Hypericin

Hypericin at a Glance

Hypericin is the red naphthodianthrone pigment of St. John’s wort (Hypericum perforatum), stored in the black glandular dots that speckle the flowers, buds and leaf margins. Crush a flower bud between your fingers and the red stain left behind is largely this molecule.

It is the compound St. John’s wort extracts are standardised to — “0.3% hypericin” is the number on most product labels — and that fact has produced one of the most persistent misattributions in herbal medicine. Hypericin was assumed for years to be the antidepressant principle. On current evidence it is not: the antidepressant activity of the extract is attributed principally to the phloroglucinol hyperforin, and hypericin’s role in standardisation is that of a convenient, stable, easily-measured marker rather than the active ^{2,3,4Reference 2Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →Reference 3Müller WE et al. · 2001Hyperforin — antidepressant activity by a novel mechanism of actionView study →Reference 4Nahrstedt A · 2010Lessons learned from herbal medicinal products: the example of StView study →}.

What hypericin unambiguously is is an efficient photosensitiser. It absorbs visible light, crosses to a long-lived triplet state, and hands that energy to molecular oxygen to make singlet oxygen and other reactive oxygen species ^{1,23,26Reference 1Kubin A et al. · 2005Hypericin — the facts about a controversial agentView study →Reference 23Wierrani F et al. · 2002Photodynamic action of some sensitizers by photooxidation of luminolView study →Reference 26Diwu Z · 1995Novel therapeutic and diagnostic applications of hypocrellins and hypericinsView study →}. That single photochemical fact runs through everything real about this molecule: it is why grazing animals that eat Hypericum develop hypericism, why St. John’s wort carries a (much milder, dose-dependent) photosensitivity caution in people, and why the same pigment is being developed deliberately as a photodynamic cancer therapy and a fluorescent tumour-detection dye ^{9,10,11,12Reference 9Gulick RM et al. · 1999Clinical trialPhase I studies of hypericin, the active compound in StView study →Reference 10Kim EJ et al. · 2022RCTEfficacy and safety of topical hypericin photodynamic therapy for early-stage cutaneous T-cell lymphoma (mycosis fungoides): the FLASH phase 3 randomized clinical trialView study →Reference 11Dong X et al. · 2021ReviewHypericin-mediated photodynamic therapy for the treatment of cancer: a reviewView study →Reference 12Straub M et al. · 2015A phase IIA dose-finding study of PVP-hypericin fluorescence cystoscopy for detection of nonmuscle-invasive bladder cancerView study →}.

The Marker That Isn’t the Active

This is the point of the page, so it is worth stating plainly.

Standardisation to hypericin is a manufacturing convention, not a claim about mechanism. Hypericin is coloured, chemically stable, easy to quantify by HPLC, and effectively unique to Hypericum — everything you want from a marker compound. Hyperforin, by contrast, is unstable and degrades on storage. So the industry measured what it could measure, and the label number stuck.

The antidepressant evidence points elsewhere. Hyperforin inhibits the reuptake of serotonin, noradrenaline, dopamine, GABA and glutamate through a novel mechanism — raising intracellular sodium rather than binding the transporters directly ^{3Reference 3Müller WE et al. · 2001Hyperforin — antidepressant activity by a novel mechanism of actionView study →}. A hydroalcoholic extract from which hyperforin has been removed loses its antidepressant-like activity in rodent models ^{2Reference 2Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →}. And on pharmacokinetic and receptor-binding grounds, “the antidepressant effect of Hypericum extract is unlikely to be due to an interaction of hypericin with central neurotransmitter receptors” ^{2Reference 2Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →}.

The earlier mechanistic claims for hypericin have not held up. The molecule was screened in the 1980s and 1990s against a long list of pharmacologically interesting enzymes — MAO, protein kinase C, dopamine-β-hydroxylase, reverse transcriptase, telomerase — and the resulting literature is, in the words of one review, “controversial” ^{1Reference 1Kubin A et al. · 2005Hypericin — the facts about a controversial agentView study →}. The monoamine-oxidase story is the clearest casualty: in a dedicated study, pure hypericin showed no relevant MAO inhibition, and no fraction inhibited MAO ex vivo, leading the authors to conclude that the antidepressive effect of Hypericum extract cannot be explained in terms of MAO inhibition ^{5Reference 5Bladt S · 1994Inhibition of MAO by fractions and constituents of hypericum extractView study →}. The protein kinase C finding is real but modest and light-independent (IC₅₀ ~1.7 µg/mL in vitro), and was proposed to explain antiretroviral activity that later failed in humans ^{18Reference 18Takahashi I et al. · 1989Hypericin and pseudohypericin specifically inhibit protein kinase C: possible relation to their antiretroviral activityView study →}.

