Standardized Plant Extracts (EPS): Modern Phytotherapy

Presentation

Standardized Plant Extracts, known by the acronym EPS, represent a major pharmaceutical advancement in phytotherapy. Developed in the 1990s by PhytoPrevent laboratories (Pileje group), EPS were born from the desire to reconcile two seemingly contradictory requirements: respecting the complete molecular heritage of the fresh plant (the totum) while ensuring rigorous, lot-to-lot reproducible pharmaceutical standardization.

The concept relies on a patented cryogrinding process followed by multi-step extraction with increasing alcohol concentrations. The fresh plant, harvested at its optimal development stage (balsamic time), is immediately frozen at -196°C in liquid nitrogen to preserve all its constituents — including the most fragile and volatile compounds that would be degraded by conventional drying or heat exposure. Grinding at cryogenic temperature produces an ultrafine powder with considerably increased contact surface, optimizing subsequent extraction.

The extraction process then uses a series of water-ethanol mixtures at increasing concentrations: first a highly aqueous mixture (low alcohol degree) to extract polar compounds — polysaccharides, amino acids, mineral salts, glycosylated flavonoids — then progressively more alcoholic mixtures for intermediate polarity compounds — condensed tannins, saponosides, free base alkaloids — and finally the most apolar compounds — terpenes, essential oils, resins, waxes. This sequential extraction, called "polarity gradient lixiviation," yields an extract containing virtually all constituents of the fresh plant.

The final extract is stabilized in vegetable glycerin (glycerol), a neutral excipient ensuring preservation without residual alcohol, and giving the product a pleasant-tasting syrupy texture. Glycerin replaces residual ethanol through vacuum evaporation, enabling EPS use in children, pregnant women (for authorized plants), and patients in alcohol detoxification.

In France, EPS hold the status of phytotherapy medicines listed in the French Pharmacopoeia and are dispensed in pharmacies by prescription or pharmaceutical advice. They are reimbursable as magistral preparations made by the pharmacist. Each EPS has a detailed monograph specifying its standardization markers, chromatographic profile (HPLC fingerprint), indications, dosage, and contraindications.

Fundamental Principles

The founding principle of EPS is the complete preservation of the fresh plant's totum. In phytotherapy, the totum designates the full set of a plant's chemical constituents which, through synergistic interactions, produce the overall therapeutic effect. EPS are distinguished from other galenical forms by their ability to preserve this totum through cryogrinding and multi-solvent extraction.

Standardization to active markers is the second pillar. Each EPS is characterized by one or more analytical markers quantified by HPLC, whose content must fall within a defined range. For example, St. John's wort EPS is standardized for hyperforin and hypericin, valerian EPS for valerenic acid and valepotriates, ginkgo EPS for flavone glycosides and terpene lactones. This dual approach — preserved totum and quantified markers — distinguishes EPS from conventional standardized dry extracts.

Bioequivalence to the fresh plant totum is verified by comparing chromatographic profiles (HPLC fingerprint) between the EPS extract and a reference extract of the fresh plant. This analytical approach, called "comparative metabolomics," goes beyond simple marker quantification and guarantees the integrity of the overall phytochemical profile.

The magistral prescription concept is essential to EPS use. The practitioner prescribes a personalized blend of 2 to 5 unit EPS that the pharmacist prepares as a magistral preparation. This approach enables maximum therapeutic individualization. The pharmacist ensures checking for incompatibilities, cross-contraindications, and galenical coherence.

EPS dosage is expressed in milliliters per day. The standard adult dose is 5 ml per unit EPS, 1 to 2 times daily (5–10 ml per day per plant). In blends, total daily dose is generally 10–20 ml for a 2–4 EPS mixture. EPS are taken diluted in a large glass of water, preferably before meals for optimal absorption. For children, dosage is adjusted by age and weight: 1 ml per 10 kg body weight per EPS, 1–2 times daily.

Technical Aspects of the EPS Process

Cryogrinding is the first critical step. The fresh plant, verified for botanical and phytochemical conformity, is immersed in liquid nitrogen at -196°C. At this temperature, all constituents are "frozen" in their native state: oxidative enzymes (polyphenol oxidases, peroxidases) are inactivated, labile covalent bonds are preserved, volatile compounds are trapped in the plant matrix. Cold grinding produces a powder with particle size below 500 µm and very high specific surface area.

The polarity gradient extraction proceeds in three to five successive steps. The first uses a 15–25% alcohol water-ethanol mixture, extracting the most hydrophilic compounds: sugars, amino acids, organic acids, mucilages, glycosylated flavonoids. The second uses a 40–60% alcohol mixture targeting intermediate polarity compounds: condensed tannins, proanthocyanidins, saponosides, free-base alkaloids. The third uses a 70–90% alcohol mixture extracting the most lipophilic compounds: terpenes, sesquiterpenes, diterpenes, essential oils, resins, phytosterols.

