How New Medicinal Plants Are Discovered: Key Stages of Selection and Testing

Selecting a promising medicinal plant means putting each candidate through three demanding "rounds of competition" — chemical, pharmacological and clinical — and only the plant that passes all three earns a place in modern medicine. A winning medicinal plant must contain compounds with the pharmacological or chemotherapeutic action being sought, its therapeutic effect must exceed that of existing drugs with the same action, and its harmful side effects must be smaller.

What are the stages of medicinal plant selection?

Medicinal plant selection follows a sequence of scientific evaluations, each with its own methods and each eliminating many contenders. A plant judged on scientific merit alone must sit three "exams": the chemical stage (identifying and isolating active compounds), the pharmacological stage (testing biological action and toxicity in animals), and the clinical stage (trials in patients). Each step is specialized, and at every step many participants are, regrettably, screened out.

Criteria for selecting a promising medicinal plant

A candidate plant qualifies only when it satisfies pharmacological, chemotherapeutic, comparative and economic requirements together. The chemical constituents must produce the desired action, that action must be measurably better than existing therapies, and the whole undertaking must be affordable and supplied by a secure raw-material base. A plant can be scientifically brilliant and still be rejected because its raw material is too scarce or too expensive to gather.

Pharmacological and chemotherapeutic requirements

The first requirement is that the plant contain chemical substances with a clearly defined pharmacological or chemotherapeutic effect. Identifying the active substances is straightforward when a single compound is responsible for the therapeutic effect. When the effect is produced by a complex of substances — which unfortunately happens often — the individual bioactive compounds cannot always be pinned down, and the plant must be studied as an extract rather than as a pure molecule.

Comparing efficacy against existing drugs

A new plant preparation is only worth developing if its therapeutic effect surpasses that of drugs already in use for the same purpose. Drawing on the record of empirical medicine, it is easy to list dozens of new remedies for diarrhoea, cough, headache or lower-back pain, but they cannot compete with the powerful arsenal scientific medicine already deploys in those cases. The best preparations are those with a genuine advantage — a stronger effect, fewer side effects, or an action that holds up beyond one-off observations.

Economic factors in plant selection

Economic viability decides the fate of many otherwise promising plants. The search for the cheapest, simplest and safest production technology is a decisive problem. When a valuable natural compound lacks an inexpensive natural source, partial synthesis is often used — building complex substances from simpler, more available precursors. In the post-war years, for example, industry switched entirely to semi-synthetic camphor made from bornyl acetate obtained from Siberian fir twigs, replacing the scarce imported resin of an aromatic Indonesian tree and the leaves of the subtropical camphor laurel with cheap, widely available domestic material.

The chemical stage

The chemical stage establishes what a plant actually contains and in what quantities. Where nothing is known about the chemistry, a preliminary survey is done first to answer whether the target substances are present at all and roughly at what levels.

Preliminary chemical screening

Preliminary chemical screening tests the raw plant material for the presence of particular classes of bioactive compounds. This inexpensive first pass can rescue an interesting but weakly active plant from being discarded, and it guides all later, more costly work by showing which chemical groups are worth pursuing.

Isolation of biologically active compounds

In-depth chemical study then isolates every bioactive substance of interest — for instance the mixture of a plant's alkaloids — and measures the percentage of each in the plant organ under examination. Chemists next try to separate the individual substances in pure form and to determine whether they were already known or are new compounds isolated for the first time.

Determining the structural formula

Establishing the structural formula — working out the architecture of a molecule — is the most absorbing and difficult part of the work, and the crowning achievement of the chemists' effort. It is not always attainable: sometimes a substance can be isolated but its formula cannot be resolved; in other cases the active substances cannot be separated, or cannot be isolated at all.

Single compounds vs. complex mixtures

How closely a therapeutic effect tracks a single chemical compound determines the whole path of study. When one compound is responsible, the active substance is easy to identify and a "pure" preparation of strictly defined composition can be made — the hypotensive action of the alkaloid reserpine from Rauvolfia serpentina rhizomes, for instance, is many times stronger than a tincture of the same rhizomes, and pure preparations can be dosed precisely and their activity easily controlled. When a whole complex of substances acts together and the sum outperforms the parts, a galenic or novogalenic preparation must be produced instead.

Galenic and novogalenic preparations

Galenic and novogalenic preparations are the answer when the therapeutic action comes from an as-yet chemically unstudied mixture whose components are weaker individually than together. The experience of empirical medicine, partly already confirmed in the clinic, supports the use of such complexes. Well-chosen "pure" fractions containing alkaloids, saponins, coumarins or flavonoids can also be combined into compound preparations that keep the advantages of single-component drugs — stable composition, standard quality, ease of dosing — while acting on several body functions at once.

Removing ballast and harmful substances

Removing ballast and harmful substances can turn a poor candidate into a usable drug. The rhizomes of a hedge bindweed, for example, show almost no laxative action in experiments because the resins that would purge are accompanied by tannins with the opposite, astringent effect; only after the tannins are removed does the laxative action appear. Clearing away inert and toxic material yields infusions, tinctures and extracts that can convert an interesting but low-yield plant into a low-toxicity medicine of high biological activity.

