St. John's Wort

Last Updated: September 28 2022

Hypericum Perforatum (St. John's Wort) is an anti-depressant herb that is commonly used for its neurological effects. While it appears effective, it is well known to adversely interact with a variety of pharmaceuticals.

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1.

Sources and Composition

1.1

Composition

St. John's wort (SJW) refers to a plant by the botanical name of hypericum perforatum (of the family hypericaceae), with this species in particular being called Common St. John's wort or Perforate St. John's wort to distinguish it from other species in the plant genus of hypericum which all share the common name of St. John's wort.

Contains:

  • Hypericin, initially thought to be the major psychoactive component of the plant
  • Pseudohypericin
  • Hyperforin, a phloroglucinol derivative currently thought to be the major psychoactive component of the plant
  • Adhyperforin[1]

1.2

Formulations and Variants

LI-160 refers to a standardized extract of hypericum perforatum which contains precisely 0.3% hypericin (250µg per 300mg) and approximately twice as much pseudohypericin (0.6% of the total extract) according to HPLC analysis.[2][3]

2.

Molecular Targets

2.1

Ion Channels

Hyperforin from St.John's Wort has been suggested to be the major neuroactive component of the plant, and it has been noted that hyperforin can activate nonselective cation channels (NSCCs) at 10μM although the EC50 in neurons was found to be 720nM.[4] This activation increases sodium uptake in the cell, and is dependent on NSCC1 and NSCC2,[4] and this is thought to underlie the antidepressant effects as those two channels are present in neurons[5] and the increase in sodium uptake correlates well with inhibition of serotonin uptake in vitro.[4]

The NSCC that appears to be specifically implicated is TRPC6[6][7] and it appears that the related molecule adhyperforin also possesses this reuptake property.[1]

It was noted that hyperforin also elevated calcium ion concentrations in neurons (PC12) with an EC50 of 1.16μM, only slightly less potent than its influence on sodium ions.[4]

Hyperforin appears to be capable of causing an influx of ions (primarily sodium) into various cells such as neurons due to acting on channels which mediate their uptake

This is potentially related to the antidepressant effects of St.John's Wort since it is known to inhibit serotonin reuptake despite not influencing the serotonin transporter[8] like SSRIs would; the reuptake has been tied into an increase in intracellular sodium ion concentrations.[9] Reuptake inhibition has occurred with many other neurotransmitters as well including dopamine, noradrenaline, glutamate, and GABA[10] although dopamine may be most sensitive (serotonin less sensitive and noradrenaline potentially unresponsive from standard doses[11]).

This has been noted in the prefrontal cortex with oral supplementation in rats[11] and in vitro in corticol neurons[8] and hippocampal cells.[7] Oral supplementation failed to influence neurotransmitters in the striatum.[11]

The influx of ions seems to be related to the inhibition of neurotransmitter reuptake that is seen with hyperforin, and thus this mechanism may underlie the antidepressant effects of St.John's Wort (as it appears dopamine and serotonin are primarily affected, their reuptake inhibition leading to antidepressant effects)

3.

Pharmacology

3.1

Absorption

The bioavailability of hypericin has been stated to be approximately 14%.[12]

3.2

Transportation in Serum

Following oral administration of 300, 600, or 1,800mg hypericum perforatum containing 0.3% hypericin (250, 750, and 1,500µg), the Tmax appeared to occur 4.6 hours later with the concentrations reached being dose-dependent between 1.5-14.2µg/L (median values).[13] Similar numbers have been found elsewhere with a similar study design, where the same supplement reached a Cmax of 1.3-16.6µg/L after 5.5-6.0 hours.[3]

Steady state plasma concentrations of hypericin can be reached after four days supplementation of hypericum perforatum (300mg thrice daily) of approximately 8.5µg/L.[13]

Oral ingestion of St.John's Wort at 300mg/kg (WS 5572) in rats has resulted in plasma hyperforin concentrations of 370ng/mL (690nM) at a Tmax of three hours.[14]

Ingestion of 300mg St.John's Wort (14.8mg hyperforin) in otherwise healthy subjects increases plasma hyperforin to 150ng/mL (280nM).[14] Increasing the dose to 600mg increased the exposure to hyperforin while 900-1,200mg St.John's Wort had less exposure than the lower doses, and the estimated steady state exposure with the standard 300mg thrice daily dosing is 150nM.[14]

3.3

Neurological Distribution

One review[12] has stated (via referencing the 1997 American Herbal Pharmacopoeia) that brain concentrations of hypericin may only reach 5% of what is observed in plasma, although the half-life may be weeks.

