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Hypericum perforatum: Traditional uses, clinical trials, and drug interactions

Hypericum perforatum (Hypericaceae), 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. The plant and its active constituents such as hyperforin and hypericin have a wide range of medicinal uses, particularly as anti-depressant, wound-healing, and antibacterial agents. In recent decades, many clinical trials have been performed to investigate the safety and efficacy of this medicinal plant. However, to the best on our knowledge, there is no comprehensive review article in this regard. In the current study, we aim to have a comprehensive review of the clinical trials of SJW to evaluate its efficacy and safety as well as its application in traditional medicine. Clinical studies investigating the safety, interactions, and efficacy of SJW were identified and summarized, including contributions from 2000 until December 2021. According to the results, these clinical studies were divided into three main categories based on the type of disease: psychiatric, endocrine, and skin problems. Important details of the studies, including the type and duration of the study, the type and percentage of the effective compounds or the extract used, the number of patients, and the obtained results were also discussed. In addition, co-administration and drug interaction of SJW with other drugs were summarized. SJW is a valuable medicinal plant, especially for psychiatric disorders. However, precautions should be taken while administrating the plant.


Introduction
The Hypericum Tourn. ex L. is a cosmopolitan genus with 508 species worldwide. Hypericum dogonbadanicum Assadi is the only endemic species of the genus in Iran (1). The most well-known species of this genus is Hypericum perforatum L. (Hypericaceae), known as St. John's wort (SJW). It is an herbaceous perennial plant native to western Asia, Europe, and northern Africa (2). The plant has been given its common name due to blooming in midsummer around St. John the Baptistʼs day in June. Klamath weed, Tipton's weed, Rosin-rose, Goat weed, etc., are the less common names (3).
It is a very popular traditional herbal medicine due to its wide range of applications, including treatment of skin problems such as wound healing in burns, stomach ulcers, biliary disorders, inflammation of the bronchi and genitourinary system, colds, migraines, headache, diabetes mellitus, and obesity (4,5). However, the reason for its popularity can be attributed to the effectiveness of this plant in the treatment of mild to moderate depression (6).
Because of its wide therapeutic effects, many clinical trials have evaluated the efficacy and safety of SJW. Since there is not a recent review on the clinical trials studying the efficacy and safety of SJW, we aim to have a comprehensive review of the clinical trials studying the interactions, safety, and efficacy of SJW and its related compounds and preparations in the present study.

Greek medicine
Ancient Greek physicians such as Dioscorides, Theophrastus, and Galen used SJW to treat diseases such as snake or reptile bites, gastrointestinal distress, menstrual cramping, melancholy, depression, ulcers, superficial wounds, burns, and sciatica (9). SJW oil made with flowering tops of this plant was also used by surgeons to disinfect wounds and also heal bruises (10).

Islamic traditional medicine
Well-known physicians of Islamic traditional medicine, such as Avicenna, Râzi (Rhazes), Anṭâki, Herawi, Ansâri Shirazi, Ghassâni, Ibn Beyṭâr, and ʿAqili have mentioned various therapeutic applications for SJW. According to the contents written in the reference books of Islamic traditional medicine, the poultice of SJW has been used to heal infectious wounds, burns, and bruises (11)(12)(13)(14)(15)(16). Laxative effects for the seeds of SJW have also been mentioned in several references (11,12,16). Other uses for this plant include improving sciatica (11,12,(15)(16)(17)(18). Ibn Sinâ (Avicenna) prepared a decoction of this plant in wine and prescribed it for forty consecutive days to alleviate this disease (13). Also, topical application of its combined poultice with olive oil has been used in the treatment of paralysis with the curvature of the back of the neck (16,19). In general, other common uses of SJW in Islamic traditional medicine include diuretic, emmenagogues, antipyretic (especially malarial fever), antispasmodic, anti-gout, and anti-hemorrhoidal effects (11,(14)(15)(16)(17)19). In addition to the previous cases, SJW has been used in the treatment of jaundice, polydipsia, severe swelling, urinary stones, and even induction of abortion (11)(12)(13)19).

