St John's wort: The benefits of low dose hyperforin in herb-drug interactions

Clinical Takeaways from this Research Article

• Low hyperforin St John’s wort extracts (≤1mg/day) have a lower incidence of clinically relevant pharmacokinetic interactions
• Lack of effect on the important CYP enzymes and P-gp transporter is important in the clinical prescribing of St John’s wort.

The benefits of low dose hyperforin in herb-drug interactions

The therapeutic use of St John’s wort (Hypericum perforatum) stretches back to ancient Greek times.¹ Within traditional and folk paradigms, medicinal uses included immune support (bacterial, viral and respiratory infections), wound healing and cognitive imbalances (neuralgia, anxiety, neurosis and depression).^1,2 

Today, this herb is mostly used for modulating mood symptoms commonly experienced in mild-to-moderate depression.² However, it is as well-known for its use and efficacy in supporting healthy mood patterns as it is for potential side effects and drug interactions. This is despite adverse effects mostly being mild and transient, and the incidence of drug interactions documented to be ten times lower than for pharmaceutical antidepressants.^1,2

Hyperforin – dosage is important 

As with any medicinal herb, St John’s wort has many naturally occurring constituents, with the predominant therapeutically relevant compounds being phloroglucinols (hyperforin) and naphthodianthrones (hypericin).^1-3 The level of these constituents vary from extract to extract; however, it is the level of hyperforin that has been linked to clinically relevant pharmacokinetic drug interactions.

Specifically, high dose hyperforin (>1mg/day) can dose-dependently reduce the endogenous plasma concentrations and therapeutic activity of many medications by inducing hepatic cytochrome p450 enzymes (CYP) and the intestinal and hepatic xenobiotic transporter p-glycoprotein (P-gp).^2-5

Conversely, low hyperforin St John’s wort extracts (≤1mg/day) have a lower incidence of clinically relevant pharmacokinetic interactions. ^2,3

The evidence for the lack of drug interactions with low dose hyperforin

In a phase one, open-label, nonrandomised, single sequence study, involving 20 healthy adults, researchers assessed the potential interactions of a specific St John’s wort extract (0.2% total hypericins and <1% hyperforin) when used concomitantly with a drug cocktail.³

During the 18-day study period, subjects took 500mg per day of the specific low hyperforin St John's wort extract. On days 1, 8 and 17, they also received a combination of seven drugs to test whether this specific St John's wort extract induced or inhibited the CYP enzymes or P-gp. 

No inhibitory or induction activity of the probe drugs and their main metabolites were observed following analysis. This demonstrated no pharmacokinetic interaction of the low hyperforin St John's wort extract with CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, or P-gp. The extract was also well tolerated when ingested both individually and concomitantly with the drugs.^3,5

This lack of effect on the important CYP enzymes and P-gp transporter is important in the clinical prescribing of St John’s wort. Along with a good tolerability profile, the specific St John’s wort extract with low hyperforin content (0.2% total hypericins and <1% hyperforin)  also demonstrates significant efficacy for mood-related symptoms. This shows a positive therapeutic benefit even with a low hyperforin content. 

REFERENCES:

1. Braun L et al. Herbs & natural supplements: an evidence-based guide, volume 2. 2015. Elsevier: Sydney; pgs. 933, 934,944
2. Nicolussi S et al. Clinical relevance of St John’s wort drug interactions revisited. Br J Pharmacol. 2020;177:1212-1226
3. Zahner C, et al. No clinically relevant interactions of St John’s wort extract Ze 117 low in hyperforin with cytochrome p450 enzymes and p-glycoprotein. Clin Pharmacol Ther. 2019;106 (2):432-440
4. Whitten et al. The effect of St John’s Wort extracts on CYP3A: a systematic review of prospective clinical trials. Br J Clin Pharmacol. 2006;62:5. 
5. Krenn L. European Scientific Cooperative on Phytotherapy (ESCOP).
6. Brattstrom A. Phytomedicine. 2009;16:277-83
7. Schrader E. 2000;15:61-8
8. Woelk H. BMJ. 2000;321:536-9
9. Schrader E et al. Hum Psychopharmacol. 1998;13(3):163-9