A Systematic Review of the Potential of Acmella Genus Plants for the Treatment of Musculoskeletal Disorders

1. Introduction

Medicinal plants have long been a primary and widely used source of safe and effective remedies among populations. Although the use of synthetic medicines has grown in recent years [1,2], the World Health Organization (WHO) estimates that approximately 80% of the global population continues to rely on medicinal plants as a primary means of addressing health issues, particularly in developing countries [3].

Musculoskeletal disorders are a significant global public health concern, impacting the muscles, bones, joints, tendons, ligaments, and related structures. Conditions such as arthritis, osteoporosis, tendonitis, and myopathies are prominent contributors to disability and diminished quality of life. While pharmacological treatments like nonsteroidal anti-inflammatory drugs, corticosteroids, and disease-modifying antirheumatic drugs are commonly used, their effectiveness is often constrained by side effects, highlighting the need for alternative therapeutic approaches [4,5,6,7].

Plant-derived natural products are increasingly recognized for their potential in addressing pain, inflammation, and other musculoskeletal conditions. Within traditional medicine, species from the Asteraceae family have been extensively utilized for their pain-relieving and anti-inflammatory effects [8]. Notably, plants from the Acmella genus, including Spilanthes acmella, Blainvillea acmella, Acmella oleracea, and Acmella uliginosa, are being actively studied for their bioactive properties.

The objective of this systematic review is to summarize the evidence on the use of Acmella genus plants, specifically Spilanthes acmella, Blainvillea acmella, Acmella uliginosa and Acmella oleracea, for musculoskeletal disorders by evaluating preclinical and clinical evidence.

Background on Acmella Genus Plants

Spilanthes acmella, Blainvillea acmella, Acmella uliginosa and Acmella oleracea are all plants that belong to the Asteraceae family, commonly known as the daisy family or sunflower family. These plants are typically herbaceous and perennial, often growing in tropical and subtropical regions. They generally have yellow or orange flower heads with a daisy-like appearance. They are also called toothache plant, buzz button or paracress, depending on cultural or regional naming conventions [9,10].

This family includes a wide variety of plants, many of which are used in traditional medicine for their anti-inflammatory, antibacterial, and analgesic properties. The primary compounds of interest include spilanthol and other alkylamides and flavonoids, contributing to their medicinal properties [11,12,13,14].

They are all related through the Acmella genus but the species within this genus are sometimes grouped under different scientific names. The confusion in the classification and naming of herbal plants results from several factors including taxonomic changes, variations in common names across regions and cultures, morphological variability, and a lack of standardization in classification systems [15,16].

To avoid confusion, this systematic review addressed all these plants as Acmella genus plants. In the search for relevant journal articles, the keyword ‘Acmella’ was used to retrieve all the articles on related plants such as Spilanthes acmella, Blainvillea acmella, Acmella uliginosa, Acmella oleracea and Acmella caulirhiza. The keyword ‘spilanthol’ was also used since it is the active compound for the Acmella genus plants.

2. Materials and Methods

2.1. Search Strategy

This systematic review analyzed all published studies investigating the antibacterial properties of plants from the Acmella genus, including Spilanthes acmella, Acmella oleracea, Acmella paniculata, Acmella uliginosa, and Acmella caulirhiza. The selection of eligible studies was guided by the PICOS framework (Population, Intervention, Comparison/Comparator, Outcomes, and Study design) [17] (Table 1). The goal was to identify relevant studies investigating the therapeutic effects of plants from Acmella genus in treating musculoskeletal disorders. A systematic review of the literature was conducted across Scopus, Google Scholar, and PubMed databases to identify the relevant studies.

The search strategy to identify relevant articles involved using the following keywords: Acmella; spilanthol; musculoskeletal; arthritis; osteoarthritis; tendonitis; osteoporosis; bone; muscle. These keywords were combined using Boolean operators such as AND, OR, and parentheses to ensure logical grouping and exhaustive retrieval (Table 2).

In the screening phase, the articles were selected according to the inclusion and exclusion criteria (Table 3).

2.2. Eligibility of Research Articles

Articles to be included in the review were selected in three phases. First, the titles of the articles were screened and any article that did not match the inclusion criteria were excluded. During this phase, duplicates were also removed. Second, the abstracts of the remaining articles were screened and excluded if they did not meet the inclusion criteria. Lastly, the full text of the remaining articles from the second phase were obtained. The selected articles were thoroughly read to exclude any articles that did not meet the inclusion criteria.

The screening was carried out by at least two reviewers. The selection of articles to be included in the review had to be agreed by at least two reviewers before proceeding into the data extraction phase. Any discrepancies were resolved through consensus between the reviewers.

