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Hyperforin is a plant-derived compound that has been found useful in the treatment of depression. In fact, this phytochemical was shown to be superior to popular antidepressants such as Prozac. What is this natural compound extracted from St. John’s wort? How does it improve the symptoms of depression and what are the main studies to back its claim? How should it be used? Read on to find the answers to these questions.
by Brad Chase
Hyperforin is a phytochemical found only in plants belonging to the Hypericum genus.
However, not all the plants in this family produce hyperforin. In fact, only Hypericum perforatum or St. John’s wort contains a significant amount of the phytochemical.
The plant parts from which hyperforin can be obtained includes fruit, oil glands and pistil. These locations indicate that the phytochemical is produced to make the plant unpalatable for herbivores.
The chemical structure of hyperforin was first revealed in 1975. However, it was not until 2010 that the molecule was first synthesized in the laboratory. Hyperforin is easily destroyed when exposed to oxygen and light.
Hyperforin is believed to be responsible for most of the medicinal benefits of St. John’s wort. Its anxiolytic and antidepressant effects are the reasons the herb is used to relieve anxiety and depression while improving mood.
St. John’s wort refers to multiple members of the Hypericum plant family. However, this name refers to Hypericum perforatum which is also differentiated as common St. John’s wort.
The chief use of St. John’s wort is in the treatment of depression. The herb is commonly prescribed for mild to moderate depression especially in children and adolescents.
In a Cochrane Review of past studies done on the antidepressant effects of St. John’s wort, the reviewers concluded that there was strong evidence from available clinical studies that St John’s wort
A 2005 study published in the Journal of Clinical Psychopharmacology also showed that St. John’s wort was a much better antidepressant than Prozac.
Besides hyperforin, St. John’s wort contains another important bioactive phytochemical known as hypericin.
Hypericin was discovered well before hyperforin and it was once believed to be responsible for all the medicinal effects of St. John’s wort. However, recent evidences show that the effect of the herb on mood is due to hyperforin and not hypericin.
Still, hypericin has some medicinal effects. It crosses the blood-brain barrier into the central nervous system to block the actions of the enzyme, dopamine beta-hydroxylase.
This enzyme is responsible for the conversion of dopamine to norepinephrine. Therefore, hypericin can increase dopamine levels in the brain while reducing the levels of norepinephrine and epinephrine.
Although, St. John’s wort extract is still being standardized according to its hypericin content, scientists now know that the primary bioactive phytochemical in the herb (at least, when it is used as an antidepressant) is hyperforin.
In addition, hyperforin is responsible for all the drug interactions caused by St. John’s wort.
It induces two cytochrome P450 enzymes: CYP3A4 and CYP2C9. This leads to increased breakdown of a long list of drugs. Therefore, St. John’s wort is not recommended to be co-administered with many drugs.
In the treatment of depression, 300 mg of standardized St. John’s wort extract taken three times daily is recommended. Studies have shown that as much as 1800 mg daily of the herbal extract can be taken.
Although overdose of the herb is rare, there are reports of side effects. Some of these include sedation, tiredness, confusion, dizziness and gastrointestinal discomforts.
In rare cases, St. John’s wort may cause visual and skin photosensitivity. It should not be taken by schizophrenic patients as it may increase psychosis.
St. John’s wort should also not be combined with drugs that increase the level of serotonin in the brain since it also increases serotonin levels. Therefore, St. John’s wort should not be combined with most standard antidepressants, opioids, stimulants, psychedelic drugs, lithium, 5-HTP and tryptophan.
Such combinations will cause a type of serotonin toxicity known as serotonin syndrome, a toxicity that is potentially life-threatening.
To produce its anxiolytic and antidepressant effects, hyperforin blocks the reuptake of monoamine neurotransmitters in the brain.
Examples of neurotransmitters influenced by hyperforin include serotonin, dopamine, glutamate, epinephrine, norepinephrine and GABA (gamma aminobutyric acid). These neurotransmitters are stored in vesicles in the synapses between nerves. Therefore, they are released in the gaps between nerves to facilitate signal transmission and communication in the central nervous system
These neurotransmitters are released into the synaptic gap, allowed to work for a while and then removed from these gaps back into the vesicles where they are stored. To prolong their activities, hyperforin prevents the clearance of these neurotransmitters.
Besides the monoamine neurotransmitters, hyperforin also blocks the reuptake of glycine and choline.
