As provided in the supplemental file, review of the secondary research yielded 403 citations from 139 ethnobotanical publications, including full or partial matches to species/genus, plant part and administration by indication (malady or condition), providing full or partial corroboration of 193 (73%) of the 263 reported use applications. Of the 70 use applications which were not found in any earlier ethnobotanical reports, 16 (22%) were found to be possibly supported by secondary data from in vitro and in vivo studies, including those involving compounds reported to be present in the respective taxon or genus.

Of the 263 use applications by taxon listed in Table 2, 191 are at least partially corroborated by one or more earlier ethnobotanical studies drawn from across the entire Africa region. Indeed, several of the cited taxa have been identified among the earliest medicinal plant remains recovered by archeological studies in northern Nigeria, including Vitex spp. dating back to c. 2800–2450 BP, and Bridelia scleroneura, Pavetta sp. and Sarcocephalus latifolius dated earlier than 800 CE [64].

No earlier mention can be found within the earlier ethnobotanical literature of 72 of the 263 medicinal applications in the current study (about 27% all use reports obtained. One notable example is Lepistemon owariense (Convolvulaceae), with an RI value of 79% based on four reported pharmacological properties affecting seven body systems, for which no earlier mention has been found. Other use applications undocumented in the earlier literature include seven taxa used to treat measles (Albizia coriaria, Gardenia ternifolia., Leonotis nepetifolia, Pavetta crassipes, Strychnos innocua, Vitex madiensis and Zanthoxylum chalybeum); three as anti-emetic (Celosia leptostachya, Indigofera arrecta, Phoenix reclinata); Dicoma sessiliflora for urinary problems, and Vernonia perrottetii for eye problems.

Of the apparently novel use applications, eight have some association with bioactivity in pharmacological (in vitro or animal model) or phytochemical studies, including antiviral compounds in Commiphora Africana, Chrysanthellum americanum and Vernonia perrottetii; antibacterial compounds in Albizia amara and Synedrella nodiflora; anti-inflammatory compounds in Vachellia hockii and Senegalia polyacantha, diuretic compounds in Sarcocephalus latifolius, and antimicrobial, anti-inflammatory, analgesic and antipyretic compounds in Physalis minima, the leaf-paste of which is applied to the umbilical cord of the new-born infant.

Figure 5 provides a geographic and historical context of the ethnopharmacological studies undertaken within Uganda, indicating that no earlier data were collected within the study area.

Geographic context of the Uganda studies

Of the earlier Ugandan studies mapped in Fig. 5, most accounts were limited to a specific ailment or condition [53, 65, 66] or a specific locality and culture [51, 52, 67,68,69,70].

From an ecological perspective, the number of cited taxa and use reports was compiled by plant family with intention to compare the findings with earlier studies, and with what is known of the floristic composition of the study area. Unfortunately, the earlier data (notably including the species lists compiled by Langdale-Brown et al. [14]) do not indicate relative abundance or frequency of occurrence, and the inventory and size-class distribution data collected on fixed and variable plots within the study area concurrently with data collection, some results of which were presented in an earlier paper [71], include only woody and not herbaceous species. Nonetheless, the degree to which Fabaceae have been selected for medicinal use stands in contrast to their natural occurrence—comprising over 24% of all medicinal use reports, as compared to the woody species inventory data, which places the family at just 4.2% of woody species by basal area in Otuke, and 18.6% by species composition in Amuria.

Table 2 is organized by family, and some commonality of use is visually evident within particular genera and families—examples including the remedies for cough and diarrhea within the Combretaceae, wound care among the Compositae, treatment for diarrhea in Moraceae, hernia among the Rubiaceae, and measles and cough among the Rutaceae.

Table 2 provides the common vernacular phytonyms for each taxon cited according to each of the cultures citing it for a medicinal use. Classification systems within the vernacular nomenclature reflect emic dimensions of cultural meaning [32] by which plants are classified according to folk systematics [72]. In general, the vernacular phytonyms presented here differ between cultures in the interpretive accessibility of information held within them, partly a function of the linguistic structures of the vernacular languages in which they are recorded.

Among the Lwo phytonyms, such linguistic qualifiers include adjectives referring to morphological characters, with the adjectives white, black and red (atar, achol and rema) commonly used to distinguish plant species within a genus or family. Taxonomically, the generic name for a group of species formerly classified together under the genus Acacia is okutu, of which Vachellia sieberiana is known as okutu atar, or white acacia; the genus Terminalia is called opok (of which T. mollis is opok acol, black terminalia), and in the genus Albizia (ibata), A. schimperiana (ibata atar) is distinguished from another, non-medicinal species known as ibata achol.

