Low-Hyperforin Extracts of St John’s Wort are Safe to Combine with Prescription Medications of All Classes and are Effective in Treating Common Mental Health Concerns

Abstract

St John’s wort (hypericum perforatum) (SJW) has both a rich history of use as well as a well-established body of modern human intervention trials showcasing its ability to benefit a wide array of common mental health concerns. However, academic curriculums training healthcare providers of all disciplines highlight the potential for horrifying herb-drug interactions with SJW. It may be the most well-known contraindication across all disciplines of medicine; do not combine SJW with prescriptions of any type! The objective of this review is to showcase evidence forcing a re-evaluation of the long-held notion that SJW cannot be combined with prescriptions. Specific molecules within SJW (hyperforin and hypericin – most relevant being hyperforin) are known inducers of several cytochrome P450 enzyme systems, and thus the interactions so broadly feared. There are now available preparations of SJW that deliver at or below detection limits of these molecules, and an important body of literature clearly demonstrates that these preparations do not induce P450 systems. SJW is an incredibly valuable tool in the front-line of the war that is mental health, and low-hyperforin preparations are a critical tool in the arsenal of integrative healthcare providers working in this realm.

Introduction

St John’s wort (Hypericum perforatum) (SJW) has had a rich history of use. Herbal texts describe it as sedative, astringent, and pain-relieving. It was also known to have significant antiviral effects which were confirmed in later modern study. Historical indications included excitability, anxiety, depression, and as a nerve tonic. It was also viewed as useful for neuralgia, fibrositis, sciatica, menopausal neurosis, wound healing, and rheumatic pain (Barnes et al 2002, Hoffmann 2003, Mills and Bone 2012).

SJW belongs to the family Hypericaceae. It has nearly global distribution, missing only from polar regions and desserts. It is an aggressive perennial plant with almost exclusively yellow-coloured flowers. It is often considered an invasive weed. When glands on the petals are crushed, a red stain occurs. The modern common name of the plant came from Paracelsus in the 16^th century naming the plant “Johannes-blut” (“blut” meaning blood and soil, a term linking German people to their land) and linking the plant to the martyr St John (Wikipedia 2021).

As anyone trained in naturopathic medicine can attest, hyperforin and hypericin are often showcased as the active constituents in St John’s wort. All three herbal texts reviewed for this review (Barnes et al 2002, Hoffmann 2003, Mills and Bone 2012), and certainly many others, declare these molecules to be the active constituents of the plant. However, certain critical facts have since emerged.

1. Hyperforin and hypericin are inherently very unstable molecules. While ultra-specialized extraction processes targeting preservation of hyperforin and hypericin contain appreciable amounts of the two molecules, any processing stress to the plant rapidly degrades them (Madabushi et al 2006, Mueller et al 2004, Orth et al 1999).
2. Low hyperforin/hypericin extracts of SJW have been shown to have important magnitudes of efficacy in management of common mental health concerns (Brattstrom 2009, Camfield et al 2013, Friede et al 2001, Schrader 2000, Woelk 2000).
3. Low hyperforin/hypericin extracts of St SJW have been reproducibly demonstrated not to appreciably impact cytochrome P450 enzyme systems, and thus do not impact metabolism of prescription medication (Arold et al 2005, Chrubasik-Hausmann et al 2019, Madabushi et al 2006, Mai et al 2004, Mathijssen et al 2002, Mueller et al 2004, Mueller et al 2009, Will-Shahab et al 2009, Zahner et al 2019).

Stability of Hyperforin/Hypericin

Tremendous research interest exists in achieving stable isolates of hyperforin. It is important to note that no herb-drug interactions with SJW were reported until 1998, very shortly after a new extraction process was developed that preserved significant amounts of hyperforin (Madabushi et al 2006, Mueller et al 2004, Willmar 1997, Willmar 1998). Further advancements in processing methodologies have led to a six-step system that can be found in Table 1 (Orth et al 1999).

Table 1. Hyperforin-Preserving Processing of SJW

Step	Process
1	Extraction of deep-frozen blossoms (-20C) with hexane.
2	Separation of lipophilic substrates on a silica gel column.
3	Purification with high performance liquid chromatography (HPLC).
4	Evaporation under reduced pressure.
5	Removal of remaining water by freeze-drying.
6	Storage of hyperforin under nitrogen at -20C.