3.4

Elimination

When looking at the elimination of hypericin, it seems that the alpha half-life (t1/2α) is relatively rapid at 1.9 hours (250µg hypericin) or 5.8-6.0 hours (750-1,500µg hypericin) but the beta half-life (t1/2β) is prolonged between 24.5 hours (250µg) or 43.1-48.2 hours (750-1,500µg);[3] this suggests hypericin is being deposited/retained in bodily tissue. Pseudohypericin follows similar kinetics, and daily dosing of 750µg hypericin over 14 days does not appear to alter the kinetics of elimination.[15]

3.5

Phase I Enzyme Interactions

Hypericum perforatum induces many CYP450 isozymes such as CYP3A4, CYP2C19, and CYP2C9 according to in vitro studies. Hypericum perforatum lowers drug plasma levels by pregnane X receptor activation resulting in CYP450 isotype 3A4.[16] Other CYP isoenzymes that are regulated by pregnane x receptor activation are CYP2B6[17] and CYP2C9[18]. The two compounds in St. John’s wort extract, hyperforin and hypericin, can interact with phase I metabolism in a few ways. Hyperforin activates pregnane X receptor activation which leads to the expression of retinoid X receptor and results in the induction of CYP3A4. One paper has suggested that Hypericum perforatum should only be used with low hyperforin content and under careful monitoring as the combination can lead to undertreatment in vivo since this is the main compound which induces 3A4.[19] Hypericin has also shown to be a CYP3A4 inducer, along with CYP2D6 and a CYP2C9.[20]

Studies have also been done in humans examining St. John’s wort's effect on phase I metabolism. A study with 12 healthy individuals showed that CYP2C9, CYP1A2, and CYP2D6 were not influenced after 900 mg daily (as 300 mg thrice daily) of St. John’s Wort for 14 days, although CYP3A4 was induced.[21] In another study where CYP3A4 was induced, another cytochrome, CYP2C19, was induced in 12 healthy adult males where St. John’s Wort was given 300 mg three times a day for two weeks.[22] Patients with low CYP3A4 baseline activity are more likely to undergo 3A4 induction with St. John’s wort.[23] Also, a human study showed that, in addition to St. John’s wort being a CYP2B6 inducer, it significantly induces intestinal and hepatic CYP3A4 when administered over 2 weeks.[24] A study with 12 healthy subjects with 900 mg St. John’s wort determined that long term use did not alter the CYP2C9, CYP1A2, or CYP2D6 activities.[25] Although, in females treated with 300 mg three times a day for 14 days, a study showed CYP1A2 induction by St. John’s wort.[26] CYP3A activity returns to baseline approximately 1 week after cessation of St. John's wort.[27]

St. John’s Wort has been shown to induce several enzymes in phase I metabolism both in vitro and in humans. This could lead to several significant drug-drug and drug-supplement interactions.

3.6

Known Drug Interactions

Hypernicum perforatum can interact with several drugs that affect the central nervous system, such as antidepressants, antipsychotics, antiepileptics, anxiolytics, anaesthetics, and analgesics. These interactions included reduced plasma concentrations due to enzyme induction or a summation of effects, depending on the specific drug.[28]

SSRIs and St. John’s Wort cause additive effects on serotonin reuptake inhibition which could lead to serotonin syndrome.[28]

In regard to bronchodilators, theophylline with 300mg of St. John’s wort showed decreased AUC and blood concentrations through CYP3A4 inhibition,[29] although when taken for 15 days it showed that St. John’s Wort did not play a role on plasma or urine levels; proper monitoring should be done when given together[30] .

