Pseudohypericin

Pseudohypericin at a Glance

Pseudohypericin is the second naphthodianthrone of St John’s wort — the blood-red phenanthroperylene-quinone pigment that sits beside hypericin in the plant’s black glandular dots, differing from it by a single hydroxyl group ^{12Reference 12Karioti A · 2010Hypericins as potential leads for new therapeuticsView study →}.

It is also, in most material that has been measured, the more abundant of the two. The clinical extract LI 160 delivered roughly twice as much pseudohypericin as hypericin per capsule ^{1,2Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →Reference 2Staffeldt B et al. · 1994Pharmacokinetics of hypericin and pseudohypericin after oral intake of the Hypericum perforatum extract LI 160 in healthy volunteersView study →}, and the two compounds are quantified together as “total hypericins” — the number on every St John’s wort label ^{3,4,5Reference 3Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →Reference 4Draves AH · 2003Analysis of the hypericin and pseudohypericin content of commercially available St John’s Wort preparationsView study →Reference 5Rückert U et al. · 2007Simultaneous determination of total hypericin and hyperforin in StView study →}. That convention has a consequence worth stating plainly at the top of the page: a large slice of the literature that says “hypericin” is really about a mixture in which pseudohypericin dominates.

The isolated molecule has never been given to a human as a single agent. What exists is a genuinely useful body of head-to-head comparisons — pharmacokinetics, phototoxicity, enzyme inhibition, antiviral activity — and, unusually, in one area (light-activated anti-inflammatory activity) the isolate literature puts pseudohypericin ahead of its famous twin ^{14,16Reference 14Hammer KD et al. · 2008Pseudohypericin is necessary for the light-activated inhibition of prostaglandin E2 pathways by a 4 component system mimicking an Hypericum perforatum fractionView study →Reference 16Huang N et al. · 2011AnimalIdentification of anti-inflammatory constituents in Hypericum perforatum and Hypericum gentianoides extracts using RAW 264.7 mouse macrophagesView study →}.

The Compound That “Total Hypericins” Hides

Standardisation of St John’s wort has always been anchored on the naphthodianthrones, because they are coloured, easy to detect and characteristic of the genus. But the pharmacopoeial measure is not hypericin — it is total hypericin, the sum of hypericin, pseudohypericin and their light-convertible precursors protohypericin and protopseudohypericin ^{5,11Reference 5Rückert U et al. · 2007Simultaneous determination of total hypericin and hyperforin in StView study →Reference 11Poutaraud A et al. · 2001Improved procedure for the quality control of Hypericum perforatum LView study →}. Exposing an extract to daylight converts the protoforms into the mature pigments, and the assay reports one combined number ^{5Reference 5Rückert U et al. · 2007Simultaneous determination of total hypericin and hyperforin in StView study →}.

Three things follow, and they shape everything that comes after:

• The label figure is a mixture, and pseudohypericin is usually the larger part of it. In the Berlin pharmacokinetic programme, single doses of 300, 900 and 1,800 mg of LI 160 supplied 250, 750 and 1,500 µg of hypericin against 526, 1,578 and 3,156 µg of pseudohypericin — a stable ratio of about 2.1 : 1 in pseudohypericin’s favour ^{1,2Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →Reference 2Staffeldt B et al. · 1994Pharmacokinetics of hypericin and pseudohypericin after oral intake of the Hypericum perforatum extract LI 160 in healthy volunteersView study →}.
• “0.3% hypericins” is a class claim, not a molecule claim — and it is often wrong anyway. An HPLC survey of 54 commercial St John’s wort products found total naphthodianthrone content ranging from 0% to 108% of label claim, with only two products landing within 10% of what they promised; on average labels overstated hypericin plus pseudohypericin by nearly a factor of two ^{4Reference 4Draves AH · 2003Analysis of the hypericin and pseudohypericin content of commercially available St John’s Wort preparationsView study →}.
• Extract studies cannot be attributed to hypericin alone. Where a trial or an in-vitro experiment used whole extract standardised to total hypericins, pseudohypericin was present — usually in excess — and its contribution is unresolved rather than excluded ^{19Reference 19Hammer KD · 2014Evidence for contributions of interactions of constituents to the anti-inflammatory activity of Hypericum perforatumView study →}.