2.3. Data Extraction

Data extraction was performed in a standardized manner with the use of a data collection form. Extracted data included: (1) authors; (2) type of plants and dose; (3) study design and sample size; (4) objectives; (5) parameters; (6) findings, and (7) conclusion. Extracted data were tabulated to facilitate comparative analysis.

2.4. Quality Assessment

To ensure the reliability of the included studies, their quality was assessed by two independent researchers using standardized evaluation tools. The Newcastle-Ottawa Scale (NOS) was applied to evaluate the quality of human interventional studies, while SYRCLE’s risk of bias tool was used for in vivo and in vitro studies, assessing biases such as selection, performance, detection, attrition, and reporting. Studies deemed to be of low quality were either excluded from the review or their limitations were explicitly acknowledged.

2.5. Data Synthesis

The data synthesis was carried out using a narrative synthesis approach. Preclinical studies (including in vitro and in vivo models) were analyzed separately from clinical trials due to variations in methodologies and outcome measures. The process involved the following steps:

• Summarizing preclinical findings related to mechanisms affecting inflammation, bone formation, and joint health.
• Assessing clinical evidence with a focus on key musculoskeletal outcomes, such as pain reduction, decreased joint inflammation, and functional improvement.
• Investigating shared mechanisms of action observed in both clinical and preclinical studies, particularly the effects of compounds like spilanthol on pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κ), Wnt/β-catenin, and others involved in bone metabolism.

2.6. Handling Missing Data

For studies with incomplete or missing data, efforts were made to reach out to the corresponding authors to request clarification or supplementary information. If no response was obtained, the study was either excluded or analyzed solely using the data that were available.

2.7. Ethical Considerations

While this systematic review did not involve direct experimentation on humans or animals, it adhered to ethical research standards. The included studies were all peer-reviewed publications that had obtained ethical approval for their respective experiments and clinical trials.

3. Results

The literature searches on the databases identified 322 relevant articles. Two reviewers independently assessed the title and abstract of all articles for inclusion or exclusion criteria. Differences of opinion between the reviewers regarding the selection of the articles were resolved by discussion. A total of 18 articles were retrieved for further assessment on their full texts. Seven of these articles were excluded because the interest of this review was not part of their primary studies, or they were not related with objective of the systematic review.

In terms of quality assessments, all the selected articles have low risk of bias. For the human studies by Rondanelli et al. [18] and Pradhan et al. [19], by using Newcastle-Ottawa Scale (NOS), the quality of these interventional studies were found to be acceptable. While for the rest of the studies, SYRCLE’s risk of bias tool did not detect any major biases. Finally, 11 articles were included for the purpose of this review. The characteristics of these articles are presented in Appendix A (Table A1). A flow chart of the selection process, including reasons for exclusion, is shown in Figure 1.

3.1. Overview of Evidence

3.1.1. Effects on Bone

There are 4 studies selected in relation to the effects of Acmella genus plants on bone cells, with three in vitro and one in-vivo studies. As for the in vitro studies of Widyowati et al. [20] and Abdul Rahim et al. [21], MC3T3-E1 cells (osteoblast-like cells) were treated with either ethanol or methanol extract of Spilanthes acmella or Blainvillea acmella leaves at doses ranging from 2.93 µg/ml to 1,500 µg/ml. In another study by Widyowati et al. [22], MC3T3-E1 cells were exposed to 12 isolated compounds of Spilanthes acmella at doses of 12.5 and 25 μM.

All the in vitro studies had measured alkaline phosphatase (ALP) activities to determine bone formation activities by osteoblasts. In addition, Widyowati et al. [22] had measured calcium deposition, while Abdul Rahim et al. [21] measured calcium deposition and collagen formation as well. All the studies have concluded that Acmella genus plants were able to promote bone formation. Widyowati et al. [22] have also identified 6 compounds responsible for bone formation. While Abdul Rahim et al. [21] managed to positively correlate the phenolic contents of the plants with the bone formation activities.

With regards to the in vivo study using steroid-induced osteoporosis mice model, combination of the plant with exercise had increased the osteoblast cells [23]. Overall, it can be concluded that the leaves extract of this plant had exhibited bone formation activities in both in vitro and in vivo studies. Therefore, it has potential to be investigated further as an anti-osteoporotic agent, especially in terms of animal and human studies.

3.1.2. Effects on Muscle

There is only one study by Pradhan et al. [19] investigating the effects of Acmella genus plant on muscle mass. It was a human study carried out on 240 subjects receiving commercial preparations of Spilanthes acmella (SA3X) for 2 months. Muscle mass was assessed by measuring the circumferences of mid-upper arm (MUAC), chest (CC), and thigh (TC). It was found that Spilanthes acmella had caused a significant increase in mid-upper arm circumference. There were no significant changes in the circumferences of chest and thigh. Thus, this indicated that Spilanthes acmella may be used to stimulate muscle growth.