Other Lwo adjectives and descriptive nouns are likewise used as qualifiers in the vernacular nomenclature to distinguish related species within a genus, such as Amaranthus caudatus L. (ocobo), from which A. graecizans L. is distinguished as local by the qualifier ‘Lango’ (as ocobo Lango), in the same manner that ash filtrate is called ‘local salt’ (kado Lango). Similarly, the cultivated Cleome gynandra L. (akeo) is distinguished from C. monophylla L. as akeo Jok, in which the qualifier may signify its wild occurrence, or other properties.

While some Lwo plant names have a clear meaning for which a basis is not evident (for example, kongo ogwal-ogwal or ‘frog’s beer’ for Physalis minima), the basis for others is more directly related to the pharmacological activities attributed to the plants. Notable examples here include ocoko lac for Dicoma sessiliflora, a treatment for urinary infections, in which ocoko stands for the name of the plant, while the suffix ‘lac’ signifies urine, thus indicating its application.

Perhaps the most pharmacologically significant example is the qualifier ‘yat’. Defined by Kokwaro and Johns as “a general term for shrub, tree or medicine” [73], these three meanings are listed separately by other sources [74, 75], the latter separating its meanings as referring to a tree (or wood), to medicine or to an herb. In each such case, yat is followed by a second noun, often indicating a malady or condition to which the plant can be applied as a remedy, and thus indicative of its primary pharmacological property according to the current or past therapeutic application.

Examples of such nomenclature provided in Table 2 include Aerva lanata, yat dobo (or ‘leprosy medicine’ in leb Acholi); Pleurolobus gangeticus, yat aola (cough medicine); Oxalis corniculata, yat leny (heartburn medicine). Another example is Gloriosa superba.—yat ania, referring to its use in treatment of pneumonia (despite the notoriously extreme colchicine toxicity of the plant), and the tuber of an unidentified creeper called yat cak (milk medicine), credited with increasing milk production in humans and in livestock. Although no identification could be made on basis of the specimen provided, the taxonomic description and reported morphology of the plant are consistent with Dioscorea L. species, of which several are known to contain estrogenic compounds [76], and nine are present within the study area [77]. Estrogen is known to stimulate development of the mammary ducts, and, in association with progesterone, to stimulate proliferation of secretory tissues [78].

Examples of Ateso plant names which seem to imply their given therapeutic use may include Vachellia hockii (ekisim), the flowers of which are rubbed on the breasts (ekisin) of a mother who has lost her child to stop milk flow; Pseudocedrela kotschyi (eputon), the root of which is used to treat measles (epuru), and Zanthoxylum chalybeum (eusuk), various parts of which are used as a cough treatment—the word for lung given being euko [79]. By contrast, the name for Rhynchosia sp. (ookot) is strongly suggestive of blood (aokot [80]), but is only cited here as a diarrhea treatment in Teso. This again may imply a former medicinal use no longer in practice within the respondent communities of the study area.

From the etic perspective, results are consistent with the documented epidemiology of the study area. Together accounting for over 36% of use reports, the findings around the three major maladies—measles, diarrhea and cough—largely reflect the historical prevalence of these conditions among the respondent communities [81]. The national measles vaccination coverage rate in 2002 was just 74% [82], leaving over a quarter of all Ugandan children unprotected against measles; this number is likely to be considerably higher within the study area, given regional disparities in health-related outcomes and access and availability of treatment [83]. Bbaale [84] notes that rates of both diarrhea and acute respiratory infection are highest in the northern region, which he conjecturally linked to the history of civil conflict and displacement ending in 2008.

While measles was the malady most cited by number of taxa and number of combined use reports, this ranking is based specifically on the 27 use reports from Teso (Amuria District), the highest value (by a factor of two) of any malady by district. The highly contagious disease measles (rubeola) is caused by a single-stranded, negative sense RNA virus in the genus Morbillivirus of the family Paramyxoviridae, which also includes other parainfluenza viruses, e.g., mumps, rubella, and respiratory syncytial virus (RSV); measles results in a wide variety of health complications including pneumonia, blindness and chronic neurological conditions—and, although largely preventable by vaccine, measles remains responsible for an estimated 100,000 deaths each year [85,86,87,88,89]). Given the limited coverage of measles vaccination, these figures underline the relevance of locally available ameliorative treatments to manage the symptoms of the disease [90].