Standard extraction and manufacturing processes lead to very low yields of hyperforin and hypericin (Ang et al 2004, Fuller et al 2018, Gaid et al 2018, Maisenbacher and Kovar 1992). Hyperforin (C35H52O4) makes up 2-4% of crude, dried SJW (Orth et al 1999). A well-studied proprietary extract of SJW (Ze 117) is reported to contain ≤0.2% hyperforin (Brattstrom 2009, Camfield et al 2013, Friede et al 2001, Mueller 2004, Schrader 2000, Will-Shahab et al 2009, Woelk 2000, Zahner et al 2019). Unpublished data from the manufacturer of the low-hyperforin extract prescribed by the Author state that the herbal extract begins with 1.22% hyperforin, yet following the manufacturing process of the final product, hyperforin is nearly undetectable (0.076%). A second unpublished report from yet another company offering low-hyperforin SJW reports the final product as containing below detection limit of hyperforin (<0.1%).

Herb-Drug Interactions with St John’s Wort

It is generally accepted that SJW extracts containing less than 1% hyperforin will not interact with prescriptions (Chrubasik-Hausmann et al 2019, Madabushi et al 2006). Chrubasik-Hausmann and colleagues (2019) review 56 unique publications evaluating interaction of SJW with a very wide array of common prescriptions. Hyperforin dose among these studies ranged from 0.04mg to 41mg per day. It is important to note that many of the studies evaluated interaction with multiple prescription medications as opposed to evaluation of one. Only four of the 56 papers evaluated SJW extracts with hyperforin dose of less than 1mg per day. The authors conclude that a high magnitude of safety can be expected from preparations with less than 1% hyperforin, and that >3mg per day of hyperforin would be required to achieve interactions of concern. Others echo the less than 1% hyperforin content as safe, yet recommend a total daily dose of hyperforin to be <1mg (Madabushi et al 2006).

Hyperforin acts as an inducer of several key P450 enzymes (CYP3A4, CYP2C19, CYP2C9) as well as an inducer of p-glycoprotein (ABCB1) (P-pg), a drug efflux pump (Chrubasik-Hausmann et al 2019).

Well-controlled human trials have shown a lack of interaction of low-hyperforin SJW with cyclosporine (Mai et al 2004), low-dose oral contraception (Will-Shahab et al 2009), digoxin (Mueller et al 2004), and irinotecan (Mathijssen et al 2002). A well-validated seven probe drug cocktail showed no impact of low-hyperforin SJW with caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine (Zahner et al 2019). Another study found no interaction of low-hyperforin SJW extract with alprazolam, caffeine, tolbutamide, and digoxin (Arold et al 2005). Lack of interaction was again demonstrated with midazolam (Mueller et al 2009).

Soleymani and colleagues (2017) highlight the potential harm from combining hyperforin-rich SJW extracts with medications. They review an alarming number of case reports demonstrating severe and on occasion life-threatening interactions between SJW and a wide array of common prescription medications including immunosuppressants, anticancer agents, cardiovascular drugs, oral contraceptives, and lipid lowering agents.

Hyperforin is certainly a molecule of tremendous research focus. Preclinical evidence is revealing the molecule to be antileukemic (Billard et al 2013), antidepressant (Pochwat et al 2018), neuroprotective (Oliveira et al 2016), apoptotic in cancer cell lines (Hsu et al 2020), inducer of post-stroke neuroangiogenesis (Yao et al 2019), antidiabetic (Novelli et al 2020), protective against acute cerebral ischemic injury (Ma et al 2018), and potentially improving memory and cognition in Alzheimer’s (Griffith et al 2010).

Modern extraction processes aiming to preserve the hyperforin content of St John’s wort have succeeded, and as reviewed above, there are inevitably important roles for such preparations. However, given the potential for aggressive and dangerous herb-drug interactions with hyperforin-rich SJW extracts, low-hyperforin SJW extracts are a welcome addition to the tool bag of integrative healthcare providers.