None of this makes pseudohypericin the more important molecule. It makes the attribution sloppier than the literature’s phrasing suggests.

Pseudohypericin vs. Hypericin

The structural difference is small and its consequences are not. Hypericin carries two methyl groups on the phenanthroperylene skeleton; in pseudohypericin one of those methyls is hydroxylated to a hydroxymethyl (–CH₂OH) group ^{12,25Reference 12Karioti A · 2010Hypericins as potential leads for new therapeuticsView study →Reference 25Zheng X et al. · 2016Apoptosis of THP-1 macrophages induced by pseudohypericin-mediated sonodynamic therapy through the mitochondria-caspase pathwayView study →}. That single extra hydroxyl makes the molecule measurably more polar — and polarity is what drives most of the differences below.

Pharmacokinetically, the twins behave like different drugs. After the same extract dose, pseudohypericin appears in plasma faster (absorption lag ~0.4 h vs ~1.9 h for hypericin), distributes into roughly twice the volume (39.3 L vs 19.7 L at steady state), is cleared almost five times faster (43.3 vs 9.2 mL/min) and has a shorter elimination half-life (~24.8 h vs ~43.1 h) ^{1Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}. Systemic availability from LI 160 was roughly comparable — about 21% for pseudohypericin and 14% for hypericin ^{1Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}. The authors of the earliest of these studies put it bluntly: in spite of their structural similarities there are substantial pharmacokinetic differences between the two ^{2Reference 2Staffeldt B et al. · 1994Pharmacokinetics of hypericin and pseudohypericin after oral intake of the Hypericum perforatum extract LI 160 in healthy volunteersView study →}.

Pharmacodynamically, neither one wins across the board. This is the honest answer to “are they interchangeable?” — they are not, and the ranking flips depending on the target:

Comparison	Hypericin	Pseudohypericin	Winner
Thioredoxin reductase 1 inhibition (IC₅₀) 24Reference 24Sorrentino F et al. · 2011Hypericins and thioredoxin reductase: biochemical and docking studies disclose the molecular basis for effective inhibition by naphthodianthronesView study →	157.08 µM	4.40 µM	pseudohypericin, ~36×
Thioredoxin reductase 2 inhibition (IC₅₀) 24Reference 24Sorrentino F et al. · 2011Hypericins and thioredoxin reductase: biochemical and docking studies disclose the molecular basis for effective inhibition by naphthodianthronesView study →	43.12 µM	7.45 µM	pseudohypericin, ~6×
Protein kinase C inhibition (IC₅₀) 22Reference 22Takahashi I et al. · 1989Hypericin and pseudohypericin specifically inhibit protein kinase C: possible relation to their antiretroviral activityView study →	1.7 µg/mL	15 µg/mL	hypericin, ~9×
Survival in Friend-virus leukaemia (mice) 21Reference 21Lavie G et al. · 1989Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericinView study →	greater potency	active	hypericin
Light-activated inhibition of LPS-induced PGE₂ 14,16Reference 14Hammer KD et al. · 2008Pseudohypericin is necessary for the light-activated inhibition of prostaglandin E2 pathways by a 4 component system mimicking an Hypericum perforatum fractionView study →Reference 16Huang N et al. · 2011AnimalIdentification of anti-inflammatory constituents in Hypericum perforatum and Hypericum gentianoides extracts using RAW 264.7 mouse macrophagesView study →	not the driver	the driver	pseudohypericin
In-vitro photoirritant potential 13Reference 13Onoue S et al. · 2011In vitroIn vitro photochemical and phototoxicological characterization of major constituents in StView study →	positive	positive	no clean separation reported
Plasma clearance 1Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →	slow (9.2 mL/min)	fast (43.3 mL/min)	context-dependent