Defining quality by biochemical content

The quality of a medicinal plant is defined not by its bulk but by its content of biologically active secondary metabolites. Bioactive compounds — the alkaloids, saponins, phenolics and glycosides synthesised as part of a plant's chemical defence — are the true measure of value, so a batch is judged by its biochemical profile rather than its weight. Chinese researchers including Chunhong Zhang at Baotou Medical College and the Inner Mongolia Key Laboratory of Characteristic Geoherbs Resources Protection and Utilization have shown, for example, that the saikosaponins that make Bupleurum chinense Franch. and Bupleurum scorzonerifolium Willd. medicinally useful vary sharply in concentration, which is why Traditional Chinese Medicine has long insisted on "geoherbs" from defined origins.

Chemical composition variation by region

The same species can differ chemically from one region to another, so provenance is itself a quality criterion. Panax ginseng C. A. Mey. and Panax notoginseng accumulate different saponin ratios depending on where they grow, and Lycium barbarum L. from the Qaidam Basin of Qinghai Province is prized because the high-altitude, arid environment shifts its metabolite profile. Selecting a production area with the right ecological suitability is therefore part of guaranteeing a standardised, effective final drug.

Environmental factors affecting plant biochemistry

Environmental factors — light, temperature, altitude, soil nutrients, water stress and pollution — steer secondary metabolite biosynthesis and accumulation. Because these compounds are chemical defences, mild stress often raises their levels, which is one reason field management practices deliberately regulate nutrients rather than simply maximising them. Pollution prevention matters just as much for quality as for safety: plants readily take up heavy metals, so growing sites must be chosen and monitored to keep contamination out of the finished medicine.

Harvest timing and active compound levels

Optimal harvest timing can double or halve the yield of the active compound, because metabolites rise and fall through the day, the developmental stage and the season. Known patterns of biosynthesis, accumulation and decline let researchers predict the phase of maximum content and forecast the best regions, dates and growing conditions for collection. Documented examples of species-specific timing include:

• Echinacea — root phenolic compounds peak at particular points in the growing cycle, so root harvest timing governs potency.
• German chamomile — essential oil content follows a daily cycle, favouring harvest on a specific daily rhythm to capture peak oil.
• Peppermint — menthol concentration climbs through defined developmental stages, so the mint is cut when menthol is highest.
• Garden thyme and pennyroyal — active levels are optimised at the flowering stage.
• Horse chestnut — escin builds up as the seed develops.
• American mayapple — sunlight exposure and harvest timing influence podophyllotoxin content.
• Labrador Tea — traditional harvesting by the Innuit of Northern Maine and around the Bay of Fundy tracks seasonal peaks in active compounds.

Structure–activity relationships and production technology

Uncovering the link between a compound's structure and its biological activity opens the way to transforming that structure and creating new substances with the properties sought. It also lets chemists intervene deliberately in the make-up of natural compounds, altering them in a chosen direction. Alongside this comes the practical problem of finding the most economical, simple and safe technology for producing plant drugs.

Improved technology repeatedly rescues once-scarce medicines and protects wild populations. Extracting platyphylline — including its epoxide form — from a ragwort's rhizomes and switching to its above-ground parts as raw material secured an uninterrupted supply of a formerly deficient drug while sparing its wild stands from destruction. Manufacture of berberine from barberry roots, solasodine from lobed nightshade, and morphine from the ripe capsules of ordinary oilseed poppy rather than opium poppy was likewise sharply improved. Technologists, taking account of where bioactive substances are localised in the raw material, also work out the optimal regimes for drying and processing it.

The pharmacological stage

The pharmacological stage tests whether the chemistry actually produces a therapeutic effect in a living organism. Suppose a sum of bioactive substances, or even individual compounds, has been isolated — they still cannot be called active substances, because nothing is yet known about how they affect the bodies of experimental animals and, ultimately, of humans. Plants that carry significant quantities of promising compounds are passed to this next round of deeper medico-biological study.

Experimental testing of therapeutic action

Several dosage forms of the preparation, cleared as far as possible of ballast and low-activity matter, are prepared and tested on laboratory animals — rabbits, cats, dogs, rats and mice. Researchers establish the drug's action on all the main body functions, regardless of the intended use, because an entirely new and unknown property may emerge. Thermopsis, long used as an expectorant, is the classic example: pharmacological study of some batches revealed stimulation of the respiratory centres, and the cause proved to be the alkaloid cytisine in seeds present in material collected after flowering — turning thermopsis into a source of respiratory stimulants as well as expectorants.

Assessing toxicity and side effects

A plant preparation is set aside when its action is markedly weaker and offers no special advantage over existing drugs of the same type, even if that action is experimentally confirmed. Only preparations that both show a real advantage and demonstrate the wanted medico-biological effect consistently — not merely in single observations — are judged worthy of advancing. Establishing low toxicity of the recommended doses is the precondition for moving on at all.

The clinical stage

The clinical stage is decisive because the body of any laboratory animal differs greatly from that of a sick human being. Permission for wide clinical testing is granted only when there is full confidence that the recommended doses are non-toxic. Testing begins as a preliminary trial and, if results are encouraging, expands to hundreds and sometimes thousands of patients.

