Hypericin: A Comprehensive Encyclopedic Reference
1. Identity, Chemical Nature, and Natural Sources
1.1 Chemical Names and Classification
Hypericin, with the systematic chemical name 4,5,7,4′,5′,7′-hexahydroxy-2,2′-dimethylnaphtodianthrone, is a naturally occurring chromophore found in some species of the genus Hypericum, especially Hypericum perforatum L. (St. John's wort). It is one of the most important phenanthoperylene quinones extracted mainly from plants of the genus Hypericum, belonging to the sections Euhypericum and Campylosporus of Keller's classification.
Biochemically, hypericin is a polycyclic quinone possessing four hydroxyl groups that are positioned adjacent to two carbonyl groups. Owing to resonance of the molecule and the relatively short distance between oxygen atoms (approximately 2.5 Å), the hydroxyl hydrogen is capable of transferring between the hydroxyl oxygen and the carbonyl oxygen in the presence of fluorescent light. St. John's wort contains this large aromatic molecule, hypericin, twisted by steric interactions into the shape of a propeller. Hypericin is a photosensitive and red-colored naphthodianthrone.
A number of compounds isolated from St. John's wort possess pharmacologic activity, including naphthodianthrones (hypericin, pseudohypericin, protohypericin, protopseudohypericin, and cyclopseudohypericin), flavonoids (quercetin, rutin, and luteolin), hyperforin, several amino acids, and tannins. Hypericin always appears in nature accompanied by the chemically related compound pseudohypericin.
1.2 Botanical and Fungal Sources
Hypericum perforatum, commonly known as St. John's wort, is a flowering plant in the family Hypericaceae. It is a hairless, perennial herb with woody roots, yellow flowers marked by black glands, and leaves that appear perforated due to translucent glands, producing thousands of seeds per plant. H. perforatum is the type species of its genus, known for its historical use in folklore and traditional medicine.
Hypericin is found not only in species of the genus Hypericum, but also in some basidiomycetes (Dermocybe spp.) and endophytic fungi (Thielavia subthermophila). Hypericin is a prominent secondary metabolite mainly existing in the genus Hypericum, and has become a research focus for a long time owing to its extensively pharmacological activities, especially the anti-cancer, anti-bacterial, anti-viral and neuroprotective effects.
1.3 Localization Within the Plant
Hypericin and its derivatives are accumulated in special morphological structures, so-called dark nodules, occurring in the aerial parts of hypericin-producing Hypericum species. These specialized secretory structures are composed of clusters of secretory cells that develop early in ontogeny and persist in mature tissues, including leaves, stems, and flowers, and serve as morphological markers of hypericin accumulation. In H. perforatum, fully opened flowers contained greater hypericin levels than leaves and stems.
1.4 Biosynthesis
Emodin is the key precursor in the biosynthesis of hypericin, with complex synthesis pathways involving multiple steps. In chemical synthesis, emodin has been found to be the ultimate likely hypericin precursor. A major gene termed Hyp-1 encoding for hypericin (HyH) biosynthesis was cloned and characterized from Hypericum perforatum (St. John's wort) cell cultures. The gene coding POCP (hyp-1) has been originally reckoned as the gene capable of catalyzing conversion of precursor emodin to hypericin, although this presumption has never been definitively proved, and it is possible that different gene variants coding POCP homologous to hyp-1 may catalyze this reaction.
1.5 Common Preparations and Forms
Medicinally, the aerial parts (flowering tops and leaves) are used to produce extracts rich in hypericin, hyperforin, flavonoids, and xanthones. Standardized extracts used in clinical trials typically contain 0.3% hypericin, with solid dosage forms (tablets or capsules) providing daily hypericin doses between 0.288 mg and 0.636 mg; liquid tinctures and infusions are less commonly used for depression, as ethanolic extracts are preferred for central nervous system effects. The standardization of St. John's wort is normally based on hypericin and hyperforin contents. Hypericin is also produced as a synthetic compound for pharmaceutical use; synthetic hypericin (SGX301, trade name HyBryte) has been developed as a topical preparation for dermatological photodynamic therapy applications.