Both compounds are also chiral — the phenanthroperylene core is helically twisted — but their enantiomers interconvert with barriers low enough (≈97–101 kJ/mol) that neither is expected to exist as a single enantiomer under physiological conditions ^{29Reference 29Ciogli A et al. · 2010Determination of enantiomerization barriers of hypericin and pseudohypericin by dynamic high-performance liquid chromatography on immobilized polysaccharide-type chiral stationary phases and off-column racemization experimentsView study →}. This is a chemistry footnote rather than a pharmacological one, but it is one of the few places where the two molecules have been characterised side by side with real precision.

What It's Used For

Everything below is preclinical. Pseudohypericin has human pharmacokinetic data — good data, in fact — but no human efficacy data of any kind, and no trial has ever administered it as an isolate. The compound’s own literature is in-vitro cell work plus a small number of rodent studies, most of which ran it alongside hypericin.

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. Every score here is capped low by design: there is no human efficacy evidence for this isolate in any application.

01Anti-inflammatory (light-activated)Shaky32%Repeated macrophage bioassay-guided work naming pseudohypericin the lead of four constituents ^{14,15,16,17Reference 14Hammer KD et al. · 2008Pseudohypericin is necessary for the light-activated inhibition of prostaglandin E2 pathways by a 4 component system mimicking an Hypericum perforatum fractionView study →Reference 15Hammer KD et al. · 2007AnimalInhibition of prostaglandin E(2) production by anti-inflammatory Hypericum perforatum extracts and constituents in RAW264.7 mouse macrophage cellsView study →Reference 16Huang N et al. · 2011AnimalIdentification of anti-inflammatory constituents in Hypericum perforatum and Hypericum gentianoides extracts using RAW 264.7 mouse macrophagesView study →Reference 17Huang N et al. · 2012The inhibition of lipopolysaccharide-induced macrophage inflammation by 4 compounds in Hypericum perforatum extract is partially dependent on the activation of SOCS3View study →}

02Antiviral and virus inactivationShaky28%Murine retrovirus models (1988–89) + modern SARS-CoV-2 cell work ^{20,21,23Reference 20Meruelo D et al. · 1988Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericinView study →Reference 21Lavie G et al. · 1989Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericinView study →Reference 23Mohamed FF et al. · 2022Hypericum perforatum and its ingredients hypericin and pseudohypericin demonstrate an antiviral activity against SARS-CoV-2View study →}

03Photodynamic and sonodynamic cytotoxicityShaky22%In-vitro ROS/apoptosis assays; no in-vivo tumour model for the isolate ^{13,25Reference 13Onoue S et al. · 2011In vitroIn vitro photochemical and phototoxicological characterization of major constituents in StView study →Reference 25Zheng X et al. · 2016Apoptosis of THP-1 macrophages induced by pseudohypericin-mediated sonodynamic therapy through the mitochondria-caspase pathwayView study →}

04Enzyme inhibition (redox and kinase targets)Shaky20%Isolated-enzyme IC₅₀s + docking; one corrected rodent study ^{22,24,26Reference 22Takahashi I et al. · 1989Hypericin and pseudohypericin specifically inhibit protein kinase C: possible relation to their antiretroviral activityView study →Reference 24Sorrentino F et al. · 2011Hypericins and thioredoxin reductase: biochemical and docking studies disclose the molecular basis for effective inhibition by naphthodianthronesView study →Reference 26Chen XG et al. · 2018AnimalZafirlukast in combination with pseudohypericin attenuates spinal cord injury and motor function in experimental miceView study →}

Mechanisms

The two rows worth holding onto are the thioredoxin-reductase line and the protein-kinase-C line, because they point in opposite directions. Any statement that pseudohypericin is “the weaker hypericin” — or that the two are interchangeable — is contradicted by one of them.

