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.
Hypericin, initially thought to be the major psychoactive component of the plant
Hyperforin, a phloroglucinol derivative currently thought to be the major psychoactive component of the plant
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.
2.1. 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. This activation increases sodium uptake in the cell, and is dependent on NSCC1 and NSCC2, and this is thought to underlie the antidepressant effects as those two channels are present in neurons and the increase in sodium uptake correlates well with inhibition of serotonin uptake in vitro.
The NSCC that appears to be specifically implicated is TRPC6 and it appears that the related molecule adhyperforin also possesses this reuptake property.
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.
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 like SSRIs would; the reuptake has been tied into an increase in intracellular sodium ion concentrations. Reuptake inhibition has occurred with many other neurotransmitters as well including dopamine, noradrenaline, glutamate, and GABA although dopamine may be most sensitive (serotonin less sensitive and noradrenaline potentially unresponsive from standard doses).
This has been noted in the prefrontal cortex with oral supplementation in rats and in vitro in corticol neurons and hippocampal cells. Oral supplementation failed to influence neurotransmitters in the striatum.
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)
The bioavailability of hypericin has been stated to be approximately 14%.
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). 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.
Steady state plasma concentrations of hypericin can be reached after four days supplementation of hypericum perforatum (300mg thrice daily) of approximately 8.5µg/L.
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.
Ingestion of 300mg St.John's Wort (14.8mg hyperforin) in otherwise healthy subjects increases plasma hyperforin to 150ng/mL (280nM). 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.
3.3. Neurological Distribution
One review 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.
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); 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.
3.5. Phase I Enzyme Interactions
3.6. Known Drug Interactions
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). These mechanisms also appear to apply to the high affinity β2 adrenergic receptor subsets and hypericin may also be active on adrenergic receptors although with a different time for efficacy than hyperforin. 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.
Hyperforin appears to downregulate β-adrenergic receptors in the rat frontal cortex following subchronic exposure 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.
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; 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.
This observation is in line with in vitro observations of hypericum perforatum inhibiting dopamine reuptake due to hyperforin, as while a methanolic extract of the plant inhibits dopamine reuptake to a potent degree (IC50 of 0.85µg/mL) pure hyperforin is said to be more potent. This is thought to be unrelated to the dopamine transporter (DAT) itself, as a DAT inhibitor failed to replicate the effects (the effect on serotonin reuptake from hyperforin is also unrelated to its transporter) and although blockade of the NA transporter could also prevent dopamine reuptake NA concentrations were unaffected.
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.
Potential influence on serotonin receptors
Hypericum perfotatum is known to inhibit serotonin reuptake in a manner not associated with the serotonin transporter (SERT), which is the common mechanism of SRI/SSRI antidepressants. The active component is known to be hyperforin (amongst other possible components) and appears to work by increasing intracellular sodium concentrations. Unlike monensin, a chemical that can increase intracellular sodium concentrations unilaterally leading to toxicity, hyperforin appears to only do so to a certain degree before losing efficacy in vitro.
Mild elevations of serotonin have been noted in the prefrontal cortex of rats given 300mg/kg St.John's Wort (4.1% hyperforin).
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 and the flavanol fraction of hypericum perforatum are known to inhibit monoamine oxidase (MAO), with hypericin being activate at 1mM. The extract of the plant itself seems more potent at inhibiting MAO (showing efficacy at 10µM) 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).
Catechol-O-methyltransferase (COMT) can also be inhibited by hypericum perforatum at 100µM while hypericin is inactive on this enzyme.
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
A 2008 Cochrane Meta-Analysis 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. 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.
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. 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.
The studies included in this meta-analysis that were against placebo are cited here, with those comparative in nature (against pharmaceuticals) cited here against SSRIs or TCAs.]
Non-response to St. John's Wort has been noted in some persons.
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