The strong hydrophobicity of hypericin makes it hard to absorb and its low bioavailability brings difficulties to clinical use; therefore, modification of hypericin to obtain hypericin derivatives with moderate solubility and satisfactory activity has been an area of ongoing research.
2. Traditional and Historical Use
2.1 Ancient Greek and Roman Medicine
Hypericum perforatum has been used medicinally since antiquity. It was commonly referred to as "Fuga daemonum" (the devil's scourge) since it was used to protect against demonic possession and "evil spirits." Historical information dating back to 400 B.C. tells the story of St. John's wort and its medicinal and spiritual evolution: the ancient Greeks and Romans noted the medical use of the plant.
Dioscorides, the foremost herbalist of the ancient Greeks, mentions four species of Hypericum — Uperikon, Askuron, Androsaimon, and Koris — which he recommended for sciatica "when drunk with 2 heim of hydromel (honey-water)." It was written about by many of the most significant herbalists of the ancient world, namely Hippocrates, Pliny, Dioscorides, and Galen.
2.2 Medieval Europe
From the time of the ancient Greeks down through the Middle Ages, the plant was considered to be imbued with magical powers and was used to ward off evil and protect against disease. The herb would be hung on house and stall doors on St. John's Feast Day to ward off evil spirits and to safeguard against harm and sickness to people and livestock. In other traditions it was burned in bonfires for the protection of crops along with other herbs believed to be magical.
Among the English herbalists of the past, St. John's wort was well regarded. Nicolas Culpeper, the renowned herbalist, stated that it "dissolves swelling and closes up the lips of wounds." The plant's common name derives from its tendency to bloom around St. John's Day (June 24th), and the red pigment released when the flowers are crushed was associated in Christian tradition with the blood of St. John the Baptist.
2.3 Traditional Chinese Medicine and Islamic Medicine
Hypericum perforatum, known as Saint John's wort (SJW), has been used in different systems of traditional medicine such as Chinese traditional medicine, Greek traditional medicine, and Islamic traditional medicine. In traditional Chinese medicine (TCM), SJW is known as Guan Ye Lian Qiao, with aliases including Xiao Zhong Huang and Xiao Dui Yue Cao (Guizhou), and various other regional names across Chinese provinces.
2.4 Eclectic and Early American Medicine
While its internal use for mood disorders is well-known in the West, St. John's wort has long been used topically over the centuries and was addressed by many significant herbalists of the ancient world. Early American pharmacists and Eclectic physicians recognized its therapeutic value and applied the herb externally as an ointment for bruises and ulcers. Due to its usefulness, it is found in the official pharmacopoeias of numerous countries including Russia, Romania, France, Czechoslovakia, and Poland.
2.5 Traditional Purposes
As a practical folk-remedy, the plant has been used widely to heal wounds, remedy kidney troubles, and alleviate nervous disorders, even insanity. The aerial parts of the plant, containing hypericin and its related naphthodianthrones, were prepared as oil macerations (infused oil of the red-colored flowers in olive oil), teas, tinctures, and poultices, and were applied both internally and externally. The bright red color of the oil infusion — directly attributable to the presence of hypericin pigments — was considered a sign of the plant's therapeutic virtue in many folk traditions.
3. Key Constituents and Active Compounds
3.1 Principal Naphthodianthrones
The principal bioactive naphthodianthrones of Hypericum perforatum directly associated with hypericin include hypericin itself, pseudohypericin, protohypericin, protopseudohypericin, and cyclopseudohypericin. Extracts of St. John's wort are used in treatment of depression and contain various substances with the naphthodianthrones hypericin and pseudohypericin as characteristic ingredients. Pseudohypericin, a structural analogue, differs from hypericin by the substitution of one methyl group with a hydroxymethyl group and is present in the plant in comparable or slightly higher concentrations than hypericin itself.
