Toothache plant

Toothache Plant (Acmella oleracea): A Comprehensive Reference

1. Identity and Botanical Classification

1.1 Accepted Botanical Name and Synonymy

Acmella oleracea is a species of flowering herb in the family Asteraceae. Common names include toothache plant, Szechuan buttons, paracress, jambu, buzz buttons, tingflowers, and electric daisy. It was previously known as Spilanthes acmella, and older literature frequently uses Spilanthes oleracea L. as an equivalent designation. The species is also identified as A. oleraceae Murr., a therapeutically important annual or short-lived perennial medicinal herb with yellow, non-fragrant flowers. Because the synonymy between Acmella oleracea and Spilanthes acmella is taxonomically complex and the two names appear interchangeably across the scientific literature, both designations refer, for most practical purposes, to the same medicinal plant.

Its specific epithet oleracea means "vegetable/herbal" in Latin, reflecting its traditional use as a food plant. Commonly known as the "toothache plant" or "jambu," it is a significant medicinal plant that has been traditionally used in Brazil and other tropical and subtropical regions for relieving dental pain, as an anti-inflammatory agent, and as a culinary spice. Due to its versatile utility, this plant has been extensively studied in modern medicine and pharmacy for its diverse pharmacological properties, including anesthetic, analgesic, anti-inflammatory, antioxidant, and antimicrobial activities.

1.2 Botanical Description and Distribution

Its native distribution is unclear, but it is likely derived from a Brazilian Acmella species. A small, erect plant, it grows quickly and bears gold and red inflorescences. It is frost-sensitive but perennial in warmer climates. The plant is found in tropical and subtropical countries, mainly India and South America. The Mizo people of India and Myanmar have cultivated this plant as a common vegetable and have produced a variety that is easily noticeable with its highly serrated and corrugated leaves and dome-shaped, completely yellow inflorescence.

Analytical research on the chemical compositions responsible for pharmacological activities has led to the identification of approximately 120 secondary metabolites in this species.

1.3 Common Forms and Preparations

As a dietary supplement, it is made from the dried leaf, flower, and stem of Acmella oleracea, a small herbaceous plant in the Asteraceae family native to Brazil and widely naturalized throughout tropical and subtropical regions worldwide. A concentrated extract of the plant, sometimes called jambu oil or jambu extract, is used as a flavoring agent in foods, chewing gum, and chewing tobacco. The oil is traditionally extracted from all parts of the plant.

Commercial supplement forms include:

• Internal-use extracts such as capsules, tablets, and liquid tinctures, often standardized to a specific percentage of spilanthol; topical cosmetic extracts included in serums, creams, and oils designed to smooth fine lines and improve the perception of skin firmness; and oral-care formulations such as mouthwashes or herbal sprays.
• Mucoadhesive film preparations containing Acmella oleracea extract for topical use on oral mucosa have also been developed, with ethanolic extracts from aerial parts prepared by maceration.
• Jambu extract as a flavoring agent is described as having a citrus, herbal, tropical, or musty odor, and its taste can be described as pungent, cooling, tingling, numbing, or effervescent.

2. Traditional and Historical Use

2.1 The Americas

The flowers were traditionally chewed by people living in the Amazon to relieve mouth, tooth, and throat pains, and from this the common name "toothache plant" emerged. Jambu, the traditional name for Acmella, has been used for centuries to treat oral pain because of its analgesic properties. The leaves and inflorescence are used as household medicine in the northern region of Brazil to treat oral and throat diseases.

Historically, the plant has been claimed to cure scurvy. Other traditional uses include treatment for snakebite, tuberculosis, rheumatism, malaria, and other fevers. A decoction of the plant has been used in Brazil as an antiseptic. The Peruvians also used Acmella as an insecticide against the yellow fever mosquito and corn earworm moth and as an anti-parasitic.

The plant is a species widely used in traditional Amazonian medicine to treat sexual dysfunction. In the northern parts of Brazil, the flower is also added to vegetables during cooking.

2.2 South Asia and the Indian Subcontinent

The plant has been widely used in Ayurveda and folk systems of medicine as an anti-inflammatory, antiseptic, and anesthetic drug since historic times. In particular, this plant is famous as a folklore remedy for toothache and for throat and gum infections. The flowers are crushed and applied at the site of toothache, particularly in the Irula tribe of Hasanur Hills in Erode District of Tamil Nadu, where it is known by the local name "Mandal Poo Chedi." Apart from Tamil Nadu, root paste of the plant is used in throat problems in Chindwara and Betul districts of Madhya Pradesh. The plant is also known to be used as a panacea (Sumatra), as a stimulant and for toothache (Sudan), for stomatitis (Java), and for wound healing (India).

In Cameroon, the plant is used as a snakebite remedy and in the treatment of articular rheumatism. It is supposed to be useful in cases of tuberculosis. In India, S. acmella flower heads are used to treat stammering in children.

It is known in Indian medicine as an aphrodisiac and is used as a therapy for impotency. It is also used for treating articular rheumatism, dysentery, snakebite, and tuberculosis.

2.3 Southeast Asia and Africa

It is used in traditional medicine throughout Asia and South America, where it is known as Jambu. The Mizo people of India and Myanmar have cultivated this plant as a common vegetable. Traditional uses recorded in Africa include treatment of toothaches, sore throats, stomatitis, and malaria. The plant has been well documented for its uses as spices, as antiseptic, antibacterial, antifungal, and antimalarial treatment, and as a remedy for toothache, flu, cough, rabies diseases, and tuberculosis.

