Labisia pumila (Kacip Fatimah) Extracts: Aligning Extraction Research with the Clinical, Regulatory and Safety Evidence—A Critical Review

1. Introduction

Labisia pumila (Blume) Fern.-Vill., also classified as Marantodes pumilum and known in Malaysia as kacip fatimah, is one of the most widely used women's health herbs in Southeast Asia. Traditionally its leaves are boiled and drunk, including to ease childbirth, and it is now sold as powders, capsules and beverages [1,2]. Two comprehensive reviews published in 2025 catalogued more than 100 constituents and a wide range of pharmacological activities, while noting that clinical and safety evidence remains limited [3,4].

A large part of the recent literature concerns extraction. Radzali and colleagues compared eight solvents for maceration and seven co-solvents for supercritical carbon dioxide extraction of L. pumila leaves, and recommended carbon dioxide with 70% ethanol–water for further optimisation because it gave the best combination of gallic acid, methyl gallate, caffeic acid, total phenolic content and antioxidant activity [5]. The approach is typical: solvents are ranked by yield, a few phenolic acids and in vitro antioxidant assays.

This review asks a question the extraction literature rarely addresses: does an extract optimised in this way resemble the extracts that have been tested in humans, assessed by regulators or studied for safety? It compares the material and markers of the source study with those of the clinical and regulatory evidence, recalculates the source data to show what the selected markers represent, and considers what a fit-for-purpose specification for L. pumila extracts should contain.

2. Methods

Europe PMC and Crossref were searched to October 2026 for human studies, regulatory opinions, toxicological studies and phytochemical studies of L. pumila or M. pumilum, with emphasis on randomised trials, safety assessments, variety authentication and the identification of oestrogenic constituents. Reference lists of recent reviews were screened [3,4,6,7]. From the source study [5], extraction conditions, yields and phenolic acid contents were extracted from its Table 1 and Table 2, and marker recovery per gram of leaf was calculated as yield multiplied by content. This is a narrative critical review; no pooled analysis was attempted.

3. What Has Been Tested in Humans and by Regulators

Table 1 summarises the L. pumila materials with human, regulatory or toxicological evidence. The single-herb randomised trial gave 400 mg daily of a proprietary water extract of var. alata to women aged 40 to 60 years for 16 weeks; among 197 women analysed, the extract improved several quality-of-life domains and cardiovascular parameters without changing gynaecological hormones in postmenopausal women [8]. A second trial tested a combination with Eurycoma longifolia and found no significant difference from placebo in hot flushes, its primary endpoint [9]. Neither trial used an extract of var. pumila leaves.

The European Food Safety Authority assessed a hydroalcoholic extract of the dried whole plant, including roots, standardised to contain up to 3.7% gallic acid and mixed with maltodextrin. The applicant proposed up to 750 mg/day; the Panel concluded that the extract is safe only up to 350 mg/day, corresponding to 5 mg/kg body weight, and excluded pregnant and lactating women from the target population [10]. An aqueous extract had a no-adverse-effect level of 50 mg/kg in a 28-day rat study, with toxicity concerns at higher doses [11]. A case of spontaneous uterine rupture with fetal death has been reported in a woman who drank a leaf decoction continuously in late pregnancy [2]. These sources show that the safety of L. pumila depends on the material and the dose, and that the evidence attaches to specific extracts.

4. Variety and Plant Part

Three varieties of L. pumila are recognised in Malaysia, of which var. alata dominates the clinical and pharmacological literature. The varieties differ in phenolic, flavonoid and volatile composition [12], and DNA barcoding and infrared fingerprinting can distinguish var. alata from var. pumila and have exposed variability among commercial products [1,13]. The source study used leaves of var. pumila [5]. The clinical trial used var. alata [8], and the EFSA-assessed extract used the whole plant including roots [10]. Optimising extraction of var. pumila leaves may be valid in its own right, but its results cannot be assumed to apply to the materials that carry human or regulatory evidence, and products made from var. pumila leaves cannot cite those studies for support.

5. Solvent, Process and What the Markers Represent

5.1. The Markers Account for Little of the Extract

Table 2 shows selected data from the source study. Gallic acid, methyl gallate and caffeic acid together made up at most 1.69% of any extract, so more than 98% of each extract was uncharacterised [5]. The ranking of solvents was driven mainly by caffeic acid, which rose from 0.01% of the water macerate to 1.11% of the supercritical 70% ethanol extract. Gallic acid, the marker specified in the EFSA-assessed product at up to 3.7% [10], ranged only from 0.06% to 0.30%. The best supercritical extract therefore contained about one-twelfth of the maximum gallic acid content specified for the EFSA-assessed extract, and the water macerate about one-twentieth. A milligram of these extracts is not equivalent to a milligram of the assessed product, and dose statements cannot be transferred between them.