While a wide variety of phytochemical compounds have been found to inhibit viral replication via various pathways [91, 92], very few compounds are specifically linked to inhibition of the measles virus itself. Recently identified as antiviral agents with therapeutic value [93, 94], non-flavonoid phenolic coumarins and their derivatives (including pyranocoumarins) have been found to inhibit measles virus replication [95]. Although the mechanism of action is not understood, coumarin-like compounds have been found to interfere with or inhibit the viral enzymes of other, single-stranded positive sense Ribonucleic acid (RNA) viruses including Human Immunodeficiency Virus (HIV) [85]. According to the compositional studies consulted, coumarins and coumarin derivatives have been reported as present in 9 of the 27 taxa cited by respondents as being used in treatment of measles (Table 2).

Diarrhea was the highest-ranked malady by taxon and use report in three of the four cultures (Lango, Acholi and Ethur), by a factor of two over the second-ranked malady in those cultures. Diarrhea is the second leading cause of death globally in children under five years old, and a leading cause of malnutrition in that age group; nearly 1.7 billion cases of childhood diarrheal disease result in an estimated 525,000 child deaths each year [96]. Ugandans suffer the highest mortality rate of children under 5 years old in the East Africa region [97], with diarrhea accounting for over 20% of child deaths, against a global average of 8.6% [98, 99]. At the time of the data collection, prevalence of diarrhea within the northern region was the highest in Uganda, at any moment affecting 29.3% of the population [100], while a 2018 study specific to Agago District found the proportion children under 5 suffering from diarrhea to be over 40% [98].

Causative organisms of acute diarrhea include viruses (notably Rotavirus), Gram-positive and Gram-negative strains of bacteria (notably Shigella and Campylobacter spp., Escherichia coli and Staphylococcus aureus), and protozoa (notably Giardia lamblia) [101]. Phytochemical compounds effective in treating diarrhea include polyphenol catechins and tannins [102, 103] and the flavonol quercetin [104], specifically through increased colonic water and electrolyte reabsorption [103].

Cough was ranked at second in terms of use reports in all for regions, including Teso with 16 use reports. Persistent cough in Uganda has been linked to household air pollution including exposure to indoor smoke from cooking and lighting [105], and to infection by human pathogens including the influenza virus, particularly during the rainy season [106] and the Gram-negative, aerobic, pathogenic, encapsulated coccobacillus Bordetella pertussis, responsible for an estimated 400,000 annual deaths, mostly of infants in developing countries [99]. Several other bacteria—most notably the Gram-positive Streptococcus pneumoniae but also the Gram-negative Mycoplasma pneumoniae and Chlamydophila pneumoniae—are implicated in infectious pneumonia, the leading cause of mortality among children under 5 in sub-Saharan Africa, accounting for 12.8% of all such deaths [98]. In Uganda, Acute Respiratory Infections (ARIs) remain the leading cause of childhood morbidity and mortality among under-five children [107].

Phytochemical compounds with documented therapeutic activity in the treatment of cough include polysaccharides, anthraquinones and their derivatives. An in vivo study of cats [108] found cough suppressive activity in polysaccharide compounds isolated from nine plant species. [109]. Another study found that anthraquinone derivatives ameliorate lung inflammatory response, an effect recently reviewed with particular reference to Aloe (Asphodelaceae), Senna (Fabaceae) and Rheum L. (Polygonaceae) species [110].

Of the taxa cited for treatment of cough, Aloe volkensii is conspicuously abundant in polysaccharides [111], with a phytochemical profile including anthraquinones and pre-anthraquinones [112], as well as alkaloids, saponins, glycosides, flavonoids, and tannins [113] [114], noting that antioxidant compounds have been associated with a protective effect in cough suppression [115, 116].

Other maladies and conditions for which fewer use reports were obtained and species cited are nonetheless highly significant in terms of their mortality or morbidity, notably including snakebite—responsible for an estimated 32,000 annual deaths across sub-Saharan Africa (a quarter of the global total), leaving as many as 100,000 survivors with permanent physical disabilities [117]. The health burden on survivors of snakebite may involve hemorrhage, tetanus, contractures (debilitating stiffening of muscle or connective tissue), myonecrosis (life-threatening muscle infection), scarring, and tissue inflammation that result from the bites [118], resulting in 5000–15,000 amputations annually [119].

Horse-derived antivenin sera comprise the sole medical treatment for snakebite—but these are highly perishable, are unable to prevent local tissue damage, can induce adverse reactions including anaphylactic shock, and are scarce and unaffordable in the rural areas where nearly all envenomation occurs [118]. A 2018 study decried a compound global "crisis" of poor antivenom quality, availability and reliability of supply [120], and other authors have questioned the clinical effectiveness of available products within the Africa region in particular, as many such antivenin products were developed specifically to treat envenomation by Asian snake species [117]. In northern Uganda, where more than a third of snakebite victims are younger than 18 years, antivenom supplies are insufficient even at hospitals for optimum treatment of envenomation according to WHO guidelines [121]. These interrelated factors underline the importance of locally available envenomation treatments.