Fractions are then recombined in defined proportions to reconstruct an extract representative of the totum. Ethanol is evaporated under vacuum at low temperature (below 40°C). The residue is taken up in vegetable glycerin (pharmaceutical-grade vegetable glycerol) which serves as preservative, solvent, and pleasant-tasting excipient.

Quality control includes: botanical identity verification by microscopy, active marker quantification by HPLC-DAD or HPLC-MS, complete chromatographic profiling (fingerprint), contaminant screening (pesticides, heavy metals, aflatoxins, residual solvents), microbiological testing, and accelerated stability testing (ICH guidelines).

From a pharmacokinetic perspective, EPS offer significant advantages over dry forms (capsules, tablets). The liquid glycerin solution allows partial sublingual absorption, bypassing first-pass hepatic metabolism for some compounds. Glycerin improves solubility of poorly water-soluble compounds and facilitates intestinal absorption. Comparative bioavailability studies have shown EPS achieve plasma marker concentrations 20–40% higher than equivalent dry extracts, with Tmax reduced by 30–45 minutes.

Clinical Indications and Major EPS

• St. John's wort EPS (Hypericum perforatum): standardized for hyperforin (3–5%) and hypericin (0.1–0.3%). Primary indication: mild to moderate depression (efficacy comparable to SSRIs per Cochrane meta-analyses). Mechanism: serotonin, norepinephrine, and dopamine reuptake inhibition. Dosage: 5 ml twice daily for minimum 6–8 weeks. Caution: potent enzyme inducer (CYP3A4, CYP2C9, P-gp)
• Valerian EPS (Valeriana officinalis): standardized for valerenic acid (0.3–0.8%) and valepotriates. Indication: sleep-onset insomnia, anxiety. Mechanism: positive allosteric modulation of GABA-A receptor, GABA degradation inhibition. Dosage: 5 ml in the evening 30 min before bedtime
• Turmeric EPS (Curcuma longa): standardized for curcuminoids (3–5%) including curcumin. Indication: chronic joint inflammation, digestive disorders, metabolic syndrome. Mechanism: NF-κB, COX-2, LOX-5, TNF-α inhibition. Combine with black pepper EPS (piperine) for 2000% bioavailability increase
• Echinacea EPS (Echinacea purpurea): standardized for alkylamides and chicoric acid. Indication: prevention and adjunctive treatment of acute respiratory infections. Mechanism: macrophage stimulation, NK cell enhancement, direct antiviral activity. Dosage: 5 ml 3 times daily from first symptoms for 7–10 days
• Desmodium EPS (Desmodium adscendens): standardized for saponosides and isoflavonoids. Indication: hepatoprotection (chemotherapy, hepatotoxic drugs), adjunctive viral hepatitis. Mechanism: hepatocyte membrane stabilization, anti-fibrotic and choleretic activity. Dosage: 10 ml/day during hepatic insult
• Milk thistle EPS (Silybum marianum): standardized for silymarin (flavanolignans: silybin, silychristin, silydianin). Indication: hepatic steatosis, chronic hepatitis, liver protection. Mechanism: hepatocyte antioxidant, cellular regeneration, hepatic toxin penetration inhibition. Dosage: 5 ml twice daily for 2–3 months
• Rhodiola EPS (Rhodiola rosea): standardized for rosavins (3%) and salidroside (1%). Indication: physical and mental fatigue, chronic stress, burnout. Mechanism: adaptogen — HPA axis regulation, cortisol modulation, neuroprotection. Dosage: 5 ml in the morning for 4–12 weeks
• Saw palmetto EPS (Serenoa repens): standardized for fatty acids and phytosterols. Indication: benign prostatic hyperplasia (stages I–II). Mechanism: 5α-reductase inhibition, prostatic anti-inflammatory activity, local anti-estrogenic effect. Dosage: 5 ml twice daily for minimum 3–6 months

Prescription Process

A consultation leading to EPS prescription follows a structured clinical approach. The practitioner — physician, pharmacist, or trained naturopath — conducts a complete interview and directed clinical examination. Differential diagnosis eliminates pathologies requiring priority conventional management. Laboratory workup may be requested as clinically appropriate.