One honest counterpoint. The picture is not quite “hypericin does nothing centrally.” In rats, hypericin and pseudohypericin solubilised with procyanidins were active in the forced swimming test, with an inverted U-shaped dose–response antagonised by the dopamine antagonist sulpiride — the authors argued naphthodianthrones are antidepressant constituents ^{6Reference 6Butterweck V et al. · 1998Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming testView study →}. That result is preclinical, depends on a co-formulated solubiliser, and sits against the extract-subtraction and receptor-binding evidence above. It is a reason to say “principally hyperforin” rather than “hypericin does nothing” — not a reason to keep calling hypericin the active.

Photosensitisation: The Chemistry That Defines It

Hypericin is one of the more efficient natural photosensitisers known. In a comparative HPLC assay that ranked sensitisers by their production of reactive oxygen species, hypericin and pseudohypericin were tested alongside Rose Bengal, methylene blue, protoporphyrin IX and Photofrin — the standard reference photosensitisers of clinical photodynamic therapy ^{23Reference 23Wierrani F et al. · 2002Photodynamic action of some sensitizers by photooxidation of luminolView study →}.

The sequence is the classic Type II photodynamic mechanism:

1. Hypericin absorbs visible light (it is strongly coloured, with absorption running out into the orange-red — which is why hypericin PDT can be driven with ordinary visible light rather than the deep-red lasers many photosensitisers need).
2. The excited molecule crosses to a triplet state, aided by an unusual intramolecular proton-transfer photochemistry that has been studied in detail ^{26Reference 26Diwu Z · 1995Novel therapeutic and diagnostic applications of hypocrellins and hypericinsView study →}.
3. That triplet transfers energy to ground-state oxygen, producing singlet oxygen (¹O₂), with a Type I electron-transfer route also contributing superoxide and other radicals ^{1,23Reference 1Kubin A et al. · 2005Hypericin — the facts about a controversial agentView study →Reference 23Wierrani F et al. · 2002Photodynamic action of some sensitizers by photooxidation of luminolView study →}.
4. Because hypericin is highly lipophilic, it partitions into membranes — endoplasmic reticulum, Golgi, mitochondria, and the lipid envelope of enveloped viruses — so the oxidative damage is delivered exactly where it does the most harm ^{11,17Reference 11Dong X et al. · 2021ReviewHypericin-mediated photodynamic therapy for the treatment of cancer: a reviewView study →Reference 17Mariewskaya KA et al. · 2021Photosensitizing antiviralsView study →}.

This is a genuinely dual-use property. Delivered to a tumour lesion under a controlled light dose, it is a therapy. Delivered to the ear of a white-faced sheep standing in a summer field, it is a burn.

What It's Used For

Almost everything hypericin does that is worth measuring is light-dependent. The sections below separate the genuine human clinical signal — which now includes a positive phase 3 trial — from the much larger preclinical literature and from the antidepressant claim it does not support.

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. Note that the top-ranked application is a topical drug use of synthetic hypericin plus light, not an effect of swallowing St. John’s wort.

01Photodynamic Therapy (Cutaneous T-Cell Lymphoma)Promising64%FLASH phase 3 RCT, n=169, positive with a favourable safety profile ^{10Reference 10Kim EJ et al. · 2022RCTEfficacy and safety of topical hypericin photodynamic therapy for early-stage cutaneous T-cell lymphoma (mycosis fungoides): the FLASH phase 3 randomized clinical trialView study →}

02Photodynamic Diagnosis (Bladder Cancer)Promising46%Phase IIA dose-finding cystoscopy study, n=40; extra CIS/pTa lesions found ^{12Reference 12Straub M et al. · 2015A phase IIA dose-finding study of PVP-hypericin fluorescence cystoscopy for detection of nonmuscle-invasive bladder cancerView study →}

03Photodynamic Anticancer (Preclinical)Shaky34%Large in-vitro/animal literature across many tumour lines; one phase 1/2 oral glioma study ^{11,13,24Reference 11Dong X et al. · 2021ReviewHypericin-mediated photodynamic therapy for the treatment of cancer: a reviewView study →Reference 13Couldwell WT et al. · 2011A phase 1/2 study of orally administered synthetic hypericin for treatment of recurrent malignant gliomasView study →Reference 24Solár P et al. · 2011Photoactivated hypericin induces downregulation of HER2 gene expressionView study →}

04Antiviral PhotoinactivationShaky28%Strong in-vitro virucidal data incl. SARS-CoV-2 envelope binding; the one human trial was negative ^{14,15,16,9Reference 14Hudson JB et al. · 1991Antiviral activities of hypericinView study →Reference 15Meruelo D et al. · 1988Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericinView study →Reference 16Delcanale P et al. · 2022The interaction of hypericin with SARS-CoV-2 reveals a multimodal antiviral activityView study →Reference 9Gulick RM et al. · 1999Clinical trialPhase I studies of hypericin, the active compound in StView study →}