Efficacy of Low Hyperforin Extracts of St John’s Wort

A selection of human trials of SJW extracts with <1% hyperforin for outcomes of relevance in mental health is presented in Table 2. The trials reproducibly demonstrate important magnitudes of benefit. Three of the four studies in Table 2 compare low-hyperforin SJW with commonly prescribed antidepressants (Friede et al 2001, Schrader 2000, Woelk 2000). Of note, they collectively demonstrate equivalence/superiority of SJW vs medication for treating depression and anxiety, fewer adverse events, and superior tolerability.

Table 2. Human Trials of Low-Hyperforin St John’s Wort Extracts in Mental Health

Methods	Outcomes	Reference
RCT 240 participants randomized to SJW extract Ze 117 or fluoxetine. Baseline HAM-D 16-24. Six-week intervention.	HAM-D decreased 11.54 vs 12.2 SJW vs fluoxetine, respectively. CGI and responder rate superior SJW vs fluoxetine. Adverse events 8% vs 23% SJW vs fluoxetine respectively.	Schrader 2000
Multicentre (40 outpatient clinics) RCT 324 participants. Imipramine 150mg/d vs SJW extract Ze 117 500mg/d for six weeks. HAM-D, CGI and PGI as endpoints. Baseline HAM-D 22.4 vs 22.1 SJW vs imipramine.	HAM-D decreased from 22.4 to 12 with SJW, 22.1 to 12.75 with imipramine. CGI and PGI improved equally. SJW significantly superior for tolerability. Four participants assigned to SJW withdrew from trial vs 26 assigned to imipramine.	Woelk 2000
Multicentre 12 month open-label RCT with 440 participants, SJW extract Ze 117 500mg/d. Baseline HAM-D 20.58, CGI 3.99.	HAM-D 12.07 at week 26, 11.18 at week 52. CGI 2.20 at week 26, 2.19 at week 52. 49% of patients reported a total of 504 adverse events, of which 30 (6%) were possibly or probably related to treatment.	Brattstrom 2009
Multicentre RCT 240 participants, baseline HAM-D 16-24, SJW extract Ze 117 500mg/d vs fluoxetine 20mg/d for six weeks.	Significant difference in responder rate 60% SJW vs 40% fluoxetine. Adverse events 25% fluoxetine vs 14% SJW. SJW “Particularly effective in depressive patients suffering from anxiety”	Friede et al 2001

Note

SJW extract Ze 117 contains ≤0.2% hyperforin

Abbreviations

HAM-D = Hamilton Depression Rating Scale

CGI = Clinical Global Impression

PGI = Patients Global Impression

Discussion

Things deemed sacred in medicine can change over time. Clinicians are taught that a great evil is to combine vitamin K with warfarin, yet powerful evidence has since emerged demonstrating vitamin K supplementation as a key strategy for managing warfarin-treated patients with highly variable INR (International Normalized Ratio) (Ford et al 2007, Reese et al 2005, Rombouts et al 2007, Sconce et al 2007).

Low-hyperforin extracts of SJW containing less than 1% hyperforin and delivering a total daily dose of hyperforin of less than 1mg are safe and appropriate to combine with prescription medications of all types. However, hyperforin-rich extracts of SJW are widely available as over-the-counter supplements. Hyperforin-rich extracts of SJW certainly have utility and may achieve outcomes not achievable with low-hyperforin preparations. Using hyperforin-rich extracts requires diligence and caution on behalf of the clinician.

Low-hyperforin SJW extracts are an indispensable tool for the clinician working in the realm of mental health. The author has had the privilege of administering such extracts to over 1000 patients with tremendous success. Offering low-hyperforin SJW extract to patients with principally mental health concerns revolutionized my practice. It is tremendously effective for depression and anxiety. It is the only “natural” treatment ever observed to powerfully impact OCD. It reproducibly stabilizes mania and over time reduces many common presentations of psychosis.

It is incumbent on the clinician to directly verify hyperforin content with the manufacturer of the product they are recommending. The potential harm of combining a hyperforin-rich SJW extract with almost any prescription medication is immense and can be life threatening. Low-hyperforin SJW extracts are safe and effective in treating a wide array of common mental health concerns.

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