The specific mechanism by which hyperforin achieves these blockages involve the activation of an ion channel known as transient receptor potential ion channel or TRPC6.
By activating this ion channel, hyperforin allows the inflow of calcium and sodium ions into nerve cells and this prevents the reuptake of monoamine neurotransmitters.
Other medicinal properties of hyperforin include anti-inflammatory and antibiotic effects.
As an anti-inflammatory agent, hyperforin inhibits the cyclooxygenase, COX-1, and the lipoxygenase, 5-LO. The anti-inflammatory effect of hyperforin is 3 – 18 times that of aspirin.
Hyperforin is also a potent topical antibiotic. It is effective against gram-positive bacteria especially MRSA (methicillin-resistant Staphylococcus aureus).
In a 1998 study published in the journal, Pharmacopsychiatry, a group of researchers compared the efficacies and safeties of two different concentrations of St. John’s wort in the treatment of depression.
The randomized, placebo-controlled, multi-center study recruited 147 patients and divided them into 3 groups after a week on placebo. Over the next 42 days, one group continued on placebo; another group received an extract with 0.5% hyperforin while the third group was given another extract containing 5% hyperforin.
The results showed that the 5% hyperforin extract was vastly superior to both the 0.5% hyperforin extract and placebo.
This study further proved that hyperforin is the active phytochemical responsible for the antidepressant effects of St. John’s wort. In addition, the study suggests that there is a need to determine the optimal concentration of hyperforin (the 0.5% extract was ineffective) in the treatment of depression.
In addition, the researchers believed that the hyperforin content of the herb should be the determining factor in choosing St. John’s wort extracts even though they are standardized for hypericin content.
To explain the possible contribution of hypericin content to the antidepressant effect of St. John’s wort, a group of researchers published their findings in the journal, Life Sciences, in 2004.
In that study, the researchers were able to demonstrate that an extract of the herb lacking hyperforin but containing hypericin was unable to produce the desired antidepressant effect while another extract containing only hyperforin did.
A 1999 study published in the journal, Neuroscience Letters, confirmed that the antidepressant effects of St. John’s wort was due to hyperforin and that the phytochemical acts by increasing the concentrations of monoamine neurotransmitters and glutamate in the synaptic cleft.
In the study, 10 mg/kg of hyperforin was given to a rat. Subsequently, the researchers found that the levels of dopamine, serotonin and noradrenaline (as well as glutamate, an excitatory neurotransmitter) were increased in the rat’s locus coeruleus.
In contrast, the concentrations of 5-hydroxyindolacetic acid, a serotonin metabolite, remained unchanged. This suggests that the breakdown of serotonin was not increased even though more serotonin was being released in the brain.
Another 1999 study published in The Journal of Pharmacology and Experimental Therapeutics demonstrated the unique mechanism by which hyperforin produces its antidepressant effects.
The researchers showed that hyperforin increases the intracellular levels of sodium ions in order to inhibit the reuptake of serotonin. This makes it the first antidepressant agent to increase serotonin levels by influencing sodium ion levels.
When possible, St. John’s wort extracts standardized by hyperforin content should be taken instead of the extracts standardized by hypericin content.
Hyperforin pills are St. John wort extracts standardized to contain 3 - 5% hyperforin. 300 mg of such pills taken 3 times daily is the recommended dosage for mild to moderate depression.
While St. John’s wort has been widely publicized to be potentially dangerous, the truth is that it is mostly well-tolerated, cause mild side effects and can only cause serious drug interactions in high doses. Even then hyperforin pills should only be combined with other medications when taken under the supervision of a physician.
Furthermore, since hyperforin pills only qualify as an herbal supplement, its manufacture is not subjected to the tight control of the FDA (Food and Drug Administration).
This means that different brands of hyperforin and St. John’s extract pills will widely vary in hyperforin content. This is especially so because most of the herbal extract pills in the market are standardized by only hypericin content.
Therefore, care should be taken to buy hyperforin pills from reputable brands.
Lastly, the use of hyperforin pills should not be stopped suddenly. Given the fact that hyperforin acts on the central nervous system and increases the levels of most of the neurotransmitters released in the brain, sudden discontinuation of the pills can cause serious withdrawal symptoms.
Instead, the dose of hyperforin pills should be gently reduced over time until it is low enough to be safely discontinued.
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