Hypericum perforatum Pharmacological effects of hypericum perforatum
A large number of in vitro and in vivo studies have investigated the therapeutic effects of SJW and its constituents. In the following paragraphs, we will briefly discuss their therapeutic effects.

Anti-depressant effects
Hypericin was introduced as one of the main possible active compounds. Inhibiting the monoamine oxidase enzyme is a possible mechanism of action for hypericin (22). SJW is also able to inhibit the reabsorption of dopamine, serotonin, noradrenaline, L-glutamate, and γ-aminobutyric acid in nerve terminals (23). Moreover, several flavonoids such as quercetin, luteolin, and kaempferol have shown anti-depressant effects (24).

Analgesic effects
In a review study on the therapeutic effects of SJW, low doses of dry extract of the plant exhibited analgesic effects and strengthened the effect of opioids in acute and chronic animal pain models. In vitro and in vivo studies show that the compounds hypericin and hyperforin are responsible for such effects (25).

Metabolic syndrome improving effects
In the diet-induced obesity and metabolic syndrome animal model of study, administration of SJW extract could improve glucose and fat metabolism and insulin resistance (26). In addition, in a hyperlipidemia animal model of study, the extract of this plant could reduce LDL-CH and total cholesterol without affecting triglycerides and HDL-CH, improve liver parameters and decrease oxidative damage including malondialdehyde, aspartate aminotransferase, and alanine aminotransferase (27).

Antimicrobial effects
Antimicrobial effects have also been reported for the   (29). Moreover, studies have reported antiparasitic effects for hypericin and hyperforin against malaria and leishmaniosis parasites (30). Hypericin is also effective against viral protease that is well known for its activity against several viruses namely, herpes simplex, bronchitis, influenza A, and human immune (31,32).

Antineoplastic effects
Hypericin is reported to have remarkable anti-neoplastic effects among all the compounds isolated from SJW. Recently, it has been applied as a phototherapy drug helping to treat cancer (33). Sensitivity to light from hypericin mainly affects the mitochondria or endoplasmic reticulum-Golgi complex leading to cell apoptosis (34). Hypericin has been shown to have activities against a range of cell lines including melanoma and breast cancerous cells. Exfoliation of phosphatidylserines, cell shrinkage, loss of cell membrane integrity, and caspase-dependent, as well as independent apoptotic modes, are some mechanisms of action (35). In addition, hyperoside, another phytochemical constituent from this plant has shown to have inhibitory effects against cancerous cell lines by inducing apoptosis and repressing cell proliferation (36).

Wound healing effects
In a review of topical products containing plants, researchers have suggested SJW products containing oil and tincture of the plant for the treatment of mild wounds, burns, sunburn, scratches, bruises, heat burns, fire, muscle aches, and other problems (37). Synergistic effects of hypericin, isoquercitrin, rutin,hyperoside, and epicatechin may cause wound healing effects of this plant (37,38). In vitro studies show that the possible mechanism of wound healing is by increasing in production and activation of fibroblast collagen cells (39). The mechanism of pharmacological effects of SJW is summarized in Figure 2.

Methods
The scientific databases including Scopus, Web of Science, and PubMed were searched to access all relevant books and papers in English until 2021. The keywords were "Hypericum perforatum" OR "St John's wort" AND "clinical trial" OR "clinical study". All English relevant papers from 2000 to 2021 were included.

Clinical Aspects and Safety of SJW
In this section, we will discuss the clinical studies investigating the efficacy and safety of SJW as well as its major constituents.