3.2 Relationship to Hyperforin
For use as an antidepressant, St. John's wort is standardized to the content of hypericin, but this molecule was recently found not to be the active ingredient for that indication. A totally different bicyclic molecule with a complex substitution pattern — hyperforin — was then studied as the causative agent. Hyperforin and hypericin have been studied most extensively in the neuropharmacology of the plant. Although hypericin was originally thought to be the major active component for St. John's wort in depression, it is now believed that hyperforin and related compounds are mostly responsible for St. John's wort's effect on mood.
4. Mechanisms of Action
4.1 Photodynamic Mechanism (Light-Dependent)
Photodynamic therapy (PDT) is an established anticancer treatment employing a phototoxin (photosensitizer), visible light, and oxygen. The latter is photochemically converted into reactive oxygen species, which are highly toxic to the cells. Hypericin, a natural pigment of Hypericum plants, is prominent among photosensitizers. The unique perylenequinone structure of hypericin is responsible for its intriguing multifaceted photochemical cytotoxicity.
The diverse photodynamic action of hypericin targets a range of subcellular organelles, most importantly the mitochondria and the endoplasmic reticulum (ER)-Golgi complex. Hypericin exerts its phototoxicity through intricate mechanisms, implicating key proteins, vital enzymes, organelle membranes, and changes in cellular homeostasis. Depending on drug and light administration conditions, this leads to cell death, which occurs mainly by the induction of apoptosis and/or necrosis.
Another benefit of hypericin in tumor treatment is its ability to stimulate the generation of reactive oxygen species (ROS). Hypericin can also activate the caspase-dependent pathway, which leads to the death of cancer cells. Hypericin mainly accumulates in the membranes of the endoplasmic reticulum, lysosomes, Golgi apparatus, and mitochondria due to its hydrophobic character.
Recent interest in hypericin is provoked by the discovery that it possesses extremely high toxicity towards certain viruses, notably the class of enveloped viruses that includes human immunodeficiency virus (HIV), and toward tumors, and that this toxicity absolutely requires light.
4.2 Antidepressant Mechanisms (Light-Independent)
Hypericin, one of the major antidepressant constituents of St. John's wort, was shown to exert antidepressant effects by affecting cerebral CYP enzymes, serotonin homeostasis, and neuroinflammatory signaling pathways. However, its exact mechanisms remain unknown.
An early hypothesis proposed monoamine oxidase (MAO) inhibition. An inhibition of MAO could be shown at concentrations of hypericin up to 10⁻³ mol/L, while COMT inhibition could not be shown for hypericin alone. The MAO inhibiting fraction contained hypericins as well as flavonols, the COMT-inhibition fraction being mainly flavonols and xanthones. However, the concentrations of inhibition shown might not be sufficient to explain the clinically proven antidepressive effect of Hypericum, particularly with regard to the inhibition of MAO activity.
Unless the active compounds are present in much larger quantities than hypericin, or are concentrated in synaptic terminals, plasma blood levels of hypericin are several orders of magnitude below the concentrations needed to inhibit MAO. Research into epitranscriptomic mechanisms has also been pursued: hypericin was found to ameliorate depressive-like behavior in a mouse chronic mild stress model, and hypericin treatment was shown to upregulate the expression of m6A-modifying enzymes METTL3 and WTAP in the hippocampi of these mice. These are animal findings and their clinical significance is not yet established.
4.3 Anticancer and Antiangiogenic Mechanisms (Light-Independent)
As the accumulation of hypericin is significantly higher in neoplastic tissue than in normal tissue, it can be used in photodynamic diagnosis (PDD) as an effective fluorescence marker for tumor detection and visualization. In addition, light-activated hypericin acts as a strong pro-oxidant agent with antineoplastic and antiangiogenic properties, since it effectively induces the apoptosis, necrosis, or autophagy of cancer cells.
Several light-independent actions of hypericin have also been described, even though its effects in the dark have not been studied as intensively as those of photoactivated hypericin. Various experimental studies have revealed no cytotoxicity of hypericin in the dark; however, it can serve as a potential antimetastatic and antiangiogenic agent.