05Antidepressant Activity (The Misattribution)Shaky16%Rodent forced-swim data for solubilised hypericin only; extract evidence points to hyperforin ^{2,3,6Reference 2Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →Reference 3Müller WE et al. · 2001Hyperforin — antidepressant activity by a novel mechanism of actionView study →Reference 6Butterweck V et al. · 1998Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming testView study →}

Mechanisms

The first two rows are load-bearing. Hypericin has no meaningful pharmacology in the dark at achievable concentrations; it has a great deal under light, and where the light hits is where the drug acts.

Pharmacokinetics

Hypericin’s kinetics matter mainly because they set how long a photosensitiser is circulating. In the definitive human study, single oral doses of 250, 750 and 1,500 µg of hypericin (given as the LI 160 St. John’s wort extract) produced median peak plasma concentrations of 1.3, 7.2 and 16.6 µg/L respectively — the lowest dose disproportionately lower, i.e. non-linear at the bottom of the range ^{8Reference 8Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}. Absorption is slow, with a lag time of ~1.9 h for hypericin (versus 0.4 h for pseudohypericin), and systemic availability is low at roughly 14% ^{8Reference 8Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}.

The distinguishing number is the elimination half-life of ~43 h — very long for a plant constituent, and about double pseudohypericin’s ~25 h ^{8Reference 8Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}. Consequently hypericin accumulates: 14 days of dosing three times daily reached steady-state trough levels of 7.9 µg/L after about 7 days ^{8Reference 8Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}. Distribution volume at steady state was ~19.7 L and total clearance ~9.2 mL/min ^{8Reference 8Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}.

Practically, this means the photosensitivity caution is not a “stay out of the sun for four hours after your capsule” caution. Plasma levels build over the first week of use and persist for days after stopping, so any light-sensitivity precaution applies across the whole treatment period. The higher-dose human phototoxicity study measured peak total hypericin (hypericin plus pseudohypericin) of 0.028–0.159 mg/L after 900–3,600 mg of extract ^{7Reference 7Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}.

Clinical Trials

Human trials of hypericin are trials of the purified or synthetic molecule, usually with light — not of St. John’s wort. The picture is a clear positive for topical PDT, promising for photodynamic diagnosis, modest for systemic oncology, and a documented failure for systemic antiviral use.

Last checked: July 2026.

Hypericism: The Phototoxicity, Honestly Scaled

Hypericism is the veterinary name for the primary photosensitisation caused by eating Hypericum. It is a real and sometimes severe problem in grazing livestock: in a documented outbreak in German Blackface sheep, animals that had eaten St. John’s wort developed inflammatory skin lesions on every lightly-pigmented, sparsely-haired area — ears, bridge of the nose, and around the eyes — through the summer ^{19Reference 19Kümper H · 1989Kümper H (1989). [Hypericum poisoning in sheep]. Tierärztliche Praxis. https://pubmed.ncbi.nlm.nih.gov/2815063/View study →}. This is why H. perforatum is classed as a noxious weed on rangeland.

The human picture is much milder, and it is worth being precise about why. A placebo-controlled crossover study in 13 volunteers gave single doses of 900, 1,800 or 3,600 mg of standardised extract (0, 2.81, 5.62 and 11.25 mg of total hypericin) and measured minimal erythema dose against solar-simulated and selective UV-A irradiation. Sensitivity to solar-simulated light did not differ from placebo at any dose, and showed no dose-related trend. Only at the highest dose was UV-A sensitivity increased, and only marginally (tanning dose 10.8 → 8.7 J/cm², P =.03). There was no correlation between plasma hypericin levels and photosensitivity ^{7Reference 7Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}. In a 50-volunteer multiple-dose arm at 600 mg three times daily for 15 days, light sensitivity rose slightly but the authors calculated it could be compensated by shortening sun exposure by 21% ^{7Reference 7Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}.

Three qualifications keep this from being a clean all-clear:

• The doses tested were higher than typical commercial products, but the study explicitly does not exclude phototoxic reactions above 11.25 mg of total hypericin or plasma levels above 100 µg/L ^{7Reference 7Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}.
• Pure hypericin behaves differently from the extract. The authors noted that co-constituents may be protective — and the phase I HIV trial, using purified hypericin at drug doses, produced severe cutaneous phototoxicity in 48% of evaluable patients and had to stop escalating ^{7,9Reference 7Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →Reference 9Gulick RM et al. · 1999Clinical trialPhase I studies of hypericin, the active compound in StView study →}.
• Case reports exist at the individual level, including a sun-exposure-associated acute neuropathy in a patient taking St. John’s wort ^{20Reference 20Bove GM · 1998Acute neuropathy after exposure to sun in a patient treated with St John’s wortView study →}.

