Hyperforin

Hyperforin has only been found in significant amounts in Hypericum perforatum with other related species such as Hypericum calycinum containing lower levels of the phytochemical.^[2] It accumulates in oil glands, pistils, and fruits, probably as a plant defensive compound.^[6] The first natural extractions were done with ethanol and afforded a 7:1 yield of crude extract to phytochemical however, this technique produced a mixture of hyperforin and adhyperforin.^[3][7][8] The extraction technique has since been modernized using lipophilic liquid CO₂ extraction to afford a 3:1 crude to phytochemical extraction which is then further purified away from adhyperforin.^[3][7][8] This CO₂ extraction is rather tricky still because typical 'supercritical' conditions extract less material whereas anything over 40 °C (100 °F) will degrade hyperforin.^[3][7][8] Other Hypericum species contain low amounts of hyperforin.^[9]

Hyperforin is a prenylated phloroglucinol derivative and is a member of the Polycyclic polyprenylated acylphloroglucinol family, also known as the PPAP family. Hyperforin is a unique PPAP because it consists of a C8 quaternary stereocenter which was a synthetic challenge unlike other PPAP synthetic targets.^[3][4][10] The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975.^[11][12] A total synthesis of the non-natural hyperforin enantiomer was reported in 2010 which required approximately 50 synthetic transformations.^[13] In 2010, an enantioselective total synthesis of the correct enantiomer was disclosed. The retrosynthetic analysis was inspired by hyperforin's structural symmetry and biosynthetic pathway. The synthetic route undertaken generated a prostereogenic intermediate which then established the synthetically challenging C8 stereocenter and facilitated the stereochemical outcomes for the remainder of the synthesis.^[10]

Hyperforin is unstable in the presence of light and oxygen.^[14] Frequent oxidized forms contain a C3 to C9 hemiketal/heterocyclic bridge or will form furan/pyran derivatives.^[7][8]

Some pharmacokinetic data on hyperforin is available for an extract containing 5% hyperforin. Maximal plasma levels (C_max) in human volunteers were reached 3–4 hours after administration of an extract containing 14.8 mg hyperforin. Biological half-life (t_1/2) and mean residence time were 9 hours and 12 hours, respectively, with an estimated steady state plasma concentration of 100 ng/mL (approx. 180 nM) for 3 doses per day. Linear plasma concentrations were observed within a normal dosage range and no accumulation occurred.^[15]

In healthy male volunteers, 612 mg dry extract of St. John's wort produced hyperforin pharmacokinetics characterized by a half-life of 19.64 hours.^[16]

Hyperforin may be a constituent responsible for the antidepressant and anxiolytic properties of the extracts of St. John's wort.^[2][17] In vitro, it acted as a reuptake inhibitor of monoamines (MRI) (particularly of serotonin, norepinephrine, dopamine) and of GABA and glutamate, with IC₅₀ values of 0.05–0.10 μg/mL for all compounds, with the exception of glutamate, which is in the 0.5 μg/mL range.^[18] In other laboratory studies, hyperforin induced cytochrome P450 enzymes CYP3A4 and CYP2C9 by binding to and activating the pregnane X receptor.^[19]

Current research focuses on understanding the biosynthesis of hyperforin and applying advanced techniques like omics, genome editing, and synthetic biology to enhance their pharmaceutical and medical uses.^[21]

It faces production challenges that biotechnological methods, such as specialized plant root cultures and microbial biosynthesis, are being developed to overcome for scalable and modifiable manufacturing.^[3]

Two meta-analyses of preliminary clinical trials evaluating the efficacy of St. John's wort for treating mild-to-moderate depression indicated a response similar to selective serotonin reuptake inhibitors and with better tolerance, although the long-term generalization of study results was limited by the short duration (4–12 weeks) of reviewed studies.^[22][23]

• Hypericin