4.4 Protein Kinase Inhibition
Hypericin and pseudohypericin have been found to inhibit the important regulatory enzyme, protein kinase C (IC₅₀ of 1.7 µg/ml and 15 µg/ml, respectively). Receptor tyrosine kinase activity of epidermal growth factor is also inhibited by hypericin. These latter effects have been linked to both the antiviral and antineoplastic activities.
4.5 Signaling Pathway Modulation
Hypericin modulates key signaling pathways like NF-κB and MAPK, reducing chronic inflammation and making it relevant in treating autoimmune and infectious skin conditions.
5. Scientific Evidence by Area of Use
5.1 Depression and Mood Disorders
St. John's wort extracts standardized for hypericin content have been extensively studied in clinical settings. In a double-blind, randomized, placebo-controlled trial with 375 patients, investigators examined the antidepressant efficacy and safety of 300 mg three times daily of hydroalcoholic Hypericum perforatum extract WS 5570. WS 5570 is a hydroalcoholic extract with standardized contents of 3%–6% hyperforin and 0.12%–0.28% hypericin, presented in film-coated tablets, each containing 300 mg of the extract.
A meta-analysis of randomized controlled trials comparing Hypericum perforatum to SSRIs found that a total of 13 RCTs were included (n at least 1,754; range 30 to 258 participants). There was no significant difference between comparisons for the main effectiveness outcomes, including clinical response, remission, mean reduction in Hamilton Rating Scale for Depression score from baseline, and any adverse events. Clinical studies have shown that St. John's wort is effective for treating mild to moderate depression at daily doses of 600 mg to 1200 mg of standardized extract. In a large randomized trial, both 600 mg once daily and 1200 mg (600 mg twice daily) were found to be safe and more effective than placebo, with the higher dose group showing a slightly higher remission rate after 6 weeks of treatment.
Evidence characterization: For use as antidepressant, St. John's wort is standardized to the content of hypericin, but this molecule was recently found not to be the active ingredient for the antidepressant effect. The available clinical evidence pertains to whole-plant or multi-constituent extracts. Whether hypericin itself, as an isolated compound, drives clinical antidepressant outcomes in humans has not been established. Evidence for the whole extract in mild-to-moderate depression is generally rated as moderate-to-good. Evidence for severe depression is weaker and inconsistent.
5.2 Antiviral Activity — HIV
Hypericin, the active compound in St. John's wort, has antiretroviral activity in vitro. Based on these laboratory findings, clinical trials were conducted. To date, six clinical trials have been conducted and/or initiated with orally and intravenously administered hypericin. These include a bioavailability study in 10 healthy subjects, two trials (ACTG 150 and ACTG 258) sponsored by the National Institute of Allergy and Infectious Disease, a dose-determining study in HIV-infected patients to determine the maximum tolerated dose, a trial for hepatitis C patients, and a clinical trial for patients with malignant brain gliomas.
The ACTG trials enrolled 30 HIV-infected patients with CD4 counts less than 350 cells/mm³. Intervention consisted of intravenous hypericin at 0.25 or 0.5 mg/kg of body weight twice weekly or 0.25 mg/kg three times weekly, or oral hypericin at 0.5 mg/kg daily. Of the 30 patients who were enrolled, 16 discontinued treatment early because of toxic effects. Severe cutaneous phototoxicity was observed in 11 of 23 (48%) evaluable patients, and dose escalation could not be completed. Hypericin caused significant phototoxicity and had no antiretroviral activity in the limited number of patients studied.
Evidence characterization: The clinical antiviral data for hypericin against HIV is negative at the doses tested. Severe phototoxicity precluded dose escalation, and no antiretroviral activity was demonstrated in the Phase I trials. The promising in vitro findings did not translate to clinical benefit in the trials conducted.