3.1.3. Effects on Joint

The studies were carried out to determine the anti-inflammatory activities of Acmella genus plant extracts in treating osteoarthritis. The inclusion criteria of this review were satisfied by one in vitro study, five in vivo studies, and one human study. Stein et al. [24] had carried out both in vitro and in vivo studies. In the in-vitro study, Acmella oleracea extract and spilanthol treatments on Vascular Smooth Muscle Cells (VSMC) in hyperglycemic media were able to reduce chymase activity and expression and reduce reactive oxygen species.

As for the in vivo studies, the leaves or flowers extracts of Spilanthes acmella, Acmella uliginosa and Acmella oleracea were used, mostly given orally to animal model, except for Stein et al. [24], which injected the extract intraperitoneally and Moro et al. [25] which applied the extract topically to the site of tendon injury. Furthermore, Stein et al. [24] had isolated spilanthol and used it as one of the treatments.

Doses of Acmella genus plant extracts given orally or intraperitoneally to animal models varied from 10 to 833 mg/kg. For the topical application by Moro et al. [25], Acmella oleracea lyophilizate was added to a base ointment of anhydrous lanolin and solid vaseline 30:70 w/w at a concentration of 20% w/w. Several types of irritants were used to induce paw oedema or arthritis in rats such as Carrageenan and Freund’s Complete Adjuvant (CFA) [26] as well as monosodium iodate [27]. While Moro et al. [25], induced arthritis surgically by partial transection of calcaneal tendon.

In all the in vivo studies, the Acmella genus plant extracts were able to reduce pain, swelling, and inflammation, with improved joint histology. Biochemically, the extracts were also able to reduce inflammatory cytokines (interleukin-1 beta; IL-1β and tumor necrosis factor; TNF-α), nitric oxide (NO) and creatinine levels while haemoglobin, serum protein and albumin levels were raised. In the animal study by Paul et al. [28], combination of Acmella uliginosa and aloe vera was found to produce synergistic anti-arthritis and anti-inflammatory actions. Paul et al. [28] was also able to identify five potent anti-inflammatory compounds within Acmella uliginosa namely 9-Octadecenoic acid (Z)-phenylmethyl ester, à-N-Normethadol, astaxanthin, caryophyllene oxide and fenretinide.

Nevertheless, in the human study by Rondanelli et al. [18], food-grade lecithin-based formulation of Zingiber officinale (ginger) and Acmella oleracea standardized extracts (Mitidol™) in the form of tablet was given orally to 50 patients with knee osteoarthritis, twice daily for 4 weeks. The combination of Acmella oleracea and Zingiber officinale was effective in reducing joint pain as shown by the reduced a visual analog scale (VAS), improved knee function as indicated by better Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and Tegner Lysholm Knee Scoring Scale and improved 36-Item Short Form Health Survey (SF-36) physical activity and dual-energy X-ray absorptiometry (DEXA) fat distribution. This was accompanied by reduction in inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).

Table 4 shows a brief characteristics and summary of the information retrieved from the 11 studies that fulfilled the inclusion criteria and were incorporated into the review.

4. Discussion

Musculoskeletal disorders (MSD) encompass a range of conditions that impact the muscles, bones, joints, tendons, ligaments, and other structures that provide support and enable movement. These disorders can result in pain, stiffness, inflammation, and reduced mobility, greatly affecting a person’s capacity to carry out everyday tasks. Common examples of MSDs include arthritis, osteoporosis, back pain, tendonitis, and muscle strains. These conditions may arise from various factors, such as injuries, repetitive strain, aging, or underlying health issues [29,30].

The Acmella genus consists of flowering plants belonging to the Asteraceae family, known for their medicinal and bioactive properties. Species like Spilanthes acmella and Acmella oleracea contain bioactive compounds, such as spilanthol, which are thought to contribute to their therapeutic effects [31,32]. In this review the potential therapeutic effects of Acmella genus plants on MSD were assessed.

Agents that promote bone formation or bone anabolic activity have potential to be developed as drugs for prevention or treatment of osteoporosis [33,34,35]. To date, studies looking at the potential of Acmella genus plants in prevention and treatment of osteoporosis are mainly in vitro studies. There is only one in vivo study and no human studies.

The in-vitro studies were carried out using MC3T3-E1 as osteoblast-like cells. In these studies, Acmella genus plant extracts exhibited bone formation activities and therefore have potential as anti-osteoporotic agents. Osteoporosis occurs when there is an imbalance between bone formation and resorption. Besides the bone formation activity by osteoblasts, bone resorption by osteoclasts plays an important role in the pathogenesis of osteoporosis [36,37,38]. In future, osteoclasts should also be studied to determine whether Acmella genus plants may also inhibit osteoclasts activity.