Of the four taxa cited for use in treatment of snakebite, Annona senegalensis Pers. root for treatment of snakebite was corroborated nine times in the ethnobotanical reports, and has been assessed clinically against venom of puff adder Bitis arietans [122], black-necked spitting cobra Naja nigricollis [123, 124], and West African Carpet viper Echis ocellatus [125].

No clinical antivenom studies were found on Gardenia ternifolia, although a 2015 study observed anti-inflammatory cyclooxygenase-1 (COX-1) inhibitory activity in an unspecified ethanolic extract, noted as a pathway of relevance to mouse hind paw oedema induced by Bothrops insularis (Golden Lancehead pit viper) snake venom [126]. Two studies [127, 128] have evaluated the in vitro antioxidant activity of G. ternifolia leaf extract containing flavonoid aglycones.

Although Steganotaenia araliacea root is cited as a snakebite remedy in seven ethnobotanical sources (with another report for its leaves), no clinical studies nor phytochemical data could be found for the species. No clinical evidence of antivenom activity was found on Trichilia emetica, but compositional studies indicate the presence of compounds with activity along potential antivenom pathways, including limonoid triterpenoids in root bark with notable anti-inflammatory properties [129, 130], noting further that a 2007 study reported a neurotoxin blocking activity of the limonoid triterpenoid toosendanin [131]. The flavonoid glycosides found to be present in a T. emetica seed extract [132] have been found to inhibit the phospholipase A2 (PLA2)-II toxins associated with some snake venoms [133, 134].

Although malaria is evidently a malady of great significance in northern Uganda, and the leading cause of morbidity and mortality in Uganda [135], it was ranked very low in the data (with just two use reports in Teso, and one in Lango), possibly reflecting the availability of pharmaceutical treatments, which are widely sold across the region by local traders and at weekly rural markets. The vernacular name for Schkuhria pinnata, reported as being used to treat malaria, was recorded as ‘kilorokwin’ in Ateso—certainly not a word characteristic of that language, but phonetically identical in the local pronunciation to the antimalarial compound chloroquine (chloroquine phosphate)—long the first line of pharmaceutical defense against non-resistant Plasmodium infection.

The sole taxon cited by respondents (in both Lango and Acholi) as a treatment for epilepsy, Hoslundia opposita, is abundantly evidenced in both the ethnobotanical record and in clinical studies. Noting its use in treatment of convulsion and epilepsy, as well as vertigo and mental disturbance, the anticonvulsant (central nervous system depressant) activity of a chloroform root extract of H. opposita was assessed in an animal model at 60% protection against leptazol-induced convulsions, and the extract was credited with potentiating the phenobarbitone sleeping time with an anticonvulsant activity comparable to benzodiazepines [136]. A later study [137] confirmed these results with respect to in vitro γ-Aminobutyric acid (GABA)A-benzodiazepine receptor binding activity of an ethanolic H. opposita leaf extract.

Cited in 7 use applications across three body systems for an RI of 71%, the root paste of Sarcocephalus latifolius is applied to incisions, or taken orally, as analgesic 'for any pains’. This use application is corroborated by multiple ethnobotanical sources cited by Burkhill [49]. More recently, a highly controversial 2013 paper [138] claimed to have isolated from the root ( ±)cis-2-[(dimethylamino) methyl]-1-(3 methoxyphenyl) cyclohexanol—a morphine analog commonly known by its international non-proprietary name, tramadol. A 2016 study [139] followed up on this controversial finding with a comprehensive study of S. latifolius which identified multiple antinociceptive compounds, most notably indoloquinolizidine alkaloids to which they attributed antiplasmodial and antibacterial, as well as analgesic activities.

Beyond the purely medical conditions which can be cross-referenced to the clinical data, respondents cited indications for more clinically ambiguous conditions which cannot be identified with confidence, which presented interpretive challenges in terms of data triangulation, which are discussed in the limitations section below. Four taxa were cited with reference to use applications loosely corresponding to ‘debility’—interpreted by the author to reflect use of the specified extract as an immunostimulatory tonic. Among them, the ‘bulb’ (corm) of Gladiolus dalenii was said to be chewed ‘to treat any sickness,' while the root paste of Kigelia africana was indicated as treatment for ‘general body weakness’. Respondents likewise ascribed immunostimulatory activities in the leaves of Cyphostemma adenocaule and the fruit of Strychnos innocua (‘you cannot get sick after eating’).

Perhaps related to these applications are the two taxa more specifically cited for treatment of anemia—the bulb extract of Gloriosa superba (notoriou