Hypericum perforatumL. (Hypericaceae), also known as St John’s Wort, is a conspicuous flowering plant that grows in dry, open soil. It is native to Europe, Western Asia, and North Africa but has progressively spread worldwide as an invasive weed due its prodigious seed production. It is also able to alter its metabolic profile in order to colonise various habitats, thus increasing its chances of survival and reproduction (Gaid et al, 2018). In the US, it has become infamous as it is a robust plant and is phototoxic to grazing livestock (Mullaicharam and Halligudi, 2018). It is sometimes divided into four geographically distinct subspecies (Scotti et al 2018). The genus Hypericum contains more than 400 species, but H. perforatum is the most potent out of all and the only species to be cultivated for commercial purposes (Klemlow et al, 2016).
It can be easily spotted in Mecklenburgh Square Garden as it boasts bright yellow star-shaped flowers and grows in clusters. It is a perennial plant that has reddish stems that can grow up to 1 m (3ft 3in) with flowers that typically measure up to 2.5 cm across with five golden yellow petals, possessing tiny black dots. The leaves grow opposite to each other and upon closer inspection, they appear peppered with small holes, hence the species name perforatum (perforated) (Lee, 1999). In time gone by, it had established itself as a panacea due to its long history in treating a range of ailments. It is currently one of the most commonly used herbal medicines for the treatment of mild anxiety and depressive disorders.
Etymology
It has long been understood that the genus name is in direct reference to its historic use, as Hypericum comes from the Greek word yper (upper) and eikon (an image). St John’s Wort was traditionally placed over religious icons for protection from evil spirits, thunder and witches. It was hung on doorways, windows and even carried in pockets for protection (Hobbs, 1990). Additionally, its supernatural powers were also attributed to St John’s Wort being heliotrophic (sun-loving), as it would be found growing on sunny hillsides so would follow the trajectory of the sun throughout the day, from east to west and this was viewed as a phenomenon.
In relation to its common English name, St. John’s wort traditionally flowers and is harvested around St John’s Day (named after John The Baptist) 24th June. Furthermore, because the plant has red-coloured spots on the leaves (secretory glands) and the plant sap turns red upon exposure to air, it was equated with the blood of St. John. Its religious significance is indicated, for example, by its use as bookmarks in prayer books and bibles. In addition, ‘wort’ comes from the old English ‘wyrt’ which is defined as a plant or herb, specifically of medicinal value (Mullaicharam and Halligudi, 2018).
Historical and modern uses
The Greek philosopher and physician Hippocrates (5th century BC) was one of the first to speak of the health benefits of H. perforatum, describing it as a treatment against demonic possession. Similarly, in Christian tradition certain plants were viewed as effective at preventing possession of the soul by the devil, which was believed to be the cause for mental illness (Lee, 1999).
Early uses included the preparation of the oil which was a popular topical treatment in Greece for wounds and bruises, as an alternative for arnica. St John’s Wort had other various modes of preparation such in herbal infusions for the treatment of lung, bowel or urinary tract disturbances. However, for more serious conditions such as kidney ulcers, worms, fevers, jaundice and rheumatism, the harder parts of the plant such as the roots, stems and rhizomes were boiled for several hours to produce a decoction. This slower process results in a greater number of active ingredients to be extracted. Additionally, Native Americans used several indigenous species for dermatological purposes (i.e. for wound healing), as well as an antidiarrheal, snake bite remedy and as a general immune strengthener (Hobbs, 1990).
St John’s Wort is widely used today as a herbal medicine for CNS disorders (both as a licensed / registered medicines, but also as unregulated botanicals). It is still taken for many of the same conditions that it has been recommended for throughout history but has established itself as a popular treatment for mild to moderate anxiety, depression and nervous agitation (low mood). However, this use is much more recent than the dermatological uses recorded over the centuries. Studies have indicated that St John’s Wort may work similarly to antidepressants such as SSRI’s (selective serotonin reuptake inhibitors) by increasing the availability of neurotransmitters such as serotonin and dopamine in neural synapses, prolonging its activity thus uplifting mood. Additionally, St John’s Wort is fast becoming a preferred substitute to antidepressants due to decreased side effects and withdrawal symptoms. Certain chemicals have been suggested to be involved in the therapeutic effects, including hypericin, hyperforin, flavonoids and essential oils.