5.2. The Comparison of Processes Was Confounded

The supercritical extracts gave about twice the yield and up to four times the marker recovery per gram of leaf of the corresponding macerates (Table 2). The two processes, however, differed in more than the presence of carbon dioxide. Maceration used 10 mL of solvent per gram of leaf for 8 hours at room temperature, whereas supercritical extraction ran at 60 °C under continuous flow for 4.5 hours, with fresh solvent passing through the bed throughout [5]. Higher temperature and continuous renewal of solvent both increase extraction, so the advantage cannot be attributed to supercritical carbon dioxide itself. With aqueous co-solvents at 10% (v/v), the phase behaviour of the carbon dioxide–ethanol–water mixture depends strongly on composition, temperature and pressure [14], and it was not reported. Part of the extraction may therefore have proceeded as pressurised liquid extraction. A comparison with pressurised hot ethanol–water at the same temperature, flow and duration would be needed to show any specific benefit of carbon dioxide.

5.3. Antioxidant Assays Do Not Select for Relevant Activity

Total phenolic content, ferric reducing power and radical-scavenging assays measure the ability of an extract to reduce an oxidant in a test tube. They respond to almost any phenolic or reducing compound and are not indicators of a specific biological activity [15]. Food chemists have argued that they should not be used alone to claim health benefits [16]. L. pumila is used for women's health, and its proposed mechanisms involve oestrogen receptors rather than radical scavenging [3,7]. Selecting a solvent by antioxidant assays optimises for a property that is unrelated to the intended use.

5.4. The Discarded Fraction May Hold the Oestrogenic Constituents

The carbon dioxide extract without co-solvent gave a pale yellow extract at 2.95% yield, containing none of the three phenolic acids, and was ranked last [5]. Yet the constituents of L. pumila shown to bind oestrogen receptors are lipophilic. Bioactivity-guided isolation from a hexane extract identified four alkylresorcinols and a dimeric benzoquinone that bound oestrogen receptor α or β selectively [17], and a chloroform extract yielded the antiproliferative 5-henicosene-1-yl-resorcinol [18]. Long-chain alkylresorcinols of this type are poorly soluble in water and more soluble in non-polar solvents such as hexane. The fraction that the phenolic acid screen judged worthless is therefore the one most likely to contain the oestrogen receptor ligands, while the selected polar co-solvents are likely to extract them less selectively. Whether this is an advantage or a risk depends on the product: an extract intended to act through oestrogen receptors needs these compounds quantified, while one intended to avoid oestrogenic effects needs them limited. Either way, the choice of marker determined the choice of solvent.

6. Implications

6.1. For Manufacturers and Regulators

The evidence for L. pumila attaches to specific materials: a water extract of var. alata for quality of life [8] and a hydroalcoholic whole-plant extract for safety up to 350 mg/day [10]. A product made by a different process from a different variety or plant part is a different material. Table 3 proposes a minimum specification. Its central principle is that variety, plant part, solvent and drug-to-extract ratio should be declared, and that markers should include compounds relevant to the claimed mechanism as well as gallic acid. Because oestrogen receptor ligands are present [17] and an adverse outcome has been reported in late pregnancy [2], products should not be used in pregnancy or lactation, consistent with the EFSA opinion [10].

6.2. For Extraction Research

Extraction studies would be more useful if they changed their reference point. Rather than ranking solvents by yield and antioxidant activity, they could aim to reproduce, or improve on, the chemical profile of a clinically tested reference extract, measured by chromatographic fingerprint and quantified markers from several compound classes. Where a mechanism is claimed, a receptor-binding or reporter assay should replace total phenolic content. Process comparisons should hold temperature, solvent-to-feed ratio and time constant, so that any benefit can be attributed to the technology itself. Reporting marker recovery per gram of plant material, as well as per gram of extract, would allow both process efficiency and dose equivalence to be judged.

6.3. Limitations

This review is narrative and focuses on one representative extraction study; other extraction studies of L. pumila may have used different markers. The solubility argument for alkylresorcinols is based on their structure and their isolation from non-polar extracts, not on direct measurement in supercritical carbon dioxide extracts. The author's company manufactures botanical extracts, including women's health ingredients.

7. Conclusions

The extraction of L. pumila is usually optimised for yield, a few phenolic acids and antioxidant activity, using varieties and plant parts that differ from those with clinical and regulatory evidence. In a representative study, the three markers made up less than 2% of the extracts, the supercritical extract contained about one-twelfth of the maximum gallic acid content specified for the only regulator-assessed extract, the process comparison was confounded by temperature and solvent volume, and the fraction most likely to contain oestrogen receptor ligands was discarded. Extracts of L. pumila should be specified by variety, plant part, solvent and mechanism-relevant markers, dosed within the limits established for the assessed material, and developed against a clinically tested reference rather than a generic antioxidant screen.