Clinical trials and patient evaluation

Clinical trials inevitably reject a large share of the objects under study. A preparation may reveal an undesirable side effect, prove weaker than existing remedies, or turn out to be too expensive; only in the absence of all such defects was a drug recommended for wide medical use. Beyond comparing the qualitative and quantitative activity of the candidate against existing drugs, clinicians weigh many parameters that govern its therapeutic usefulness:

• toxicity and the size of the gap between therapeutic, toxic and lethal doses;
• negative and positive side effects and any allergenic properties;
• cumulative properties — the unwanted tendency to build up in the body;
• the risk of dependence and the resulting withdrawal syndrome when use stops;
• suitability for the various routes of administration.

Therapeutic indications by body system

Most drugs act on at least one body system, so therapeutic indications are classified by the system affected. A medicine may stimulate or suppress the central nervous system, constrict or dilate blood vessels, act on smooth or striated muscle, or speed up or slow the secretion of urine and bile. Even seemingly simple effects — laxative, astringent, antitussive, hypotensive — rest on very different mechanisms of action, and understanding them is essential for prescribing correctly. Every illness needs its own "drug of choice," matched to the patient and the disease, and both narrow- and broad-spectrum agents are required.

Common reasons candidate plants are rejected

Candidate plants most often fail because their action is too weak, offers no advantage, carries unacceptable side effects, or is too costly to produce. Extending the indications of an already approved drug is one of the most economical routes to new treatment options, since the search for a universal panacea is as utopian as the hunt for a remedy that works against a single disease alone. There is also the reverse problem: some plants that empirical medicine uses widely cannot be validated because chemistry fails to isolate any known active substance and pharmacology has no reliable animal model for the disease in question.

Case study: correcting opposing actions in plant extracts

When two constituents of an extract cancel each other out, the plant can be salvaged by removing the antagonist. The hedge bindweed rhizome again illustrates this: its resins would purge, but accompanying tannins exert an opposing astringent action, so the crude material shows almost no effect. Only after the tannins are stripped away does the laxative action appear — a reminder that rejection is sometimes a technology problem, not a verdict on the plant.

From selection to cultivation and supply

Selecting a promising plant is only the beginning; a stable drug depends on cultivation and a resilient supply chain. Once a species is validated, breeders pursue cultivar development and phenotype-assisted selection to raise the content of the target metabolite, drawing on genetic resources and high-quality germplasm. Lobed nightshade brought into cultivation in the south of Kazakhstan and the Northern Caucasus, for instance, supplied the steroidal glycoside solasodine that served as a starting precursor for cortisone-type hormonal drugs, and semi-synthesis of complex hormones from simpler plant steroids grows ever wider because such medicines carry great medical importance.

Cultivation factors affecting medicinal value

Cultivation decisions shape the medicinal value of the harvest as much as genetics do. Production area selection for ecological suitability, field management that regulates nutrients, pest, disease and weed control, and careful harvesting and post-harvest processing all influence how much active compound the crop finally holds. Storage methods matter too: correct drying and handling preserve the bioavailability of secondary metabolites that would otherwise degrade, which is why processing regimes are tuned to where each compound is localised in the plant.

Sustainability and traditional knowledge considerations

Sustainability and traditional knowledge together protect both wild plant resources and the accumulated wisdom that points research toward useful species. Ethnopharmacology and ethnobotany — using field methods such as free listing, herbarium documentation and socioeconomic profiling — record how communities use apparent and non-apparent plants, native and exotic alike. Work by researchers including Marcelo Alves Ramos, Taline Cristina da Silva, Josilene Marinho da Silva and colleagues at the Laboratory of Ethnobiological Studies, the University of Pernambuco and the University of Alagoas State — studying the transformed Atlantic Forest landscapes of Northeastern Brazil around Aliança, Recife and Engenho Cuieiras through the lens of the ecological apparency and diversification hypotheses — shows how secondary forests and anthropogenic areas remain vital plant sources even as acculturation erodes traditional medical knowledge. Integrating this heritage with modern science, as the World Health Organization advocates, keeps supply chains resilient and prevents valuable species from being lost.

Reserving in-depth chemical study until pharmacological activity is confirmed, and running chemical and pharmacological work in parallel rather than one after the other, is how the scheme described here is applied in practice. When chemists cannot isolate or even detect an active substance yet the plant is widely used in empirical medicine, the deep chemical "exam" is waived and the plant goes straight to pharmacologists — because its action may rest on substances still unknown to us. Until the 1930s no one knew ascorbic acid existed, and plants rich in that valuable medicine were wrongly dismissed as unpromising; chemistry advances so quickly that new bioactive substances should be expected every year. All the world's data on plant activity, the herbal experience of every era and people, and the chemistry and other markers of each plant's promise ought to be gathered into a single computerised data bank, which would speed retrieval and, by revealing trends and regularities, allow the promise of any plant to be forecast. Despite the successes of synthetic chemistry, the plant cell will remain the model of the most economical laboratory for producing biologically active substances, an inexhaustible source of ever new medicines.