Oral anticoagulants, specifically warfarin, should not be used with Hypericum perforatum as a studies showed that it decreases warfarin’s effect[31] and decreases levels of phenprocoumon[29] although there were no results of bleeding or thrombotic events seen with the combination[32].

Hypertensive medications can also be affected. St. John’s wort and calcium channel blockers such as nifedipine interact as Hypericum perforatum, which induces the metabolism of nifedipine and increases the plasma concentration of dehydronifedipine.[33] Hypericum perforatum also interacts with verapamil as it decreases the bioavailability through the induction of CYP3A4.[34]

Different statins have different interactions with St. John’s Wort as the combination with simvastatin lowers plasma levels[35] as well as increases lipoprotein levels[36], while pravastatin has no interaction[35].

Caution should be taken when taking proton pump inhibitors, specifically esomeprazole and omeprazole, as the combination with St. John’s wort results in reduced plasma concentrations of the drugs.[37]

Higher incidences of bleeding episodes was seen with the use of Hypericum perforatum and oral contraceptives as it reduces the plasma concentrations of oral contraceptive tablet components.[28] Serum estradiol and progesterone and ethinylestradiol levels are not significantly changed with Hypericum perforatum although 3-keto-etonogestrel significantly reduced with Hypercium perforatum.[38] A study showed that the combination of St. John’s wort and contraceptives significantly increased the oral clearance of norethindrone and reduced the half-life of ethinyl estradiol.[39]

Due to the induction of several metabolites, St. John’s wort also plays a role on reducing the plasma concentration of many opioids such as oxycodone, dextromethorphan and pethidine.[28]

Concomitant use of antibacterials, antifungals and antiviral drugs along with St. John’s wort should be avoided as there a large number of interactions between them.[40]

One study found that 600 mg of St. John’s wort extract reduced cyclosporin A plasma concentrations and altered the metabolite kinetics.[41]

Significant antineoplastic drugs such as irinotecan should not be used with Hypericum perforatum as the combination reduces the plasma levels and plays an impact on the treatment outcome as seen in a randomized crossover study.[42]

St. John’s wort causes a higher risk of hypoglycaemia when used in combination with tolbutamide.[43]

4.

Neurology

4.1

Adrenergic Neurotransmission

When tested in vitro, both hyperforin and hyperoside have been noted to downregulate β1 adrenergic receptors when at a concentration of 1μM over three days incubation resulting in 10% less activity under basal conditions and under stimulation (assessed by cAMP production).[44] These mechanisms also appear to apply to the high affinity β2 adrenergic receptor subsets[45] and hypericin may also be active on adrenergic receptors although with a different time for efficacy than hyperforin.[46] It is uncertain how this occurs with St. John's wort bioactives, although an oxidative component may exist since this process can be inhibited by Vitamin E in vitro.[47]

Hyperforin appears to downregulate β-adrenergic receptors in the rat frontal cortex following subchronic exposure[48] and appears to be similar to other antidepressants (imipramine and fluoxetine) where there is a mild decrease in β-adrenergic signalling in the prefrontal cortex after two weeks with a mild increase after eight weeks, although its efficacy differed based on the fractions used.[46]

4.2

Dopaminergic Neurotransmission

A single high dose of hypericum perforatum (300mg/kg of 0.3% hypericin and 4.1% hyperforin) in otherwise normal rats appears capable of increasing extracellular dopamine in the prefrontal cortex by 40% after an hour;[11] this was associated with reduced levels of dopamine's metabolites DOPAC (15% of baseline) and HVA (53%) while noradrenaline (NA) remained unchanged, and due to no overall changes in tissue dopamine concentration this was attributed to increased turnover.[11]