Despite being used for a wide range of ailments for over 2000 years, recent research has shown a glimpse of its potential for the treatment of inflammation-related disorders, bacterial/viral diseases, as a neuroprotective agent against degenerative illnesses and cancer (Klemlow et al, 2011).
Phytochemistry
St John’s Wort contains many components and many secondary metabolites have been characterised such as polyphenols: flavonoids (epigallocatechin, rutin, quercetin), naphtodianthrones (hypericin, pseudohypericin), and phloroglucinols (hyperforin, adhyperforin). It also contains tannins (e.g. proanthocyanidins) and volatile (essential) oils. Additionally, common phenolic acids such as ferulic acid, chlorogenic acid, tannins and catechin derivatives are also present at significant concentrations (Lyles et al, 2017). Not all the active components have yet been established but hypericin, hyperforin and flavonoids may contribute to the pharmacological effects.
Typically, commercial extracts use dried aerial parts with hypericin standardised to 0.3%. Hyperforin is fairly unstable due to its sensitivity to oxidation so is typically not used as a standardised component. But, if extracts are found to be standardised on hyperforin, the percentage usually lies between 3-5%.
Scientific evidence
Depression
Initially, it was suggested that hypericin and hyperforin were the main antidepressant constituents by inhibiting the enzymes MAO-A and -B which typically degrade neurotransmitters. Additionally, hyperforin has been reported to be a potent reuptake inhibitor of serotonin, dopamine, noradrenaline and GABA. Similar to conventional antidepressant pharmacology, these mechanisms increase the presence of the neurotransmitters in the synapse, thus alleviating symptoms of depression.
However, the effect of hyperforin was shown to be irreversible which questions its role as an antidepressant. Nonetheless, reversibility has been shown by flavonoid compounds (Schmidt and Butterweck, 2015) which also exhibit structural resemblance to synthetic MAO inhibitors (Greeson et al, 2001), thus may also contribute to the anti-depressant and sedative effects.
Presently there is a great deal of uncertainty surrounding the mechanisms of action for depression. Hypericins are probably not the only relevant component and different preparations may vary in their concentrations of substances with anti-depressive effects (Linde et al, 1996). St John’s Wort therefore provides an excellent example of the total extract being the ‘active constituent’, as the overall effect on depression cannot be attributed to a single constituent. Rather, the combination of different effects accounts for overall clinical efficacy rather than single mechanisms of action (Schmidt and Butterweck, 2015).
Treatment of inflammation-related disorders
Hyperforin also possesses anti-inflammatory properties as it interferes with key enzymes and functions that participate in prostaglandin biosynthesis. Prostaglandins play key roles in inflammation and pain (Koeberle et al, 2011). Additionally, hyperforin reduces immunological responses and upon activation release proinflammatory mediators like nitric oxide (NO). Excess or abnormalities in NO production have been linked to the progression of neuropathologic disorders (Schmidt and Butterweck, 2015). It is a potent, but non-specific inhibitor of the inflammatory transcription factor NF-kappaB (Bork et al 1996)
Inflammation is also related to other pathologies such as bowel disease, diarrhoea and respiratory infections, so St John’s Wort provides potential in their treatment. Besides inflammation, excessive prostaglandin production is also linked with tumorigenesis. Hyperforin was found to induce apoptosis (programmed cell-death) of many cancer cells in a variety of studies, so it seems that there is a functional correlation between the inhibition of prostaglandin synthesis and the induction of apoptosis (Koeberle et al, 2011).