The workable summary: at ordinary extract doses, clinically relevant phototoxicity is largely confined to high intakes and to fair-skinned or otherwise photosensitive people, and to anyone combining the herb with phototherapy or other photosensitising drugs. The livestock literature and the pure-compound trials are not evidence that a standard capsule will burn you — they are evidence that the underlying chemistry is real and scales with dose.

Isolate vs. Plant Studies

This molecule splits cleanly and instructively. Every therapeutic finding belongs to the isolate — and increasingly to synthetic hypericin, since the FLASH ointment, the glioma capsules and the PVP-complexed cystoscopy dye are all manufactured, not extracted ^{10,12,13Reference 10Kim EJ et al. · 2022RCTEfficacy and safety of topical hypericin photodynamic therapy for early-stage cutaneous T-cell lymphoma (mycosis fungoides): the FLASH phase 3 randomized clinical trialView study →Reference 12Straub M et al. · 2015A phase IIA dose-finding study of PVP-hypericin fluorescence cystoscopy for detection of nonmuscle-invasive bladder cancerView study →Reference 13Couldwell WT et al. · 2011A phase 1/2 study of orally administered synthetic hypericin for treatment of recurrent malignant gliomasView study →}. The plant contributes essentially nothing to those results beyond having been where the structure came from.

Conversely, every antidepressant finding belongs to the plant extract — and within that extract, to a different molecule. This is the inversion that generates the misattribution: because the extract is labelled by hypericin content, the extract’s clinical record gets silently transferred to the marker ^{2,4Reference 2Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →Reference 4Nahrstedt A · 2010Lessons learned from herbal medicinal products: the example of StView study →}.

There is one genuine middle case. Whole-extract co-constituents change what hypericin does: procyanidins solubilise it and thereby amplify its in-vivo activity ^{6Reference 6Butterweck V et al. · 1998Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming testView study →}, and co-effectors improve its bioavailability ^{4Reference 4Nahrstedt A · 2010Lessons learned from herbal medicinal products: the example of StView study →}, while the same co-constituents may be protective against phototoxicity relative to the pure compound ^{7Reference 7Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}. So “isolated hypericin” and “hypericin in an extract” are not interchangeable in either direction — not for efficacy, and not for safety.

Its Role in Plants

Hypericin is a pigment stored in dedicated anatomical structures: the multicellular dark glands that dot the leaf margins, flower petals and stamens of Hypericum. This compartmentalisation is a strong clue that the plant makes it as a defence — sequestering a photoactive toxin in discrete glands keeps it away from the plant’s own photosynthetic machinery until tissue is damaged.

The biosynthesis runs through the polyketide pathway. A type III polyketide synthase from H. perforatum (HpPKS2) condenses acetyl-CoA with malonyl-CoA to make octaketide products, and — critically — its transcripts localise specifically to the dark glands that accumulate hypericins, though the enzyme did not itself produce emodin anthrone in vitro, so additional factors are required ^{21Reference 21Karppinen K et al. · 2008Octaketide-producing type III polyketide synthase from Hypericum perforatum is expressed in dark glands accumulating hypericinsView study →}. The downstream route is still not settled: the classical proposal runs via emodin and emodin anthrone, while MALDI-imaging work has proposed a route through the dimeric anthraquinone skyrin, which co-localises with hypericin in the dark glands of some Hypericum species and is scattered through the leaf in others ^{22Reference 22Revuru B et al. · 2020MALDI-HRMS imaging maps the localization of skyrin, the precursor of hypericin, and pathway intermediates in leaves of Hypericum speciesView study →}.

As a defence, hypericin is a light-activated toxin against herbivores — the same photosensitising chemistry that burns a grazing sheep deters insects feeding in daylight. These are plant-biology functions and should not be read as human pharmacology.

Prevalence in Nature

Hypericin is unusually narrowly distributed. Unlike quercetin, rutin or kaempferol — which occur across hundreds of plant families and also appear in St. John’s wort — hypericin is effectively confined to the genus Hypericum, and it is one of the few compounds in the herb that is diagnostic of it.

Within H. perforatum, content is not uniform across the plant. It is concentrated in the black glandular dots of the flowers and buds, so flowering-top preparations run higher than whole-aerial ones, and it tracks sun exposure, chemotype, harvest timing, drying and provenance ^{21,25Reference 21Karppinen K et al. · 2008Octaketide-producing type III polyketide synthase from Hypericum perforatum is expressed in dark glands accumulating hypericinsView study →Reference 25Bagdonaitė E et al. · 2012Variation in concentrations of major bioactive compounds in Hypericum perforatum L. from LithuaniaView study →}. Reported figures for dried herb run around 0.03–0.3% measured as total hypericins — hypericin plus pseudohypericin, which are quantified together in standardisation and are structurally near-identical ^{25,28Reference 25Bagdonaitė E et al. · 2012Variation in concentrations of major bioactive compounds in Hypericum perforatum L. from LithuaniaView study →Reference 28Otero P et al. · 2024Documentary analysis of Hypericum perforatum (StView study →}.