5.3 Antiviral Activity — Hepatitis C Virus (HCV)
Hypericin is a natural derivative of the common St. John's wort plant, Hypericum perforatum. It has in vitro activity against several viruses, including bovine diarrhea virus, a pestivirus with structural similarities to hepatitis C virus (HCV). A phase I dose escalation study was conducted to determine the safety and antiviral activity of hypericin in patients with chronic HCV infection. The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day.
Hypericin given orally in doses of 0.05 and 0.10 mg/kg/day caused considerable phototoxicity and had no detectable anti-HCV activity in patients with chronic HCV infection. Five of 12 subjects receiving the 0.05-mg/kg/day dosing schedule and 6 of 7 subjects receiving the 0.10-mg/kg/day dosing schedule developed phototoxic reactions. No other serious adverse events associated with hypericin use occurred. Because uncomfortable photosensitivity reactions occurred at both dosage levels and no antiviral effect was detected in either dose cohort, the decision was made to stop enrollment early.
Evidence characterization: Clinical evidence for antiviral activity against HCV is negative at the doses evaluated. The trial was halted early due to phototoxicity and absence of measurable antiviral effect.
5.4 Photodynamic Therapy for Cutaneous T-Cell Lymphoma (CTCL)
SGX301 is a first-in-class photodynamic treatment with an active ingredient of synthetic hypericin that is applied topically and then activated using fluorescent light after 16 to 24 hours. SGX301 has been granted orphan drug and fast track designations from the FDA, as well as orphan designation from the European Medicines Agency.
The FLASH (Fluorescent Light Activated Synthetic Hypericin) trial is a multicenter, randomized, double-blind, placebo-controlled Phase III study exploring the use of SGX301 in patients with patch/plaque phase CTCL (NCT02448381). The trial enrolled 169 patients with stage IA-IIA CTCL and at least 3 evaluable lesions, who were randomized 2:1 to receive either SGX301 or placebo.
In the first double-blind treatment cycle, 50 patients received placebo and 116 were treated with SGX301 (0.25% synthetic hypericin). The findings for cycle 1 showed that at 8 weeks, 16% of patients in the SGX301 arm achieved at least a 50% reduction in their lesions per the CAILS score. Compared with placebo, SGX301 induced improved responses in terms of the Composite Assessment of Index Lesion Score (CAILS) at 8 weeks during the first cycle of treatment (P = 0.04).
In the open-label extension study, the open-label, investigator-initiated study of SGX301 is currently evaluating its extended treatment for up to 12 months in patients with early-stage CTCL. To date, 9 patients have been enrolled, with 6 completing at least 18 weeks of therapy. Of these patients, 5 have achieved treatment success, defined as a 50% or greater improvement in the cumulative modified composite assessment of index lesion severity score. Three patients responded within the first 12 weeks, and 2 reached a complete response by week 18.
In the Phase 2 trial preceding the FLASH study, topical SGX301 was tested in both CTCL and psoriasis patients. Following six weeks of twice-weekly therapy of 12 low dose treated lesions, 5 (41.7%) responded to SGX301 treatment. Of 11 high-dose treated lesions, 6 (54.5%) responded to SGX301 treatment. Of 12 placebo ointment treated lesions, 1 (8.3%) resolved with only placebo treatment, and the difference in response was statistically significant (p <0.04). Among psoriasis patients, 5 of 12 (41.7%) total low dose treated lesions responded to SGX301 treatment; 5 of 12 (41.7%) total high dose treated lesions responded; and 0 of 12 (0%) placebo ointment treated lesions resolved, and the difference in response was statistically significant (p <0.02).
This approach avoids the risk of secondary malignancies often associated with ultraviolet-based therapies. However, experts are still unsure about its efficacy, absorption, and effect on heart function parameters in patients who require greater SGX301 exposure. A second confirmatory study (FLASH2) has been planned following FDA review.
Evidence characterization: The Phase III FLASH trial showed a statistically significant but numerically modest response at 8 weeks (16% vs. 4% in placebo), and the FDA has requested a confirmatory trial before approval. Evidence is promising but awaits further Phase III confirmation.