Pharmacokinetics

This is the strongest human data on the molecule, and it is unusually clean because both naphthodianthrones were measured in the same subjects from the same capsules. In 13 healthy volunteers given single oral doses of the extract LI 160 (300, 900 or 1,800 mg, supplying 526, 1,578 or 3,156 µg of pseudohypericin), median peak plasma concentrations were 3.4, 12.1 and 29.7 µg/L, reached after an absorption lag of only ~0.4 h — against ~1.9 h for hypericin in the same subjects ^{1Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}. Median half-lives for absorption, distribution and elimination were 1.3, 1.4 and 24.8 h ^{1Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}. Pseudohypericin distributed into a steady-state volume of 39.3 L (hypericin: 19.7 L) and was cleared at 43.3 mL/min (hypericin: 9.2 mL/min); systemic availability from the extract was estimated at ~21% (hypericin ~14%) ^{1Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →}. Both compounds showed non-linear kinetics — AUC and peak concentration at the lowest dose were disproportionately low ^{1,2Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →Reference 2Staffeldt B et al. · 1994Pharmacokinetics of hypericin and pseudohypericin after oral intake of the Hypericum perforatum extract LI 160 in healthy volunteersView study →}. On 14 days of thrice-daily dosing, steady state was reached after about 4 days for pseudohypericin versus 7 for hypericin, with median trough levels of 4.8 µg/L (hypericin: 7.9 µg/L) — the accumulation gap that its faster clearance predicts ^{1,2Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →Reference 2Staffeldt B et al. · 1994Pharmacokinetics of hypericin and pseudohypericin after oral intake of the Hypericum perforatum extract LI 160 in healthy volunteersView study →}.

The consistent reading across both studies is that the extra hydroxyl buys polarity: faster in, wider distribution, faster out, less accumulation. Against that, brain penetration is poor. A review of St John’s wort constituents in the CNS concluded that the naphthodianthrones — along with hyperforin, quercetin and the biflavones amentoflavone and biapigenin — cross the blood–brain barrier badly in animals, reaching brain concentrations far below those active on neurotransmitter targets ^{28Reference 28Caccia S · 2009Caccia S, Gobbi M (2009). St. John’s wort components and the brain: uptake, concentrations reached and the mechanisms underlying pharmacological effects. Current Drug Metabolism. https://pubmed.ncbi.nlm.nih.gov/20214594/View study →}. Whatever pseudohypericin does, it is unlikely to be doing it centrally at oral extract doses.

Clinical Trials

There are no clinical trials of isolated pseudohypericin — not completed, not registered, not terminated. The human record consists of the pharmacokinetic and photosensitivity studies described above, all of which administered whole standardised extract and measured pseudohypericin as an analyte ^{1,2,3Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →Reference 2Staffeldt B et al. · 1994Pharmacokinetics of hypericin and pseudohypericin after oral intake of the Hypericum perforatum extract LI 160 in healthy volunteersView study →Reference 3Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}. Every efficacy claim here is in-vitro or rodent.

Last checked: July 2026.

Isolate vs. Plant Studies

The usual caution is that a plant’s effects get wrongly credited to one isolated molecule. Pseudohypericin’s problem is the mirror image: its contributions get credited to a different molecule.

Because St John’s wort is standardised to total hypericins and because hypericin is the named marker, extract-level findings — antiviral, photodynamic, phototoxic — are routinely narrated as hypericin’s. In the material actually dosed, pseudohypericin was present at roughly twice hypericin’s concentration ^{1,2Reference 1Kerb R et al. · 1996Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericinView study →Reference 2Staffeldt B et al. · 1994Pharmacokinetics of hypericin and pseudohypericin after oral intake of the Hypericum perforatum extract LI 160 in healthy volunteersView study →}. The correct statement about most extract work is therefore “the naphthodianthrone fraction did this”, not “hypericin did this”.