Psychiatric disorders
Most of the reviewed clinical trials (2000 to 2021) are devoted to depressive disorders and their types (Table  1). However, many other neurological and psychiatric problems such as insomnia, fatigue, obsessive-compulsive disorder, attention-deficit hyperactivity disorder, autistic disorder, social anxiety disorder, nervous agitation, shortterm memory, and somatoform disorders have also been investigated. In patients suffering from depression, SJW has been found to be able to improve CGI and reduce HAM-D scores, relapse rate, and adverse effects significantly compared with placebo and other anti-depressant drugs (40,41). The results of the studies on social phobia and polyneuropathy failed to provide evidence for the efficacy of SJW (42,43). Opposite results have been observed in clinical trials conducted on OCD. In a clinical study, SJW improved the patient's condition by increasing Y-BOCS scores, but in another study, it did not have a significant effect on the Y-BOCS score (44,45). Different study designs and different formulations used might explain these opposite findings. These opposite results were also observed in patients with attention definition disorder (46,47). In a long-term safety study on 440 patients with mild to moderate depression, Figure 2. The pharmacological effects of Hypericum perforatum a relatively high safety of this plant was observed (48). In two studies, Chinese herbal remedies, mainly SJW and Acanthopanax, showed significant effects in reducing depressive symptoms and improving post-stroke motor symptoms (49,50). It is suggested that more extensive studies be performed with higher doses of SJW or in combination with other medicinal plants affecting psychiatric disorders such as Valeriana officinalis and Lavandula angustifolia to perhaps achieve more effective results. Also, in the case of studies performed on severe depression, the patient should be monitored for physical harm and suicide attempt. It is also recommended to use standard extracts for studies (Table 1).

Endocrine disorders
Studies show that SJW and its constituents have promising activities against endocrine disorders. According to Table 2, PMS and menopausal disorders account for the largest number of clinical trials of SJW in endocrine disorders. These studies show positive results in improving the symptoms of hot flashes and the mood and behavioral symptoms associated with these disorders (64)(65)(66)(67). However, SJW has not been as successful in relieving the pain of PMS as it is in improving its psychological symptoms (65). Another clinical trial has been performed on polycystic ovary syndrome and examined the simultaneous effect of lifestyle and consumption of several herbal compounds, including Hypericum. The results of this study showed that the combination was useful in improving blood pressure, BMI, insulin resistance, and psychological problems of PCOS (68). There have also been limited studies on the effect of Hypericum on the concentrations of steroid hormones such as ACTH, cortisol, and prolactin, which 1 LI 160 is a hydroalcoholic dried extract that has been standardized to total hypericin content (0.12-0.28%) and a range of analytical marker substances; 2 Multi-fractionated extract with 0.3 % hypericin; 3 Mono-fractionated extract with 0.3 % hypericin; 4 Helarium-425® is 425 mg dry ethanolic extract in capsule that is standardized to hypericin 0.1-0.3% and 6% of hyperforin; 5 Tablet containing 100 mg of SJW dried extract (L1160) standardized to 0.28% hypericin; 6 Extract contains 60 mg SJW, 28 mg Valeriana officinalis, and 32 mg Passiflora incarnata L.; 7 It is a Chinese herbal medicine mainly composed of Acanthopanax and SJW; 8 STW 3-VI is a extract from SJW (extraction solvent ethanol 80%,v/v); 9 WS_ 5570 is a methanol extract from Herba hypericin, main constituents of which include 3-6% hyperforin, 0.1-0.3% hypericin, not less than 6% flavonoids; 10 A film-coated tablet of Ze 117 containing either 500 mg (Remotiv 500) or 250 mg (Remotiv 250) of dry extract from SJW that contains 0.1-0.3% of total hypericin SJW: St John's wort

Skin diseases
According to the results of Table 3, topical forms of SJW have shown beneficial effects in reducing inflammation, itching, and redness of scars in cesarean section and episiotomy (75,76). Also compared with acyclovir, SJW has caused a better reduction in burning sensation and parameters of acute pain, erythema, and vesiculation in HSV-1 and HSV-2 lesions (77). Reducing TNF-α concentrations in the dermis, endothelial, and dendrite cells in patients with plaque-type psoriasis can be one of the mechanisms of this plant in healing skin lesions (78,79). But it seems that the analgesic effects of this drug have not been enough for the burning mouth syndrome (80). In other clinical trials on non-melanoma skin cancers, the complete clinical response has been 50% for AKs, 28% in superficial BCC patients, and 40% in patients suffering from Bowen's disease (81). The use of modern methods of drug delivery to the skin for higher penetration of the active ingredient in topical formulations and appropriate standardization based on the active ingredients of the drug can produce better results.