Cancer
Hypericin and hyperforin were also shown to reduce tumour cell growth, cancer invasion and lymphatic capillary growth (Rothley et al, 2005; Koeberle et al, 2011), by decreasing proliferation rates and causing death of various cancer cell lines. Additionally, hypericin is a potent naturally occurring photosensitiser and its specific properties such as absorption at longer wavelengths make it a potential candidate for antitumoral photodynamic therapy (Oliveira et al, 2016). However, despite the well-recognised anti-inflammatory and anti-carcinogenic effects, the fundamental molecular mechanisms are still elusive. Evidence for clinical efficacy is insufficient to allow any recommendation for its use for such conditions.
Antibacterial effect
Phytochemical studies of St John’s Wort have led to the isolation of antimicrobial compounds. Recent research has shown that polysaccharides present in St John’s Wort have antimicrobial activity against Escherichia coli, Salmonella typhi, and Staphylococcus aureus in disc diffusion assays(Heydarian et al, 2017: Lyles et al, 2017). An additional study exhibited antibacterial effects of St John’s Wort extracts against several oral bacteria such as Lactobacillus plantarum and Enterococcus faecalis (Suntar et al, 2016; Lyles et al, 2017).
The antimicrobial properties against Staphylococcus aureus has potential therapeutic significanceas it is usually notorious for a rapid resistance rate, specifically against methicillin. Additionally, S. aureus causes a majority of infections in hospital and community settings (Tang et al, 2010; Sarkisian et al, 2012). Bacterial resistance of current antibiotics is sharply rising, so the attention is being focused to natural products, which are rich in structural diversity. (Sarkisian et al, 2012).
Wound healing
St John’s Wort oil was shown to have significant would healing effects. An accelerated rate of wound healing was observed in rats treated with the oil compared to those treated to petroleum jelly (control). This effect is related to the antimicrobial activity and is significant as any agent that shortens the inflammatory phase, increases the healing rate (Nayak, Isik and Marshall, 2017)
Clinical evidence for efficacy
The use of St John’s Wort in the treatment of psychiatric and neurological disorders such as depression has been widely documented. Several clinical studies have supported the efficacy of St John’s wort. Linde et al (2005) updated a Cochrane review and conducted a meta-analysis using a highly specific criteria, allowing for the thorough selection of high clinical quality trials. This systematic review looked at studies conducted from 1979 to 2002 and out of 68 possible trials, 37 met the inclusion criteria (randomised, placebo-controlled trials) and allowed for the comparison of St John’s Wort with placebo or antidepressants.
It was found that in fourteen trials containing 2283 patients, St John’s Wort extracts improved depression symptoms and were as effective as standard antidepressants in the treatment of mild to moderate depression. Additionally, it was found to have fewer adverse effects than other antidepressants. The remaining 26 studies involving 3320 patients, compared St John’s Wort with placebo and found superiority in results of treatment with St John’s Wort. However, regarding the treatment of severe depression, only 6 trials showed minimal improvements, which emphasises that St John’s Wort can be used for the mild/moderate depression, but immediate medical help should be sought for severe depression (Linde et al 2005).
In a more recent meta-analysis conducted by Cui and Zheng (2016) which looked at 27 studies with 3126 patients with mild-moderate depression in 2008, they found that St John’s Wort was comparable to standard SSRI’s in clinical response and mean reduction in HAMD (Hamilton Depression Rating Scale) score. Additionally, St John’s Wort was found to have superior safety over SSRIs, including no withdrawal symptoms. However, this study along with many others, only focused on adult depression. There is little clinical data available on adolescent depression, and large-scale randomised studies need to be carried out to determine the efficacy on a greater patient age-range.
Furthermore, in studies regarding major depression, St John’s Wort appears to not be an effective intervention. For instance, the Hypericum Depression Trial Study Group (2002) found no statistically significant difference between the placebo and hypericum treatments in major depression. Additionally, Linde et al (2008) stated that more recent studies regarding efficacy in major depression have also been negative or uninformative (Rapaport et al, 2011).