Where the isolate has been tested directly, the result cuts both ways. The anti-inflammatory programme deliberately isolated the four active constituents and found pseudohypericin the lead contributor ^{16Reference 16Huang N et al. · 2011AnimalIdentification of anti-inflammatory constituents in Hypericum perforatum and Hypericum gentianoides extracts using RAW 264.7 mouse macrophagesView study →} — but also found it necessary and not sufficient, i.e. the activity is a property of the combination ^{14,19Reference 14Hammer KD et al. · 2008Pseudohypericin is necessary for the light-activated inhibition of prostaglandin E2 pathways by a 4 component system mimicking an Hypericum perforatum fractionView study →Reference 19Hammer KD · 2014Evidence for contributions of interactions of constituents to the anti-inflammatory activity of Hypericum perforatumView study →}. The antiviral and photodynamic programmes tested pure compound and found real activity, but the follow-through (variants, mechanism, in-vivo models) generally used hypericin ^{23Reference 23Mohamed FF et al. · 2022Hypericum perforatum and its ingredients hypericin and pseudohypericin demonstrate an antiviral activity against SARS-CoV-2View study →}. And the enzyme work is cell-free, where potency figures are easy to obtain and hard to translate ^{24,28Reference 24Sorrentino F et al. · 2011Hypericins and thioredoxin reductase: biochemical and docking studies disclose the molecular basis for effective inhibition by naphthodianthronesView study →Reference 28Caccia S · 2009Caccia S, Gobbi M (2009). St. John’s wort components and the brain: uptake, concentrations reached and the mechanisms underlying pharmacological effects. Current Drug Metabolism. https://pubmed.ncbi.nlm.nih.gov/20214594/View study →}.

Its Role in the Plant

Pseudohypericin is not distributed evenly through Hypericum. Mass-spectrometry imaging of 17 in-vitro-cultured Hypericum species localised all four naphthodianthrones — protohypericin, hypericin, protopseudohypericin and pseudohypericin — co-localised in the dark glands of the eight hypericin-producing species, while the phloroglucinols (hyperforin, adhyperforin) sat separately in the translucent leaf cavities ^{8Reference 8Kucharíková A et al. · 2016Interspecific variation in localization of hypericins and phloroglucinols in the genus Hypericum as revealed by desorption electrospray ionization mass spectrometry imagingView study →}. The black dots along St John’s wort’s petal margins are, in effect, the naphthodianthrone organ; the “perforations” that give H. perforatum its name are the phloroglucinol one.

Content tracks development and tissue. Across ten wild Northern Turkish populations, pseudohypericin rose through the growing season and peaked at flowering, with fully opened flowers outperforming stems, leaves and other reproductive parts ^{6Reference 6Cirak C et al. · 2008Pseudohypericin and hyperforin in Hypericum perforatum from Northern Turkey: variation among populations, plant parts and phenological stagesView study →}. In a second Hypericum species followed through five phenological stages, hypericin and pseudohypericin both peaked at full flowering — at 0.71 and 1.78 mg/g dry weight respectively, again roughly a 1:2.5 ratio in pseudohypericin’s favour ^{7Reference 7Cirak C et al. · 2013Changes in the contents of main secondary metabolites in two Turkish Hypericum species during plant developmentView study →}. Interestingly, the same survey found population variability for pseudohypericin to be low — populations differed sharply in hyperforin but produced similar amounts of pseudohypericin ^{6Reference 6Cirak C et al. · 2008Pseudohypericin and hyperforin in Hypericum perforatum from Northern Turkey: variation among populations, plant parts and phenological stagesView study →}, hinting at tighter regulation of the naphthodianthrone pathway.