5.5 Photodynamic Therapy for Skin Cancer (Preclinical)
Hypericin exhibited a higher phototoxic reaction in cancer cells compared to normal keratinocytes after irradiation. Cancer cells demonstrated increased and selective uptake of hypericin. Apoptosis was observed in squamous cell carcinoma (SCC-25) and melanoma (MUG-Mel2) cells following PDT. These findings suggest that hypericin-based PDT is a promising and less invasive approach for treating skin cancer. The higher phototoxic reaction, selective uptake by cancer cells, and observed proapoptotic properties support the promising role of hypericin-based PDT in skin cancer treatment.
Evidence characterization: This evidence is entirely preclinical (in vitro). No clinical trials have been completed for hypericin-PDT in melanoma or squamous cell carcinoma as of the current literature.
5.6 Pain Conditions
Preclinical animal studies demonstrated the ability of low doses of SJW dry extracts (0.3% hypericins; 3–5% hyperforins) to induce antinociception, to relieve from acute and chronic hyperalgesic states, and to augment opioid analgesia. Clinical studies (homeopathic remedies, dry extracts) highlighted dental pain conditions as a promising SJW application. In vivo and in vitro studies showed that the main components responsible for the pain-relieving activity are hyperforin and hypericin.
Evidence characterization: Evidence for pain relief is largely from animal and in vitro studies, with limited clinical data. Evidence is preliminary and insufficient to draw firm conclusions for hypericin specifically.
5.7 Immunomodulatory and Anti-inflammatory Effects
Hypericin-PDT has not only a cytotoxic effect but, used in sublethal doses, also presents immunomodulatory properties. These may be an advantage of hypericin-PDT when used in the treatment of persistent skin inflammation connected with the release of pro-inflammatory cytokines resistant to conventional treatment methods.
Evidence characterization: Immunomodulatory findings are primarily from in vitro cell culture studies. Clinical evidence for anti-inflammatory efficacy of hypericin as an isolated compound is not established.
5.8 Necrosis Targeting and Diagnostic Imaging
A strong affinity of hypericin for necrotic tissue was discovered. Thus, hypericin and its radiolabeled derivatives have been recently investigated as potential biomarkers for the non-invasive targeting of tissue necrosis in numerous disorders, including solid tumors. This property has led to research into radiolabeled hypericin derivatives for use as tumor necrosis-targeting agents in nuclear medicine imaging, though this research is at a preclinical and early-phase stage.
6. Body Systems and Health Areas Associated with Hypericin
- Central Nervous System / Mood: Hypericin is one of the major antidepressant constituents of St. John's wort, shown to exert antidepressant effects by affecting cerebral CYP enzymes, serotonin homeostasis, and neuroinflammatory signaling pathways.
- Oncology / Dermatology: Hypericin is well-known as a potent natural photosensitizing agent with great potential in anticancer photodynamic therapy (PDT) and photodynamic diagnosis (PDD).
- Virology: Light-activated hypericin is considered to be an effective antiviral agent in in vitro settings, though clinical translation has been challenging.
- Microbiology: Besides its antineoplastic action, light-dependent in vitro fungicidal and bactericidal effects have also been reported.
- Skin / Wound Healing: Hypericum perforatum extracts have been used for thousands of years to treat abrasions, cuts, and wounds.
- Immune System: Hypericin modulates key signaling pathways like NF-κB and MAPK, reducing chronic inflammation.
7. Pharmacokinetics
7.1 Absorption and Bioavailability
After oral consumption, hypericin absorption is relatively slow, and its overall oral bioavailability is poor, estimated at 14% to 21%. The time to reach peak plasma concentration (Cmax) after a single dose is prolonged, often taking approximately 8.1 hours. These figures are consistent with a single-dose pharmacokinetic study that recorded an area under the curve (AUC₀–∞) of 75.96 h × ng/ml, a maximum plasma concentration (Cmax) of 3.14 ng/ml, and a time to reach Cmax (tmax) of 8.1 hours.
