.

Safety at a Glance

⚠️ Moderate toxicityDrug interactionsSerotonin risk

• Low direct toxicity. No characterised organ-toxicity signal for the isolate; St John’s wort extracts are consistently better tolerated than SSRIs in trials ^{38Reference 38Schrader E · 2000RCTEquivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depressionView study →}.
• Potent enzyme and transporter inducer. Via PXR → CYP3A4 + P-glycoprotein, hyperforin reduces blood levels of ciclosporin, tacrolimus, oral contraceptives, warfarin, digoxin, indinavir, nevirapine, irinotecan and imatinib, among many others ^{19,20Reference 19Nicolussi S et al. · 2020Clinical relevance of StView study →Reference 20Whitten DL et al. · 2006Systematic reviewThe effect of St John’s wort extracts on CYP3A: a systematic review of prospective clinical trialsView study →}.
• Documented drug failures, not theoretical ones. Acute heart-transplant rejection, contraceptive breakthrough bleeding with follicle growth and probable ovulation, and a 42% drop in active irinotecan metabolite ^{23,27,30Reference 23Ruschitzka F et al. · 2000Acute heart transplant rejection due to Saint John’s wortView study →Reference 27Mathijssen RH et al. · 2002Effects of StView study →Reference 30Murphy PA et al. · 2005Interaction of StView study →}.
• Serotonin-syndrome risk in combination. Additive serotonergic effect with SSRIs, SNRIs, triptans, tramadol and MAOIs — a pharmacodynamic hazard distinct from the induction one ^{36Reference 36Bonetto N et al. · 2007Serotonin syndrome and rhabdomyolysis induced by concomitant use of triptans, fluoxetine and hypericumView study →}.
• Induction builds over ~1 week and persists ~1 week after stopping — and stacks with other inducers (17.5-fold midazolam clearance with rifampicin added) ^{19,21Reference 19Nicolussi S et al. · 2020Clinical relevance of StView study →Reference 21Hohmann N et al. · 2024Dose-dependent induction of CYP3A activity by StView study →}.
• Content is unpredictable. Hyperforin oxidises readily; product content varies with chemotype, harvest, light, acidity and storage, and is frequently unlabelled ^{24,43Reference 24Orth HC et al. · 1999Isolation, purity analysis and stability of hyperforin as a standard material from Hypericum perforatum LView study →Reference 43Ang CY et al. · 2004Instability of StView study →}.
• Low-hyperforin ≠ risk-free. It reliably reduces CYP3A induction ^{20,34,35Reference 20Whitten DL et al. · 2006Systematic reviewThe effect of St John’s wort extracts on CYP3A: a systematic review of prospective clinical trialsView study →Reference 34Mueller SC et al. · 2009No clinically relevant CYP3A induction after StView study →Reference 35Arold G et al. · 2005No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John’s wort extractView study →} but does not remove serotonergic interaction risk, and other constituents show some induction in vitro ^{18Reference 18Gutmann H et al. · 2006Hypericum perforatum: which constituents may induce intestinal MDR1 and CYP3A4 mRNA expression? Planta Medica. https://pubmed.ncbi.nlm.nih.gov/16755466/View study →}.

Full Safety and Interactions Detail

The induction hazard in full. Hyperforin is one of the most potent natural PXR agonists known; the receptor’s activation induces CYP3A4 (which metabolises a majority of prescription drugs), CYP2C9, and the efflux transporter P-glycoprotein ^{16,17,18Reference 16Watkins RE et al. · 2003Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR (2003). 2.1 Å crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry. https://pubmed.ncbi.nlm.nih.gov/12578355/View study →Reference 17Komoroski BJ et al. · 2004Induction and inhibition of cytochromes P450 by the StView study →Reference 18Gutmann H et al. · 2006Hypericum perforatum: which constituents may induce intestinal MDR1 and CYP3A4 mRNA expression? Planta Medica. https://pubmed.ncbi.nlm.nih.gov/16755466/View study →}. The clinical consequence is loss of drug exposure, and it has been measured in controlled human studies for midazolam ^{21Reference 21Hohmann N et al. · 2024Dose-dependent induction of CYP3A activity by StView study →}, ciclosporin ^{22Reference 22Mai I et al. · 2004Hyperforin content determines the magnitude of the St John’s wort–cyclosporine drug interactionView study →}, tacrolimus ^{32Reference 32Mai I et al. · 2003Impact of St John’s wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patientsView study →}, digoxin ^{33Reference 33Mueller SC et al. · 2004Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxinView study →}, warfarin ^{31Reference 31Jiang X et al. · 2004Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjectsView study →}, ethinylestradiol/norethindrone ^{29,30Reference 29Hall SD et al. · 2003The interaction between St John’s wort and an oral contraceptiveView study →Reference 30Murphy PA et al. · 2005Interaction of StView study →}, indinavir ^{25Reference 25Piscitelli SC et al. · 2000Indinavir concentrations and St John’s wortView study →}, nevirapine ^{26Reference 26de Maat MM et al. · 2001Drug interaction between St John’s wort and nevirapineView study →}, irinotecan ^{27Reference 27Mathijssen RH et al. · 2002Effects of StView study →} and imatinib ^{28Reference 28Frye RF et al. · 2004Effect of St John’s wort on imatinib mesylate pharmacokineticsView study →}. Two heart-transplant patients experienced acute rejection attributed to the ciclosporin interaction ^{23Reference 23Ruschitzka F et al. · 2000Acute heart transplant rejection due to Saint John’s wortView study →}. Because CYP3A4 substrates are so numerous, the practical rule is the conservative one: treat any prescription medicine as potentially affected and check before combining.