The plant’s associations matter too. Arbuscular mycorrhizal fungi raise naphthodianthrone content: inoculation with Rhizophagus intraradices and a mixed inoculum increased both hypericin and pseudohypericin in shoots ^{9Reference 9Zubek S et al. · 2012Hypericin and pseudohypericin concentrations of a valuable medicinal plant Hypericum perforatum L. are enhanced by arbuscular mycorrhizal fungiView study →}, and under low-phosphorus conditions a separate trial recorded increases of 166.8% for pseudohypericin and 279.2% for hypericin in flowers — while lowering hyperforin by 17.5% ^{10Reference 10Lazzara S et al. · 2017Arbuscular mycorrhizal fungi altered the hypericin, pseudohypericin, and hyperforin content in flowers of Hypericum perforatum grown under contrasting P availability in a highly organic substrateView study →}. Whatever role these pigments play for the plant, it is one that intensifies under symbiosis and nutrient stress.

Prevalence in Nature

Pseudohypericin is essentially a Hypericum molecule. It occurs only in the hypericin-producing members of the genus — roughly half the species surveyed in the imaging study lacked the dark glands entirely and made no naphthodianthrones at all ^{8Reference 8Kucharíková A et al. · 2016Interspecific variation in localization of hypericins and phloroglucinols in the genus Hypericum as revealed by desorption electrospray ionization mass spectrometry imagingView study →}, and some species (H. orientale, for instance) produce neither hypericin nor pseudohypericin ^{7Reference 7Cirak C et al. · 2013Changes in the contents of main secondary metabolites in two Turkish Hypericum species during plant developmentView study →}.

In H. perforatum itself, dried aerial parts have been reported from traces to 2.94 mg/g dry weight across wild populations, with flowers the richest tissue ^{6Reference 6Cirak C et al. · 2008Pseudohypericin and hyperforin in Hypericum perforatum from Northern Turkey: variation among populations, plant parts and phenological stagesView study →}. Other Turkish Hypericum species carry it too — H. lydium, where flowers are again the main repository ^{33Reference 33Çirak C et al. · 2015Population variability of main secondary metabolites in Hypericum lydium Boiss. (Hypericaceae)View study →}, and H. triquetrifolium, where the pattern inverts and leaves hold more of both naphthodianthrones than stems or reproductive parts ^{34Reference 34Ayan AK · 2008Variation of hypericins in Hypericum triquetrifolium Turra growing in different locations of Turkey during plant growthView study →}. Levels swing with provenance, altitude, harvest timing and cultivation conditions, and within-species variation can rival between-species variation ^{6,10Reference 6Cirak C et al. · 2008Pseudohypericin and hyperforin in Hypericum perforatum from Northern Turkey: variation among populations, plant parts and phenological stagesView study →Reference 10Lazzara S et al. · 2017Arbuscular mycorrhizal fungi altered the hypericin, pseudohypericin, and hyperforin content in flowers of Hypericum perforatum grown under contrasting P availability in a highly organic substrateView study →}. Extraction chemistry adds another layer: cold methanol recovers phloroglucinols completely but naphthodianthrones only partially, and full recovery of hypericins requires hot aqueous ethanol — the same treatment that destroys some hyperforin ^{11Reference 11Poutaraud A et al. · 2001Improved procedure for the quality control of Hypericum perforatum LView study →}. A protocol optimised for one fraction under-reports the other.

Beyond the plant, the compound turns up in the sawfly Tenthredo zonula, whose larvae specialise on Hypericum. HPLC of dissected larvae and prepupae found flavonoid glycosides genuinely sequestered into hemolymph and salivary glands, while the naphthodianthrones stayed largely in the digestive tract and excrement — and there, distinctively, pseudohypericin was generally present and hypericin was not ^{30Reference 30Crockett SL · 2011Flavonoid glycosides and naphthodianthrones in the sawfly Tenthredo zonula and its host-plants, Hypericum perforatum and H. hirsutumView study →}. Even an insect processes the two differently.