It is also present in other Hypericum species. MALDI-HRMS imaging has mapped hypericin and its precursors in the leaves of H. humifusum, H. tetrapterum, H. rumeliacum, H. annulatum and H. bupleuroides, with species-specific distribution patterns ^{22Reference 22Revuru B et al. · 2020MALDI-HRMS imaging maps the localization of skyrin, the precursor of hypericin, and pathway intermediates in leaves of Hypericum speciesView study →}. Note the species discipline: data on H. perforatum should not be merged with data on ornamental or wild Hypericum spp.

Major Natural Sources

Source	Part	Hypericin content	Notes
St. John’s wort (Hypericum perforatum)	Flowering tops, dried herb	~0.03–0.3% (total hypericins)	The commercial source; concentrated in the black glandular dots 25Reference 25Bagdonaitė E et al. · 2012Variation in concentrations of major bioactive compounds in Hypericum perforatum L. from LithuaniaView study →
Hypericum humifusum, H. tetrapterum	Leaves (dark glands)	Not quantified here	Hypericin co-localised with skyrin in dark glands 22Reference 22Revuru B et al. · 2020MALDI-HRMS imaging maps the localization of skyrin, the precursor of hypericin, and pathway intermediates in leaves of Hypericum speciesView study →
H. rumeliacum, H. annulatum, H. bupleuroides	Leaves	Not quantified here	Hypericin present; precursors scattered rather than gland-localised 22Reference 22Revuru B et al. · 2020MALDI-HRMS imaging maps the localization of skyrin, the precursor of hypericin, and pathway intermediates in leaves of Hypericum speciesView study →

Alongside hypericin, St. John’s wort carries pseudohypericin, hyperforin, the biflavones amentoflavone and biapigenin, and the flavonoids hyperoside, quercetin, rutin and kaempferol ^{25,28Reference 25Bagdonaitė E et al. · 2012Variation in concentrations of major bioactive compounds in Hypericum perforatum L. from LithuaniaView study →Reference 28Otero P et al. · 2024Documentary analysis of Hypericum perforatum (StView study →}.

Discovery & Synthesis

Hypericin’s effects were known long before the molecule was. Hypericism — photosensitisation dermatitis in grazing animals that eat Hypericum — is a classical veterinary entity, described in cattle and sheep and used historically to identify the plant as a rangeland hazard ^{19Reference 19Kümper H · 1989Kümper H (1989). [Hypericum poisoning in sheep]. Tierärztliche Praxis. https://pubmed.ncbi.nlm.nih.gov/2815063/View study →}. The red pigment responsible was subsequently characterised as a naphthodianthrone: an extended, planar, hexahydroxylated polycyclic quinone built from two anthraquinone-type halves, structurally related to the anthraquinone emodin and to the fungal photosensitisers the hypocrellins ^{26Reference 26Diwu Z · 1995Novel therapeutic and diagnostic applications of hypocrellins and hypericinsView study →}.

Interest in hypericin as a therapeutic rather than a toxin dates to the late 1980s, when reports of “dramatic antiretroviral activity” placed it at the centre of AIDS-era drug screening ^{15Reference 15Meruelo D et al. · 1988Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericinView study →} — an episode that ended in a failed and phototoxic phase I trial ^{9Reference 9Gulick RM et al. · 1999Clinical trialPhase I studies of hypericin, the active compound in StView study →}. The far more productive line was the photobiological one: through the 1990s the photophysics and photochemistry of hypericin, including its intramolecular proton-transfer kinetics, were worked out in parallel with the related hypocrellins, and hypericin was commercialised for research use ^{26Reference 26Diwu Z · 1995Novel therapeutic and diagnostic applications of hypocrellins and hypericinsView study →}.

Manufacture today is synthetic for drug purposes. The clinical products are explicitly synthetic hypericin — the 0.25% topical ointment used in the FLASH trial (HyBryte / SGX301) and the oral capsules used in the glioma study — while the bladder-diagnostic agent is hypericin complexed with polyvinylpyrrolidone (PVP) to overcome the molecule’s near-total insolubility in water ^{10,12,13Reference 10Kim EJ et al. · 2022RCTEfficacy and safety of topical hypericin photodynamic therapy for early-stage cutaneous T-cell lymphoma (mycosis fungoides): the FLASH phase 3 randomized clinical trialView study →Reference 12Straub M et al. · 2015A phase IIA dose-finding study of PVP-hypericin fluorescence cystoscopy for detection of nonmuscle-invasive bladder cancerView study →Reference 13Couldwell WT et al. · 2011A phase 1/2 study of orally administered synthetic hypericin for treatment of recurrent malignant gliomasView study →}. That insolubility is the central formulation problem for this compound, and it is also why plant procyanidins that solubilise it change its in-vivo behaviour so markedly ^{6Reference 6Butterweck V et al. · 1998Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming testView study →}.