The only animal study on Acmella genus plants, had adopted steroid-induced osteoporosis rat model. Although, this is an important type of osteoporosis, the study on postmenopausal osteoporosis, the major type of osteoporosis represented by ovariectomised rat model, is lacking [39,40,41]. The Spilanthes acmella leaves extract given orally at the dose of about 200 mg/kg was successful in maintaining osteoblast number but only when combined with another intervention, exercise. The dose used was low compared to the 1500 mg/kg of Acmella uliginosa, another Acmella genus plant, which did not produce any toxic effects on rat [25]. In a toxicity study using zebrafish embryo test, Spilantes acmella was not found to have any lethal effect on zebrafish embryo at the highest concentration of 20% v/v [42].

There should be more animal studies looking at other osteoporosis models, especially estrogen-deficient or postmenopausal models. The sole intervention of the Acmella genus plants should be investigated and more robust bone parameters such as bone histomorphometry, DEXA and micro-computed tomography (micro-CT) should be employed. If there are positive outcomes with animal studies, then human study may be warranted.

A study conducted by Widyowati et al. [22] has identified 6 active compounds in Spilanthes acmella which promoted bone formation, namely 1,3-butanediol 3-pyroglutamate, 2-deoxy-d-ribono-1,4-lactone, methyl pyroglutamate, ampelopsisionoside, icariside B1, and benzylα-l-arabinopyranosyl-(1→6)-β-d-glucopyranoside. Abdul Rahim et al. [21] have reported that terpenoids of α-cubebene, caryophyllene, caryophyllene oxide, phytol and flavonoids of pinostrobin and apigenin were the compounds that may contribute to both antioxidant and bone anabolic activities of Blainvillea acmella. However, these active compounds should also be tested in animal studies, rather than using the crude extracts. This is important for the development of the compounds isolated from Acmella genus plants into anti-osteoporotic agents.

In comparison to the studies on bone, studies on the effects of Acmella genus plants on osteoarthritis are more comprehensive with many animal studies and one human study. Acmella genus plants, mainly in the form of Acmella oleracea, were found to reduce inflammation in Vascular Smooth Muscle Cells (VSMC), and various osteoarthritic animal models. The highest dose of the plant extract used was 833 mg/kg which was still lower than the LD50 dose of Acmella uliginosa of more than 1500 mg/kg [24]. In terms of route of administration, Stein et al. [24] had administered the extract intraperitoneally (IP), which was able to reduce pain and swelling of the paws induced by formalin. As opposed to oral administration, IP administration of plant extract has higher bioavailability and faster action [43]. Another study by Moro et al. [25] applied the extract topically to the surgical site after partial transection of calcaneal tendon. This method of administration acts locally and does not get into systematic circulation, therefore reducing any adverse events [44].

Moreover, Acmella genus plants may also be combined with other plants such as aloe vera and ginger to treat osteoarthritis. The combinations are synergistic as the combined effects produced greater anti-arthritis and anti-inflammatory actions. Several active compounds in Acmella uliginosa have been identified with anti-inflammatory activities. They warrant further processes to evaluate, optimize, and test them for potential therapeutic use as anti-osteoarthritis agents.

There were positive outcomes from a human study in patients with knee osteoarthritis [18]. However, it was a quasi-experimental design which lacks random assignment, making it susceptible to biases. Acmella oleracea was also combined with another plant, ginger, and therefore the sole anti-osteoarthritis effects of the Acmella genus plant cannot be elucidated. All these make it challenging to confidently attribute the observed outcomes to the effects of Acmella genus plants.

Furthermore, a human study has reported that supplementations of commercial preparation of Spilanthes acmella were able to increase the muscle mass of the mid-upper arm [19]. However, no increase in muscle mass was recorded for muscles in the chest and thigh regions. There are questions raised about the selectivity of the plant extract on muscle in certain parts of the body. There are also several limitations identified by the authors such as the recruitment of the participants was not random and selective to gym-goers and the 24-hour dietary recall method may not be reliable.

5. Conclusions

The Acmella genus, particularly species like Spilanthes acmella and Acmella oleracea, shows promise for managing musculoskeletal disorders, with evidence suggesting its potential in both osteoarthritis and osteoporosis treatment. While in-vitro studies demonstrate positive effects on bone formation, further animal research is needed, especially in estrogen-deficient or postmenopausal models, to confirm these benefits. The active compounds identified in Acmella plants may contribute to their anti-inflammatory and bone-promoting properties, warranting further investigation into their therapeutic potential. Although the existing animal studies and human trials on osteoarthritis show encouraging results, there are limitations in study design and the need for more robust data to confirm these effects. Ultimately, continued research into isolated compounds, optimal dosages, and intervention methods is essential to fully realize the therapeutic benefits of Acmella genus plants in musculoskeletal disorders.