Discovery & Synthesis

Pseudohypericin was isolated from Hypericum perforatum in the same mid-twentieth-century wave of German natural-product chemistry that characterised hypericin; a 2010 review dates the first isolation of the two naphthodianthrones to roughly seventy years earlier ^{12Reference 12Karioti A · 2010Hypericins as potential leads for new therapeuticsView study →}. It has been studied as hypericin’s companion from the beginning, which is exactly why it is under-studied — the pair was described together, standardised together, and the marker convention that followed fixed hypericin as the named compound and pseudohypericin as the other half of the sum ^{4,5Reference 4Draves AH · 2003Analysis of the hypericin and pseudohypericin content of commercially available St John’s Wort preparationsView study →Reference 5Rückert U et al. · 2007Simultaneous determination of total hypericin and hyperforin in StView study →}.

Modern isolation is a separation problem rather than a synthesis problem. Analytical methods must resolve four closely related pigments — the two protoforms convert photochemically to the mature compounds on light exposure, which is why assays deliberately illuminate samples in amber vials before quantification ^{5,11Reference 5Rückert U et al. · 2007Simultaneous determination of total hypericin and hyperforin in StView study →Reference 11Poutaraud A et al. · 2001Improved procedure for the quality control of Hypericum perforatum LView study →}. Preparative routes exist precisely because the compound is hard to obtain in quantity — researchers say so explicitly: work on the naphthodianthrones’ biology is hindered by their low content in the plant ^{31Reference 31Karioti A et al. · 2009Rapid and efficient purification of naphthodianthrones from StView study →}. One route partitions a hydroalcoholic extract between solvents and then separates hypericin from pseudohypericin on Sephadex LH-60, reaching 98% total naphthodianthrone content ^{31Reference 31Karioti A et al. · 2009Rapid and efficient purification of naphthodianthrones from StView study →}; another couples expanded-bed adsorption chromatography to two-step countercurrent chromatography, recovering 5.6 mg of pseudohypericin and 2.2 mg of hypericin at ~95% purity from 40 mg of crude sample ^{32Reference 32Cai F et al. · 2015Combination of integrated expanded bed adsorption chromatography and countercurrent chromatography for the direct extraction and purification of pseudohypericin and hypericin from StView study →} — a yield ratio that is itself a reminder of which compound the plant makes more of. Total synthesis of the hypericin skeleton is established chemistry, but there is no commercial synthetic supply of pseudohypericin comparable to the synthetic hypericin used in photodynamic-therapy research.

Patents: not yet researched.

Toxicity & Safety

Pseudohypericin carries a moderate flag, matched to hypericin’s, and for the same reason: it is a photosensitising pigment that generates reactive oxygen species and cleaves DNA under illumination in vitro ^{13Reference 13Onoue S et al. · 2011In vitroIn vitro photochemical and phototoxicological characterization of major constituents in StView study →}. There is no dedicated toxicology package for the isolated molecule — no repeat-dose study, no genotoxicity battery, no reproductive dataset. The flag is a class inheritance, not a completed assessment.

Safety at a Glance

⚠️ Moderate toxicityPhotosensitivity

• Human photosensitivity at ordinary extract doses is weak. A placebo-controlled crossover study using up to 3,600 mg of extract (11.25 mg total hypericins — far above commercial doses) found no change in solar-simulated-light sensitivity and only a marginal increase in UV-A sensitivity at the highest dose ^{3Reference 3Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}.
• It is a genuine photosensitiser. Pseudohypericin was one of only three St John’s wort constituents with in-vitro photoirritant potential, generating singlet oxygen, peroxidising lipids and cleaving plasmid DNA under light ^{13Reference 13Onoue S et al. · 2011In vitroIn vitro photochemical and phototoxicological characterization of major constituents in StView study →}. High intakes, fair skin, sunbeds and concurrent photosensitising drugs or light-based therapies all shift the risk upward.
• No isolate toxicology exists. Everything known about safety comes from the extract or from the naphthodianthrone class. Absence of findings is not evidence of safety here.
• The famous drug interactions are not this molecule’s. St John’s wort’s CYP3A4/P-glycoprotein induction is driven by hyperforin, not the naphthodianthrones — but anyone taking the herb inherits those interactions regardless, and they are the single most important safety fact about the plant.