Patents: not yet researched.

Toxicity & Safety

Hypericin carries a moderate flag, and the flag is entirely about phototoxicity. In the dark it is a poorly-absorbed, poorly-soluble pigment with no organ-toxicity signal of note — the synthetic topical product is characterised as non-mutagenic, in deliberate contrast to psoralen–UVA photochemotherapy ^{10Reference 10Kim EJ et al. · 2022RCTEfficacy and safety of topical hypericin photodynamic therapy for early-stage cutaneous T-cell lymphoma (mycosis fungoides): the FLASH phase 3 randomized clinical trialView study →}. It is not “low” because the photosensitising chemistry is real, dose-scaling, well documented in animals, and was dose-limiting in a human trial of the pure compound; it is not higher because at the doses people actually encounter — via standardised St. John’s wort extract — controlled testing found light sensitivity essentially unchanged ^{7,9,19Reference 7Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →Reference 9Gulick RM et al. · 1999Clinical trialPhase I studies of hypericin, the active compound in StView study →Reference 19Kümper H · 1989Kümper H (1989). [Hypericum poisoning in sheep]. Tierärztliche Praxis. https://pubmed.ncbi.nlm.nih.gov/2815063/View study →}.

Safety at a Glance

⚠️ Moderate toxicityPhotosensitivity

• At normal extract doses, human photosensitivity barely moves. A placebo-controlled crossover study at up to 3,600 mg of extract found no change in solar-simulated light sensitivity and only a marginal UV-A effect at the highest dose ^{7Reference 7Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}.
• No mutagenicity or organ-toxicity signal. The topical synthetic-hypericin product is characterised as a non-mutagenic photodynamic therapy, unlike psoralen–UVA ^{10Reference 10Kim EJ et al. · 2022RCTEfficacy and safety of topical hypericin photodynamic therapy for early-stage cutaneous T-cell lymphoma (mycosis fungoides): the FLASH phase 3 randomized clinical trialView study →}.
• Pure hypericin at drug doses is dose-limitingly phototoxic. Severe cutaneous phototoxicity in 11 of 23 evaluable patients (48%) on intravenous/oral hypericin; escalation had to be abandoned ^{9Reference 9Gulick RM et al. · 1999Clinical trialPhase I studies of hypericin, the active compound in StView study →}.
• It accumulates. A ~43 h half-life means plasma levels build over about a week of dosing and persist after stopping — sun caution applies across the whole course, not just after each dose ^{8Reference 8Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}.
• Fair skin, high doses, and stacked photosensitisers. The people for whom the herbal caution actually bites are fair-skinned or photosensitive individuals, those on high-dose extracts, and anyone combining it with phototherapy or other photosensitising drugs.
• Hypericism in livestock. Grazing animals eating Hypericum develop photosensitisation dermatitis on unpigmented, sparsely-haired skin — ears, muzzle, around the eyes ^{19Reference 19Kümper H · 1989Kümper H (1989). [Hypericum poisoning in sheep]. Tierärztliche Praxis. https://pubmed.ncbi.nlm.nih.gov/2815063/View study →}.
• The label percentage is not a potency claim. “0.3% hypericin” is a quality-control marker; the herb’s antidepressant activity is attributed principally to hyperforin ^{2,4Reference 2Mennini T · 2004The antidepressant mechanism of Hypericum perforatumView study →Reference 4Nahrstedt A · 2010Lessons learned from herbal medicinal products: the example of StView study →}.