This observation is in line with in vitro observations of hypericum perforatum inhibiting dopamine reuptake due to hyperforin,[49] as while a methanolic extract of the plant inhibits dopamine reuptake to a potent degree (IC50 of 0.85µg/mL[49]) pure hyperforin is said to be more potent.[50] This is thought to be unrelated to the dopamine transporter (DAT) itself, as a DAT inhibitor failed to replicate the effects[11] (the effect on serotonin reuptake from hyperforin is also unrelated to its transporter[8][9]) and although blockade of the NA transporter could also prevent dopamine reuptake[51] NA concentrations were unaffected.[11]

4.3

Serotonergic Neurotransmission

Subchronic administration of St.John's Wort has been noted to increase 5-HT2 serotonin receptors in the frontal cortex of the rat brain.[48]

Potential influence on serotonin receptors

Hypericum perfotatum is known to inhibit serotonin reuptake in a manner not associated with the serotonin transporter (SERT),[8] which is the common mechanism of SRI/SSRI antidepressants. The active component is known to be hyperforin (amongst other possible components)[49] and appears to work by increasing intracellular sodium concentrations.[9] Unlike monensin, a chemical that can increase intracellular sodium concentrations unilaterally leading to toxicity,[52] hyperforin appears to only do so to a certain degree before losing efficacy in vitro.[9]

Mild elevations of serotonin have been noted in the prefrontal cortex of rats given 300mg/kg St.John's Wort (4.1% hyperforin).[11]

Hyperforin is likely the component of St.John's Wort that increases serotonin activity overall, and this appears to be due to inhibiting serotonin reuptake in an atypical manner

4.4

Miscellaneous Mechanisms

Hypericin[53] and the flavanol fraction of hypericum perforatum[54] are known to inhibit monoamine oxidase (MAO), with hypericin being activate at 1mM.[55] The extract of the plant itself seems more potent at inhibiting MAO (showing efficacy at 10µM[55]) but it is uncertain if MAO inhibition plays a role in the effects seen with hypericum perforatum supplementation due to the high concentrations required (with one study noting that while 100µg/mL of the plant was effective on both MAO-A and MAO-B, more practical concentrations of 1-10µg/mL were not[11]).

Catechol-O-methyltransferase (COMT) can also be inhibited by hypericum perforatum at 100µM while hypericin is inactive on this enzyme.[55]

While the plant has been noted to have inhibitory actions on both MAO and COMT, which would normally confer some antidepressant properties, it is uncertain if these mechanisms are relevant to supplementation due to high concentrations needed at the level of the enzymes

4.5

Depression

A 2008 Cochrane Meta-Analysis[56] of 29 trials (5489 patients) that were blinded and randomized in patients with major depression (DSM-IV criteria) noted that in the trials against placebo that St. John's Wort was associated with less depressive symptoms with an Odds Ratio of 1.28 (95% CI of 1.10-1.49) in larger trials and 1.87 (95% CI of 1.22 to 2.87) in the smaller trials.[56] The studies in this meta-analysis were quite heterogeneous, lasting between 4-12 weeks but was comprised of high quality studies (assessed by Jadad; 5/5 median value); this meta-analysis restricted studies to those in Major Depression, rather than the previous Meta-Analysis looking at all depressive studies.[57]

When St. John's Wort was compared to Tricyclic Antidepressants (TCAs) and SSRIs, the respective Odds ratio benefitting St. John's Wort were 1.02 and 1.00 respectively; suggesting that the was no practical difference between the pharmaceuticals and St. John's Wort.[56] Additionally, dropouts associated with St. Johns wort were significantly less than both TCAs (OR of 0.24) and SSRIs (OR of 0.53) suggesting that St. John's wort has less side-effects.[56]

The studies included in this meta-analysis that were against placebo are cited here,[58][59][60][61][62][63][64][65][66][67][68][69][70] with those comparative in nature (against pharmaceuticals) cited here against SSRIs[71][72][73][74][60][75][76][77][78][79][61][80][81][82][83] or TCAs.[84]][84][85][86][87]

Non-response to St. John's Wort has been noted in some persons.[58]

St. John's Wort, overall, appears to reduce depressive symptoms with a potency not significantly different than SSRIs and TCAs (Pharmaceutical anti-depressants); some non-responders to St. John's Wort have been noted, who then respond to regular therapy

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