Co-administration of SJW with other drugs
According to Table 4, clinical trials performed with concomitant administration of SJW with other drugs are generally divided into four categories based on the mechanism of interaction: First category: One of the most important features of SJW is its inductive effects on P-glycoprotein (P-gp) and hepatic cytochrome P450 enzymes including CYP3A4, CYP2C19, CYP2C9, CYP1A2, and CYP2D6 (82). Hyperforin plays an important role in the induction of CYP enzymes and P-gp by activating the pregnane X receptor (PXR) (83). Induction of these enzymes can reduce the concentration of drugs that are metabolized by these cytochromes or increase the effect of drugs such as clopidogrel that are converted to the active form by these enzymes (84). Clinical trials in this category investigate drug interactions in the concentration and metabolism of drugs with SJW. According to the data in this table, when using low-dose hyperforin products such as Ze 117, the use of SJW could not have a significant effect on the pharmacokinetics of drugs (85)(86)(87). However, extracts containing high doses of hyperforin, such as Jarsin® and Movina ® , have significantly increased clearance, decreased the concentration and effectiveness of drugs, and sometimes failed treatment (88)(89)(90)(91)(92). Drugs that are affected by induction of CYP 450 with SJW include bupropion, oral contraceptives, docetaxel, rifampicin, rivaroxaban, oxycodone, oral s-ketamine, cyclosporine, tacrolimus, atorvastatin, irinotecan, zolpidem, metformin, and simvastatin (88,(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105).
Second category: The activity of liver CYP450 enzymes in humans is genetically different and people are divided into three genotypes: extensive, poor, and ultra-rapid metabolizers (89). Studies in this category include SJW interactions with drugs in different genotypes. According to the results of the table, those who are rapid and extensive metabolizers are more affected by the inductive effects of SJW and show more drug interactions with this plant (89,106,107).
Third category: Evaluation of efficacy and safety of SJW compared SSRIs drugs is another group of clinical trials in this table. Increased Hamilton depression total score  Table 3. Clinical trials of St. John's wort on skin diseases 1 The hydro alcoholic condensate extracts packed with sterile Vaseline as the base (%5 weight ratio) in 30 gr tubes; 2 Topical formulation containing SJW, Calendula Officinalis, and copper sulfate; 3 The products contained pseudohypericin (67.5%) and hypericin (32.5%); 4 It was prepared from an extract of SJW (5% w/w), vaseline (84% w/w), propylene glycol (10% w/w), and avicel (1% w/w); 5  and rates of remission in the SJW group were better than paroxetine and fluoxetine in people with MDD. In addition, the side effects of SJW were less reported than with these drugs (108,109). Fourth category: The latest group of clinical studies in this table discusses the concomitant use of SJW with a potent CYP450 inhibitor and its effect on drug concentrations. Studies show that the use of ritonavir and ketoconazole in combination with SJW increases the concentration of midazolam and decreases its clearance, indicating the superiority of the inhibitory effects of these drugs over SJW induction. Of course, these results depend on the amount of hyperforin in the extracts used (110,111). In the following paragraphs, the drugs interactions of SJW are discussed in detail:

Contraindicated interactions Irinotecan
Avoid consuming SJW with irinotecan at the same time. The effect of SJW on the metabolizing enzymes of irinotecan may continue for several weeks after stopping the consumption of SJW. Therefore, if the patient is being treated with irinotecan and SJW, he should stop consuming SJW and, if possible, use the drug irinotecan with a delay and after 2 weeks (101).

Major risk interactions Antiviral drugs
Drug resistance and treatment failure are two of the most important risks that can occur with the concomitant use of SJW and antiviral drugs such as indinavir, which is a viral protease inhibitor (112). Because other protease inhibitors, such as ritonavir and saquinavir, are also metabolized by liver cytochromes, SJW can also reduce their plasma concentrations and effectiveness (113,114). Therefore, concomitant use of these drugs should be avoided.