Full Safety & Interactions Detail

Phototoxicity — the dose-response. Hypericin’s harm is photodynamic: absorbed light generates singlet oxygen and radicals in the skin, producing a phototoxic (not allergic) reaction ^{1,23Reference 1Kubin A et al. · 2005Hypericin — the facts about a controversial agentView study →Reference 23Wierrani F et al. · 2002Photodynamic action of some sensitizers by photooxidation of luminolView study →}. The response scales steeply with the form and dose delivered. In grazing livestock consuming large quantities of fresh plant, it is a genuine dermatitis affecting all lightly-pigmented, thinly-haired skin ^{19Reference 19Kümper H · 1989Kümper H (1989). [Hypericum poisoning in sheep]. Tierärztliche Praxis. https://pubmed.ncbi.nlm.nih.gov/2815063/View study →}. In humans taking standardised extract, a careful placebo-controlled study found no increase in solar-simulated light sensitivity at 900–3,600 mg and only a marginal UV-A change at the top dose, with no correlation to plasma level; a 15-day repeat-dose arm found a small increase compensable by reducing sun exposure ~21% ^{7Reference 7Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}. In humans given purified hypericin at drug doses, severe cutaneous phototoxicity occurred in 48% and was the reason the trial could not escalate ^{9Reference 9Gulick RM et al. · 1999Clinical trialPhase I studies of hypericin, the active compound in StView study →}. The authors of the extract study explicitly cautioned that pure hypericin may behave differently from extract, since other extract constituents may be protective ^{7Reference 7Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}.

Accumulation. The ~43 h elimination half-life and ~7-day time-to-steady-state mean that photosensitivity risk is a property of the course, not of the last dose ^{8Reference 8Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}. Anyone planning intense sun exposure, a tanning course, laser treatment, or phototherapy should account for this.

Case-level reports. Individual reports link St. John’s wort plus sun exposure to more than sunburn — including an acute neuropathy after sun exposure in a patient on the herb ^{20Reference 20Bove GM · 1998Acute neuropathy after exposure to sun in a patient treated with St John’s wortView study →}. These are single cases and cannot establish incidence, but they support conservative advice for photosensitive individuals.

Drug interactions. The clinically important St. John’s wort interactions — CYP3A4 and P-glycoprotein induction, and the resulting loss of efficacy for contraceptives, ciclosporin, warfarin, antiretrovirals and much else — are driven by hyperforin via the pregnane X receptor, not by hypericin. Hypericin does show in-vitro effects on MDR-1 expression and on cortisol metabolism ^{27Reference 27Pal D · 2006MDR- and CYP3A4-mediated drug-herbal interactionsView study →}, but these are mechanistic observations, not the source of the herb’s interaction profile. The interaction that does belong to hypericin is pharmacodynamic: stacking it with other photosensitising agents (tetracyclines, thiazides, sulfonamides, fluoroquinolones, psoralen-based PUVA, or clinical phototherapy) compounds phototoxic risk.

Reproductive note (prose only). No dedicated reproductive-toxicity dataset exists for isolated hypericin. Reproductive and lactation decisions belong to the St. John’s wort herb page, where intake is actually decided and where the herb’s own pregnancy data (limited and judged insufficient by reviews) are assessed. No comprehensive isolate repeat-dose or genotoxicity package is characterised here beyond the photobiology and the clinical-trial safety data above.

Dosage

There is no supplemental dose for isolated hypericin, and no reason to want one — it is a photosensitiser, not a nutrient. Ordinary exposure is indirect, through St. John’s wort extracts standardised to hypericin content. Every defined figure below is a research or drug dose.

The practical reading: a standard St. John’s wort capsule delivers hypericin in the low milligrams, an order of magnitude below the exposures where human phototoxicity becomes a real clinical problem — but the herbal exposure is also the one people take for months at a time, with a molecule that accumulates. These are research and clinical figures, not a personal recommendation.