Which drug classes deserve outright avoidance. Immunosuppressants after transplant, HIV antiretrovirals, oral anticoagulants, hormonal contraceptives, and several oncology drugs are the highest-consequence categories, because in each the failure mode is severe and silent ^{19,23,25,27,30Reference 19Nicolussi S et al. · 2020Clinical relevance of StView study →Reference 23Ruschitzka F et al. · 2000Acute heart transplant rejection due to Saint John’s wortView study →Reference 25Piscitelli SC et al. · 2000Indinavir concentrations and St John’s wortView study →Reference 27Mathijssen RH et al. · 2002Effects of StView study →Reference 30Murphy PA et al. · 2005Interaction of StView study →}.

The serotonergic hazard. Distinct from induction, and it works by addition rather than subtraction. Concomitant serotonergic drugs (SSRIs, SNRIs, triptans, tramadol, MAOIs) risk serotonin syndrome; a documented case involved triptans, fluoxetine and hypericum together, with rhabdomyolysis ^{36Reference 36Bonetto N et al. · 2007Serotonin syndrome and rhabdomyolysis induced by concomitant use of triptans, fluoxetine and hypericumView study →}.

Photosensitivity belongs to a different molecule. St John’s wort’s dose-related photosensitising effect is attributed to hypericin, not hyperforin — a useful reminder that “the herb’s side effects” are not one compound’s ^{17Reference 17Komoroski BJ et al. · 2004Induction and inhibition of cytochromes P450 by the StView study →}.

Reproductive note (prose only). There is no dedicated reproductive-toxicity dataset for isolated hyperforin. The clinically relevant reproductive finding is indirect but important: by inducing contraceptive metabolism, hyperforin-containing extracts caused breakthrough bleeding, follicle growth and probable ovulation in controlled studies — i.e. the molecule’s reproductive risk is unintended pregnancy through contraceptive failure, not fetotoxicity ^{29,30Reference 29Hall SD et al. · 2003The interaction between St John’s wort and an oral contraceptiveView study →Reference 30Murphy PA et al. · 2005Interaction of StView study →}. Decisions about use in pregnancy or lactation belong to the St John’s wort herb page and to a clinician, not to this molecule page.

What is not characterised. No isolate genotoxicity or repeat-dose toxicology package is described here; no human dose-finding, no long-term isolate exposure data, and no chronic-safety data for hyperforin outside its extract context.

Dosage

There is no dose for isolated hyperforin. It is not sold as a stand-alone substance, its instability makes free-acid formulation impractical, and no human study has administered the isolate. The only meaningful figures are hyperforin contents of research extracts and the plasma levels they produce:

Resulting human plasma levels: C(max) ~150 ng/mL (~280 nM) after a single 300 mg extract dose, steady state ~100 ng/mL (~180 nM) on 3 × 300 mg/day, half-life ~9 h, no accumulation on repeated dosing ^{42Reference 42Biber A et al. · 1998Clinical trialOral bioavailability of hyperforin from hypericum extracts in rats and human volunteersView study →}.

The practical guidance is not a number, it is a decision rule: the hyperforin content of a St John’s wort product is the single most important thing to know about it, and the two things it governs — antidepressant strength and drug-interaction severity — move together. These are research figures and pharmacokinetic measurements, not a recommendation; see the St John’s wort page for whole-herb dosing and the depression page for how the extract evidence sits against other options.