Chemotherapeutic drugs
Docetaxel and imatinib are metabolized by hepatic cytochromes such as CYP3A. Their plasma concentrations and efficacy could be decreased when co-administered with SJW leading to treatment failure in cancer patients (95,115).

Immunosuppressant
One of the most important drug interactions observed with SJW is related to the simultaneous use of this plant and drugs used after transplantation such as cyclosporine and tacrolimus, which reduces their plasma concentrations (85,94,100). Disruption of appropriate doses of these drugs has reportedly led to organ transplant rejection in several transplant recipients or put them at risk for transplant rejection (85,116,117).

Warfarin and digoxin
Another very important interaction that should be considered by physicians when prescribing this drug is the concomitant administration of SJW with drugs such as digoxin and warfarin that have a narrow therapeutic index (118,119). In a clinical trial, SJW reduced the therapeutic concentration of warfarin by increasing its clearance which increased the risk of blood clots (120). In a study on the simultaneous administration of SJW with digoxin, researchers found that only extracts containing high doses of hyperforin could have a significant effect on digoxin concentration, but more careful studies are needed to determine the possible amount of hyperforin to prevent possible side effects of digoxin dose changes (87).

Moderate risk interactions Metformin
Due to the increase in glucose tolerance with increased insulin secretion independent of insulin sensitivity, it is recommended to monitor the symptoms of hypoglycemia in concomitant use of hypoglycemic drugs such as metformin with SJW (102).

Oral contraceptives
SJW can reduce the half-life of norethindrone and ethinyl estradiol by inducing CYP3A and their metabolism (96). It could increase the chance of ovulation and breakthrough bleeding and induction of unwanted pregnancy (96,103). Therefore, co-administration of SJW with contraceptives is not recommended in women who do not intend to become pregnant at all.

Statins
Several clinical studies have reported that the effectiveness of lipid-lowering drugs such as atorvastatin, simvastatin, and rosuvastatin in concomitant use with SJW could be decreased. Increased total cholesterol and LDL cholesterol are among the proposed mechanisms for SJW interactions with statins (88,100). In general, it is recommended that patients should avoid consuming SJW with blood lipidlowering drugs at the same time.

Oxycodone
The metabolism of oxycodone can be increased while co-administered with SJW leading to the reduced analgesic effects of oxycodone. Thus, simultaneous administration of these two drugs should be dose adjusted (97).

Rifampicin
Based on the clinical study performed on the simultaneous administration of rifampicin and SJW, photosensitivity was observed only in the study group of women. Therefore, in prescribing SJW with rifampicin, the aggravation of side effects of photosensitivity caused by hypericin should be considered (98).

Zolpidem
Induction of CYP3A by SJW reduces the plasma concentration of zolpidem (105). Therefore, co-administration of this drug with tea grass also requires dose adjustment.

Conclusion
Hypericum perforatum, known as Saint John's wort, is a medicinal plant widely used for psychiatric problems. Hence, most of the clinical trials performed on SJW are related to psychological problems. However, according to many in vitro, in vivo, and clinical studies it has promising effects for a range of disorders including infectious problems and skin disorders that could replace routine treatments by physicians in the future. One of the most important features of this plant is the variety of drug interactions that it can cause. The results of this article can be a guide for researchers to design stronger and more complete studies in the future.

Clinical studies on Hypericum perforatum
Nobakht et al.
Medical Sciences, Mashhad, Iran. The results presented in this paper were part of Seyedeh Zahra Nobakht thesis.

Authors' Contributions
SZN Helped with writing the original draft, investigation, and methodology; MA Provided data curation, writing, review, editing, and formal analysis; AM and ATM Helped write, review, and edit; SAE Provided supervision and helped write, review, and edit.

Funding Source
This work did not receive any financial support.

Conflicts of Interest
The authors have no conflicts of interest to declare.