References

1. Kubin A, Wierrani F, Burner U, Alth G, Grünberger W (2005). Hypericin — the facts about a controversial agent. Current Pharmaceutical Design. https://pubmed.ncbi.nlm.nih.gov/15638760/
2. Mennini T, Gobbi M (2004). The antidepressant mechanism of Hypericum perforatum. Life Sciences. https://pubmed.ncbi.nlm.nih.gov/15207650/
3. Müller WE, Singer A, Wonnemann M (2001). Hyperforin — antidepressant activity by a novel mechanism of action. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/11518085/
4. Nahrstedt A, Butterweck V (2010). Lessons learned from herbal medicinal products: the example of St. John’s wort. Journal of Natural Products. https://pubmed.ncbi.nlm.nih.gov/20408551/
5. Bladt S, Wagner H (1994). Inhibition of MAO by fractions and constituents of hypericum extract. Journal of Geriatric Psychiatry and Neurology. https://pubmed.ncbi.nlm.nih.gov/7857511/
6. Butterweck V, Petereit F, Winterhoff H, Nahrstedt A (1998). Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming test. Planta Medica. https://pubmed.ncbi.nlm.nih.gov/9619107/
7. Brockmöller J, Reum T, Bauer S, Kerb R, Hübner WD, Roots I (1997). Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry. https://pubmed.ncbi.nlm.nih.gov/9342768/
8. Kerb R, Brockmöller J, Staffeldt B, Ploch M, Roots I (1996). Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin. Antimicrobial Agents and Chemotherapy. https://pubmed.ncbi.nlm.nih.gov/8878586/
9. Gulick RM, et al. (1999). Phase I studies of hypericin, the active compound in St. John’s wort, as an antiretroviral agent in HIV-infected adults. AIDS Clinical Trials Group Protocols 150 and 258. Annals of Internal Medicine. https://pubmed.ncbi.nlm.nih.gov/10075619/
10. Kim EJ, et al. (2022). Efficacy and safety of topical hypericin photodynamic therapy for early-stage cutaneous T-cell lymphoma (mycosis fungoides): the FLASH phase 3 randomized clinical trial. JAMA Dermatology. https://pubmed.ncbi.nlm.nih.gov/35857290/
11. Dong X, et al. (2021). Hypericin-mediated photodynamic therapy for the treatment of cancer: a review. Journal of Pharmacy and Pharmacology. https://pubmed.ncbi.nlm.nih.gov/33793828/
12. Straub M, Russ D, Horn T, Gschwend JE, Abrahamsberg C (2015). A phase IIA dose-finding study of PVP-hypericin fluorescence cystoscopy for detection of nonmuscle-invasive bladder cancer. Journal of Endourology. https://pubmed.ncbi.nlm.nih.gov/25222735/
13. Couldwell WT, et al. (2011). A phase 1/2 study of orally administered synthetic hypericin for treatment of recurrent malignant gliomas. Cancer. https://pubmed.ncbi.nlm.nih.gov/21456013/
14. Hudson JB, Lopez-Bazzocchi I, Towers GH (1991). Antiviral activities of hypericin. Antiviral Research. https://pubmed.ncbi.nlm.nih.gov/1650164/
15. Meruelo D, Lavie G, Lavie D (1988). Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin. PNAS. https://pubmed.ncbi.nlm.nih.gov/2839837/
16. Delcanale P, et al. (2022). The interaction of hypericin with SARS-CoV-2 reveals a multimodal antiviral activity. ACS Applied Materials & Interfaces. https://pubmed.ncbi.nlm.nih.gov/35302731/
17. Mariewskaya KA, Tyurin AP, Chistov AA, Korshun VA, Alferova VA, Ustinov AV (2021). Photosensitizing antivirals. Molecules. https://pubmed.ncbi.nlm.nih.gov/34209713/
18. Takahashi I, et al. (1989). Hypericin and pseudohypericin specifically inhibit protein kinase C: possible relation to their antiretroviral activity. Biochemical and Biophysical Research Communications. https://pubmed.ncbi.nlm.nih.gov/2558652/
19. Kümper H (1989). [Hypericum poisoning in sheep]. Tierärztliche Praxis. https://pubmed.ncbi.nlm.nih.gov/2815063/
20. Bove GM (1998). Acute neuropathy after exposure to sun in a patient treated with St John’s wort. The Lancet. https://pubmed.ncbi.nlm.nih.gov/9798597/
21. Karppinen K, Hokkanen J, Mattila S, Neubauer P, Hohtola A (2008). Octaketide-producing type III polyketide synthase from Hypericum perforatum is expressed in dark glands accumulating hypericins. The FEBS Journal. https://pubmed.ncbi.nlm.nih.gov/18647343/
22. Revuru B, Bálintová M, Henzelyová J, Čellárová E, Kusari S (2020). MALDI-HRMS imaging maps the localization of skyrin, the precursor of hypericin, and pathway intermediates in leaves of Hypericum species. Molecules. https://pubmed.ncbi.nlm.nih.gov/32878122/
23. Wierrani F, et al. (2002). Photodynamic action of some sensitizers by photooxidation of luminol. Naturwissenschaften. https://pubmed.ncbi.nlm.nih.gov/12384722/
24. Solár P, et al. (2011). Photoactivated hypericin induces downregulation of HER2 gene expression. Radiation Research. https://pubmed.ncbi.nlm.nih.gov/21175347/
25. Bagdonaitė E, Mártonfi P, Repčák M, Labokas J (2012). Variation in concentrations of major bioactive compounds in Hypericum perforatum L. from Lithuania. Industrial Crops and Products. doi:10.1016/j.indcrop.2011.07.018
26. Diwu Z (1995). Novel therapeutic and diagnostic applications of hypocrellins and hypericins. Photochemistry and Photobiology. https://pubmed.ncbi.nlm.nih.gov/7568399/
27. Pal D, Mitra AK (2006). MDR- and CYP3A4-mediated drug-herbal interactions. Life Sciences. https://pubmed.ncbi.nlm.nih.gov/16442130/
28. Otero P, Ceric F, Miranda-Rojas S, Carreño M (2024). Documentary analysis of Hypericum perforatum (St. John’s wort) and its effect on depressive disorders. Pharmaceuticals. doi:10.3390/ph17121625

View all 28 references▾