7.2 Distribution and Half-Life
Hypericin is eliminated slowly, exhibiting a long half-life that typically ranges from 24 to 43 hours. This slow clearance requires consistent daily intake to build up and maintain stable concentrations in the bloodstream, known as steady-state. Steady-state is usually achieved after four to seven days of continuous dosing. In a clinical study of oral hypericin in HCV patients, the pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 h, respectively, for the doses of 0.05 and 0.1 mg/kg).
The pharmacokinetics of hypericin following IV bolus administration have been investigated in mice (4.5 mg/m²), rhesus monkeys (2.5 mg/kg), and cynomolgus monkeys (2 mg/kg). The average elimination half-life was reported to be 36.7 hours in the cynomolgus monkey, 40.3 hours in the mouse, and 55.8 hours in the rhesus monkey.
7.3 Bioavailability Challenges
The strong hydrophobicity of hypericin makes it hard to absorb and its low bioavailability brings difficulties to clinical use. Therefore, it is very important to modify hypericin to obtain hypericin derivatives with moderate solubility and satisfactory activity. Research into nanoparticle encapsulation, cyclodextrin complexation, and polymer-based delivery systems (such as PVP-hypericin) has been undertaken to address these limitations.
8. Dosage Forms and Reported Dosages
Dosages of hypericin in clinical research have been reported in the context of both whole-extract preparations and isolated/synthetic compound studies:
- Standardized oral extract (depression studies): Standardized extracts used in clinical trials typically contain 0.3% hypericin, and solid dosage forms (tablets or capsules) provide daily hypericin doses between 0.288 mg and 0.636 mg.
- High-dose pharmacokinetic study (oral): In the multiple-dose part of a pharmacokinetic study, 50 volunteers received 600 mg hypericum extract three times daily, with a daily dose of 5.6 mg of total hypericin.
- HIV clinical trials (oral and IV): Intervention consisted of intravenous hypericin at 0.25 or 0.5 mg/kg of body weight twice weekly or 0.25 mg/kg three times weekly, or oral hypericin at 0.5 mg/kg daily.
- HCV clinical trial (oral): The first 12 patients received an 8-week course of 0.05 mg of hypericin per kg of body weight orally once a day; 7 patients received an 8-week course of 0.10 mg/kg orally once a day.
- Topical SGX301 (CTCL): In the FLASH trial, 116 patients were treated with SGX301 at 0.25% synthetic hypericin. This photosensitizer is topically applied to skin lesions and activated by safe, visible light approximately 24 hours later.
- Phase 1 topical safety study: In a Phase 1 trial of topical SGX301, 15 healthy subjects had SGX301 applied to the skin in concentrations of 0.02% to 0.5% synthetic hypericin in hydrophilic ointment under occlusion for 2 to 24 hours, followed by exposure to 20-watt fluorescent lights yielding a total exposure ranging from 4 to 8 Joules/cm².
- Bioavailability study (single dose): A single-dose bioavailability study was conducted in 10 healthy subjects. Five subjects received 1.25 mg/kg orally and 0.25 mg/kg intravenously, while the other five subjects received 2.0 mg/kg orally and 0.375 mg/kg intravenously.
9. Safety, Adverse Effects, and Drug Interactions
9.1 Phototoxicity
A major safety concern related to hypericin's mechanism is photosensitivity, or phototoxicity. Because hypericin is a photosensitizer, it makes the skin more susceptible to sun damage, particularly when exposed to UV-A light. This property was demonstrated clinically in multiple trials. Of the 30 HIV patients enrolled in ACTG 150 and 258, 16 discontinued treatment early because of toxic effects. Severe cutaneous phototoxicity was observed in 11 of 23 (48%) evaluable patients, and dose escalation could not be completed.