Full Safety & Interactions Detail

Photosensitisation — what is and is not established. The in-vitro case is solid: in a screen of 19 St John’s wort constituents, pseudohypericin was one of three (with hypericin and hyperforin) that produced photosensitised peroxidation of linoleic acid and photodynamic cleavage of plasmid DNA under light exposure, indicating photoirritant and photogenotoxic potential ^{13Reference 13Onoue S et al. · 2011In vitroIn vitro photochemical and phototoxicological characterization of major constituents in StView study →}. The human case is much softer. In a double-blind fourfold crossover, 13 volunteers took placebo or 900, 1,800 or 3,600 mg of LI 160 (0, 2.81, 5.62 and 11.25 mg total hypericins) and were irradiated with solar-simulated light and selective UV-A: solar-simulated-light sensitivity did not change and showed no dose trend, and UV-A sensitivity rose only after the highest dose, with marginal significance and no correlation with plasma total-hypericin concentration ^{3Reference 3Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}. Fifteen days of 600 mg three times daily produced small but statistically significant increases in both, compensable by cutting irradiation time 21% ^{3Reference 3Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →}. The authors were explicit that the study does not exclude phototoxicity above 11.25 mg total hypericins or plasma levels above 100 µg/L, and that pure compound might behave differently from extract, since other constituents may be protective ^{3Reference 3Brockmöller J et al. · 1997Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humansView study →} — a point the constituent screen echoes, having found that quercitrin quenched hyperforin’s singlet-oxygen generation, though not hypericin’s ^{13Reference 13Onoue S et al. · 2011In vitroIn vitro photochemical and phototoxicological characterization of major constituents in StView study →}.

Livestock hypericism. The classic photosensitisation syndrome in grazing animals eating Hypericum is a naphthodianthrone effect and involves pseudohypericin along with hypericin, at forage intakes far exceeding any human supplement dose. It is the reason the class carries the flag at all.

Interactions. Pseudohypericin itself is not the driver of St John’s wort’s serious pharmacokinetic interactions — PXR-mediated CYP3A4 and P-glycoprotein induction is hyperforin’s doing, and it is the mechanism behind the herb’s well-documented failures of oral contraceptives, ciclosporin, antiretrovirals, warfarin and many other drugs. The practical caution transfers anyway, because no one is exposed to pseudohypericin except through the herb. Additive caution is reasonable with other photosensitising agents (tetracyclines, fluoroquinolones, amiodarone, retinoids, furocoumarin-containing herbs) and with phototherapy or photodynamic therapy.

Reproductive note (prose only). No reproductive-toxicity dataset exists for isolated pseudohypericin. Decisions about St John’s wort in pregnancy or lactation belong to the herb page, where intake is actually decided — not to a molecule page for a compound nobody takes on its own.

Dosage

There is no dose for pseudohypericin. It is not sold, not supplemented and has never been administered to a human as a single agent. Exposure is entirely a by-product of taking St John’s wort, and the only figures worth quoting are the research doses that delivered it:

The last row is the practical one. Because standardisation reports the sum of hypericin and pseudohypericin, no St John’s wort label tells you how much of either you are getting — and the survey that checked found most labels substantially overstated the total anyway ^{4Reference 4Draves AH · 2003Analysis of the hypericin and pseudohypericin content of commercially available St John’s Wort preparationsView study →}. These are research and label figures, not a recommendation.

References

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2. Staffeldt B, Kerb R, Brockmöller J, Ploch M, Roots I (1994). Pharmacokinetics of hypericin and pseudohypericin after oral intake of the Hypericum perforatum extract LI 160 in healthy volunteers. Journal of Geriatric Psychiatry and Neurology. https://pubmed.ncbi.nlm.nih.gov/7857509/
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