Prescription writing follows precise formalism. The practitioner writes: "Magistral preparation based on EPS" followed by the list of unit EPS with their proportions. Example prescription for anxious-depressive syndrome with sleep disturbance: EPS St. John's wort 2/5, EPS Valerian 1/5, EPS Passionflower 1/5, EPS Hawthorn 1/5. qsp 300 ml. Dosage: 10 ml morning and evening in a large glass of water, before meals. Duration: 2 months, renewable after consultation.

The pharmacist prepares the magistral formulation by blending the unit EPS in prescribed proportions. They verify the absence of incompatibilities, prescription coherence with the patient's condition, and apply regulatory labeling (composition, dosage, expiration date, storage).

Therapeutic follow-up is scheduled at 4 weeks for first evaluation, then every 6–8 weeks. The practitioner evaluates efficacy (target symptom improvement), tolerability (adverse effects, taste, compliance), and adjusts the formula as needed. A typical EPS treatment lasts 2–3 months for chronic conditions, with a one-to-two-week therapeutic window before renewal.

The most common synergistic combinations in clinical practice include: turmeric + desmodium (anti-inflammatory hepatoprotection), rhodiola + ginseng (chronic fatigue and adaptogenic), valerian + passionflower + California poppy (complex insomnia), echinacea + cypress + elderberry (winter immunity), chasteberry + yarrow (premenstrual syndrome), devil's claw + blackcurrant + meadowsweet (joint pain), milk thistle + rosemary + black radish (hepatic drainage).

Comparison with Other Galenical Forms

• EPS vs dry extracts (DE): dry extracts are obtained by evaporating the extraction solvent. They generally lose volatile compounds (essential oils) and may undergo thermal degradation. EPS better preserve the totum but are bulkier (liquid form). DEs are more concentrated and come in capsules (better compliance for some patients)
• EPS vs mother tinctures (MT): MTs use a single hydroalcoholic extraction (generally 60–70% ethanol) on fresh or dried plant. The extraction profile is less complete than EPS sequential extraction. MTs contain residual ethanol (contraindicated in children, pregnant women, recovering alcoholics). MT advantage: lower cost, well-established French pharmacopoeia tradition
• EPS vs infusions and decoctions: herbal teas extract only water-soluble compounds and partially volatile compounds (when covered). EPS offer a much more complete extraction profile. However, teas possess a beneficial therapeutic ritual dimension and hydration volume
• EPS vs gemmotherapy: glycerin bud macerates specifically target embryonic plant tissue rich in growth factors, hormones, and enzymes. EPS use the whole adult plant. Both approaches are complementary and often combined
• EPS vs essential oils: EOs contain only volatile and aromatic plant compounds. Their activity is potent but targeted. EPS contain the complete totum. EPS + EO combination is common in clinical practice
• Magistral EPS vs phytotherapy specialties: specialties (Euphytose, Arkogélules, etc.) are fixed-formula medicines validated by ANSM. Magistral EPS allow complete personalization but lack specific marketing authorization. Specialties offer superior regulatory guarantee but less therapeutic flexibility

Contraindications and Precautions

• EPS-specific drug interactions: the concentrated liquid form can achieve plasma concentrations sufficient for significant pharmacokinetic interactions. St. John's wort EPS is contraindicated with oral anticoagulants, cyclosporine, tacrolimus, oral contraceptives, HIV antiretrovirals, digoxin, theophylline, certain anticancer drugs (irinotecan, imatinib). Ginkgo EPS potentiates antiplatelet agents and anticoagulants (hemorrhagic risk)
• Pregnancy and breastfeeding: most EPS are contraindicated as a precaution during pregnancy and breastfeeding. Documented exceptions include ginger EPS (pregnancy nausea, safety studies available) and desmodium EPS (documented hepatoprotection). Always verify each EPS's specific monograph
• Children under 6: use possible with adapted dosage (1 ml/10 kg/day per EPS), but the number of EPS with documented pediatric safety is limited. Prefer plants with well-established safety profiles: elderberry, thyme, mallow, chamomile
• Severe hepatic or renal insufficiency: glycerin is metabolized by the liver and eliminated by the kidney. In severe organ failure, adjust dosage and monitor tolerability. Hepatotoxic EPS (greater celandine, germander, kava) are formally contraindicated
• Diabetes: glycerin has a non-zero glycemic index (approximately 5). At standard therapeutic doses (10–20 ml/day), glycerin contribution is negligible (< 10 g/day, < 40 kcal). However, inform type 1 diabetic patients on insulin
• Scheduled surgery: discontinue EPS with anticoagulant or antiplatelet activity (ginkgo, garlic, turmeric, willow, meadowsweet) 7–14 days before surgery. Inform the anesthetist about EPS use, especially sedative ones (valerian, passionflower) that may potentiate anesthetics