Hypericin and pseudohypericin were shown to cause phototoxicity in cell culture and in animals. A placebo-controlled randomized clinical trial with monitoring of hypericin and pseudohypericin plasma concentration was performed to evaluate the increase in dermal photosensitivity in humans after application of high dose hypericum extracts. There was no correlation between total hypericin plasma concentrations and photosensitivity in that study, indicating the complexity of the phototoxic response. In the topical Phase 1 trial, delayed erythema was observed in one-third of subjects using 0.1% SGX301 under occlusion for 24 hours following exposure to 4 Joules/cm² of light, while both immediate and delayed erythema occurred in all subjects with 0.1% SGX301 under occlusion for 24 hours followed by administration of 8 Joules/cm² of light.
Photocytotoxicity was responsible for the premature termination of a clinical trial that tested the efficacy of hypericin against HIV in AIDS patients.
9.2 Drug Interactions — CYP Enzyme Induction
St. John's wort has been found to have an overall high risk of drug interaction because it is a potent inducer of both cytochrome P-450 enzymes and intestinal P-glycoprotein. The primary driver of this induction is hyperforin, not hypericin. The probable reason for the drug interaction effects is the induction of the metabolic enzyme CYP3A4 and/or the P-gp transporter by hyperforin; however, considering the potential of hypericin to induce the expression of some ABC efflux pumps, this secondary metabolite might also contribute to negative drug interactions with St. John's wort.
Hypericin can induce the expression of some ABC transporters, which are often associated with the multidrug resistance (MDR) of cancer cells. Moreover, the hypericin-mediated attenuation of the cytotoxicity of some chemotherapeutics was revealed. Therefore, hypericin might represent another St. John's wort metabolite that is potentially responsible for negative herb–drug interactions.
9.3 Serotonin-Related Interactions
The mechanism by which hypericin may influence serotonin mirrors that of selective serotonin reuptake inhibitors (SSRIs) but also introduces the potential for serotonin syndrome when combined with other serotonergic agents. This risk is particularly relevant when St. John's wort preparations are co-administered with prescribed antidepressants or other serotonergic drugs.
9.4 Multidrug Resistance Concerns in Cancer Treatment
Considering the potential of hypericin to induce the expression of some ABC efflux pumps, hypericin might contribute to negative drug interactions with St. John's wort. Therefore, a much broader spectrum of antineoplastic drugs might exist, including various chemotherapeutic agents or photosensitizers, whose action might be altered due to the presence of hypericin.
9.5 Tolerability in Clinical Extract Studies
Across studies, St. John's wort was generally well tolerated, with a lower incidence of side effects compared to conventional antidepressants. There was no significant difference between comparisons for the main adverse events outcomes between Hypericum perforatum extract and SSRIs in randomized controlled trials. These observations pertain to standardized whole extracts containing low doses of hypericin (in the range of 0.3–5.6 mg/day total hypericin), rather than high-dose isolated hypericin preparations.
10. Research Directions and Current Status
In recent decades, hypericin has been intensively studied for its broad pharmacological spectrum. Among its antidepressant and light-dependent antiviral actions, hypericin is a powerful natural photosensitizer that is applicable in the photodynamic therapy of various oncological diseases.
Widespread attention to the antiviral and anti-tumor properties of hypericin has spurred investigations of the chemical synthesis and biosynthesis of this unique compound. However, the synthetic strategies are challenging for organic and biological chemists. The SARS-CoV-2 pandemic prompted renewed investigation of hypericin's antiviral properties: researchers evaluated hypericin's antiviral efficacy against SARS-CoV-2, both in the dark and upon photoactivation, with binding to viral particles directly visualized with fluorescence microscopy and a strong affinity for the viral particles, most likely for the viral envelope, measured spectroscopically. These findings are preclinical.
The most advanced clinical development of hypericin remains its topical synthetic form SGX301 (HyBryte) for CTCL, which has received orphan drug and fast-track designations from the FDA and orphan designation from the EMA. Under light illumination, hypericin displays antiproliferative and cytotoxic effects on many tumor cell lines. These properties, together with minimal dark toxicity, tumor selectivity, and high clearance from the host body, make hypericin a very promising agent in photodynamic therapy of cancer.
References
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