The majority of studies are in favour of St John’s Wort as a preferred therapeutic choice in the management of mild-moderate depression, compared to standard antidepressants. However, seeking professional help is heavily encouraged before employing the use of interventions for major depression. In the UK registered medicines (THR) are available, where the use is based on traditional use only with the products having a high level of quality assurance.
Safety, cautions, risks and interactions
St John’s Wort is generally well tolerated, and if side effects do occur, they are mild and transient which may occur in 1-3% of patients taking the herbal drug. Rare adverse effects include photosensitivity which is largely due to the photosensitive compound hypericin, which can lead to skin burns in fair-skinned individuals after prolonged exposure to sunlight. This effect is due to UV-activated hypericin killing human keratinocytes and melanocytes, which are skin cells (Davids et al, 2008; Lyles et al, 2007). This common pharmaceutical warning is termed “hypericism” and is also seen in livestock that develop extreme photosensitivity after grazing on the flowers (Lyles et al, 2017). Moreover, data on single dose toxicity and long-term safety is limited (Greeson et al, 2001).
Important are, however, herb-durg interactions. It is typical of people taking herbal medicines alongside medication, to not consult their physicians, due to the common misconception that herbal medicines are completely safe, in all instances. However, without adequate medical knowledge this proves problematic as it raises the risk of herb-drug interactions. Numerous studies have shown that St John’s Wort is the most prominent herb to interact with a range of prescription drugs. This could either reduce the therapeutic effectiveness or enhance the drug’s effects to toxic levels by multiple mechanisms. The interactions may be due to a modulation of enzymes such as cytochrome P450, which metabolises pharmaceutical drugs. Additionally, the induction of P-glycoprotein, which transports many important drugs is also a reported interaction (Oliveira et al, 2016). Alterations to these fundamental aspects of drug-interactions could either lead to a reduction of the drug in blood plasma, decreasing therapeutic efficacy or an increase which could lead to toxicity. It is for these reasons that it is advised not to combine St John’s Wort with any other drugs or to consult a doctor who could provide guidance regarding the interactions.
St John’s Wort should not be taken alongside the anti-depressant’s SSRIs due to the risk of developing serotonin syndrome which is characterised by the overactivation of serotonin receptors. This could lead to an accumulation of serotonin and could be potentially life-threatening (Volpi-Abadie et al, 2013). Additionally, pregnant women may opt for St John’s Wort as a substitute for antidepressants, perceiving herbal drugs as a safe alternative. Due to the lack of data on the possible effects on pregnancy and lactation, as well as those taking one or more pharmaceutical drugs, caution is warranted (Greeson et al, 2001). Moreover, unexpected pregnancies in women taking oral contraceptives with St John’s Wort have been well-documented, highlighting the widespread interference of St John’s Wort with a variety of medications and contraceptives (Borrelli and Izzo, 2009).
Conclusion
St John’s Wort has long been used for its plethora of medicinal uses such as for wound healing, lung, bowel or urinary tract disturbances. It is currently widely used for its antidepressant effects as seen through its marketing for the treatment of low mood or mild to moderate depression. Both regulated and unregulated products are on the market, but only regulated ones will comply with the relevant quality standards. It has also shown positive effects in the treatment of inflammatory disorders and cancers, providing a potential therapeutic research lead in these areas. However, St John’s Wort is the most prominent herb to interact with a range of prescription drugs. Care is warranted and the plant should not be taken with most prescription drugs, due to the risk of interactions which could become dangerous, especially with antidepressants. Clinical and animal studies continue to demonstrate the vast therapeutic value of St John’s Wort.
Disclaimer
In this essay we do not to advise or recommend herbs for medicinal or health use. This information is intended for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets (i.e. for THR products).
About the author
My name is Selma Maloumi and I am an MSc student at the UCL School of Pharmacy (2018 -2019) studying medicinal natural products. After completing my MSc, I aim to go into naturopathic medicine, as I believe that health should be treated holistically, not only looking at physical symptoms but also emotional, mental and spiritual aspects.
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