References

1. Gurevich AI, Dobrynin VN, Kolosov MN, Popravko SA, Riabova ID (1971). [Antibiotic hyperforin from Hypericum perforatum L]. Antibiotiki. https://pubmed.ncbi.nlm.nih.gov/5000144/
2. Beerhues L (2006). Hyperforin. Phytochemistry. https://pubmed.ncbi.nlm.nih.gov/16973193/
3. Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE (1998). Hyperforin as a possible antidepressant component of hypericum extracts. Life Sciences. https://pubmed.ncbi.nlm.nih.gov/9718074/
4. Singer A, Wonnemann M, Müller WE (1999). Hyperforin, a major antidepressant constituent of St. John’s Wort, inhibits serotonin uptake by elevating free intracellular Na+. Journal of Pharmacology and Experimental Therapeutics. https://pubmed.ncbi.nlm.nih.gov/10454515/
5. Müller WE, Singer A, Wonnemann M (2001). Hyperforin — antidepressant activity by a novel mechanism of action. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/11518085/
6. Wonnemann M, Singer A, Siebert B, Müller WE (2001). Evaluation of synaptosomal uptake inhibition of most relevant constituents of St. John’s wort. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/11518066/
7. Leuner K, Kazanski V, Müller M, Essin K, Henke B, Gollasch M, Harteneck C, Müller WE (2007). Hyperforin — a key constituent of St. John’s wort specifically activates TRPC6 channels. FASEB Journal. https://pubmed.ncbi.nlm.nih.gov/17666455/
8. Sell TS, Belkacemi T, Flockerzi V, Beck A (2014). Protonophore properties of hyperforin are essential for its pharmacological activity. Scientific Reports. https://pubmed.ncbi.nlm.nih.gov/25511254/
9. Roz N, Rehavi M (2003). Hyperforin inhibits vesicular uptake of monoamines by dissipating pH gradient across synaptic vesicle membrane. Life Sciences. https://pubmed.ncbi.nlm.nih.gov/12759140/
10. Leuner K, Li W, Amaral MD, Rudolph S, Calfa G, Schuwald AM, Harteneck C, Inoue T, Pozzo-Miller L (2013). Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca2+-permeable TRPC6 channels. Hippocampus. https://pubmed.ncbi.nlm.nih.gov/22815087/
11. Gobbi M, Moia M, Pirona L, Morizzoni P, Mennini T (2001). In vitro binding studies with two hypericum perforatum extracts — hyperforin, hypericin and biapigenin — on 5-HT6, 5-HT7, GABA(A)/benzodiazepine, sigma, NPY-Y1/Y2 receptors and dopamine transporters. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/11518075/
12. Cervo L, Rozio M, Ekalle-Soppo CB, Guiso G, Morazzoni P, Caccia S (2002). Role of hyperforin in the antidepressant-like activity of Hypericum perforatum extracts. Psychopharmacology. https://pubmed.ncbi.nlm.nih.gov/12457273/
13. Mennini T, Gobbi M (2004). The antidepressant mechanism of Hypericum perforatum. Life Sciences. https://pubmed.ncbi.nlm.nih.gov/15207650/
14. Zanoli P (2004). Role of hyperforin in the pharmacological activities of St. John’s Wort. CNS Drug Reviews. https://pubmed.ncbi.nlm.nih.gov/15492771/
15. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA (2000). St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. PNAS. https://pubmed.ncbi.nlm.nih.gov/10852961/
16. Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR (2003). 2.1 Å crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry. https://pubmed.ncbi.nlm.nih.gov/12578355/
17. Komoroski BJ, Zhang S, Cai H, Hutzler JM, Frye R, Tracy TS, Strom SC, Lehmann T, Ang CY, Cui YY, Venkataramanan R (2004). Induction and inhibition of cytochromes P450 by the St. John’s wort constituent hyperforin in human hepatocyte cultures. Drug Metabolism and Disposition. https://pubmed.ncbi.nlm.nih.gov/15100173/
18. Gutmann H, Poller B, Büter KB, Pfrunder A, Schaffner W, Drewe J (2006). Hypericum perforatum: which constituents may induce intestinal MDR1 and CYP3A4 mRNA expression? Planta Medica. https://pubmed.ncbi.nlm.nih.gov/16755466/
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