2.4 Preparation Methods in Traditional Use

A decoction or infusion of the leaves and flowers has been used as a folk remedy. In traditional medicine, flowers have been chewed to relieve toothache and infection of the throat and to paralyze the tongue. The flowers are crushed and applied at the site of toothache in direct topical applications. Other traditional uses of Spilanthes acmella include use as a stomachic, stimulant, and antidiarrhoeal agent.

3. Phytochemistry: Key Constituents and Active Compounds

3.1 N-Alkylamides (Alkamides)

Spilanthol (also called affinin) is a fatty acid amide isolated from Acmella oleracea. It is believed to be responsible for the local anesthetic properties of the plant. Its formal chemical name is N-isobutylamide of (2E,6Z,8E)-deca-2,6,8-trienoic acid, and it is the primary and defining bioactive compound of the species. The biological activities described for A. oleracea are mainly attributed to the presence of lipophilic N-alkylamides, compounds that characterize both the species and the genus Acmella. Among them, spilanthol (affinin) is the major alkamide found in the aerial parts, responsible for the local sensorial effects and the therapeutic actions, including anesthetic and anti-inflammatory effects.

Additional alkylamide constituents include related alkamides — specifically N-isobutylamides and N-2-methylbutylamides of polyunsaturated fatty acids. The main constituents "spilanthol" and "acmellonate" are sometimes used to reduce the pain associated with toothaches and can induce saliva secretion.

In analysis of the hydroethanolic extract of A. oleracea flowers, spilanthol was detected as the foremost major compound at a concentration of 97.7%, followed by 1.53% scopoletin and 0.77% d-limonene.

3.2 Flavonoids and Phenolics

Flavonoids identified in the plant include quercetin, kaempferol, and luteolin, along with phenolics, coumarins, and triterpenoids. Other important phytochemicals include alkaloids, flavonoids, saponins, steroid glycosides, and tannins, which were all detected in the three main parts of the plant.

3.3 Polysaccharides

Potential mechanisms for gastroprotective effects have been linked to rhamnogalacturonan, a polysaccharide isolated from A. oleracea, including protectively binding to the mucosal surface, increasing mucus synthesis, scavenging radicals, and diminishing secretions of acid and pepsin. Other research suggests rhamnogalacturonan promotes restoration of epithelial continuity via epithelial cell proliferation and enhances mucin production to promote gastric ulcer healing.

3.4 Essential Oil Constituents

The essential oil of A. oleracea contains beta-caryophyllene, limonene, and germacrene D. Through detailed GC-MS analysis, 180 constituents have been identified in the essential oil, including tentatively identified long-chain α-keto esters of various acids.

3.5 Nutritional Components

The leaves are rich in vitamins A, C, and K, lutein, and magnesium.

4. Mechanisms of Action

4.1 Local Anesthesia and Nociception

When chewed, the leaves and flowers generate a tingling sensation to the lips and tongue. This sensation is caused by the action of spilanthol, an isobutylamide compound that promotes local anesthetic action treating the toothache. Spilanthol is believed to be responsible for the local anesthetic properties of the plant. Spilanthol permeates the human skin and the inside lining of the cheeks in the mouth (buccal mucosa), resulting in local as well as systemic pharmacological concentrations.

In an acute pain mouse model, Acmella oleracea has been reported to have antiallodynic and anti-oedematogenic activities due to alkylamides and in particular spilanthol. The molecular mechanism involves spilanthol acting as a modulator of TRPA1 receptors and as a TRPV1 antagonist, thus promoting analgesic effects. Spilanthol displays structural similarities to capsaicin, the ligand for the nociceptor channel TRPV1, which may account for its analgesic properties.

Antinociceptive effects have been attributed to anti-inflammatory properties and engagement of opioid receptors.

4.2 Anti-Inflammatory Mechanisms

In the skin and in the pancreas, spilanthol has been shown to exert anti-inflammatory effects. The underlying mechanism involves inhibition of nitric oxide production due to reduced expression of inducible nitric oxide synthase enzyme (iNOS) in macrophages. Transcription factor array experiments revealed that spilanthol inhibits the activation of several transcription factors (NFκB, ATF4, FOXO1, IRF1, ETS1, and AP-1), which may explain the effect of spilanthol on gene expression.

Isolated spilanthol also displays immunomodulatory properties in vitro, causing dose-dependent reduction in macrophage activation and nitric oxide (NO) production, as well as inhibition of cytokine production and NF-κB activation.

Spilanthol reduced the expression of iNOS mRNA and protein and, as a possible underlying mechanism, inhibited the activation of several transcription factors (NFκB, ATF4, FOXO1, IRF1, ETS, and AP1) and sensitized cells to downregulation of Smad. The iNOS inhibitory effect translated into an anti-inflammatory effect, as demonstrated in phorbol 12-myristate 13-acetate-induced dermatitis and, to a smaller extent, in cerulein-induced pancreatitis.

4.3 Vasorelaxation and Cardiovascular Mechanisms

The antihypertensive effect of spilanthol was blocked by CB1 antagonist rimonabant and TRPV1 antagonist capsazepine, suggesting spilanthol mediates some activity by interaction with the cannabinoid receptors and TRPV1 channels. Evidence indicates that affinin (spilanthol) activates vascular endothelial cannabinoid receptors (CB1 and eCB), as well as endothelial TRPA1 and TRPV1 channels. Affinin-induced vasodilation is also partly mediated via activation of the HNO-TRPA1-CGRP pathway.

4.4 Salivary and Sensory Activation

Spilanthol, the major constituent of jambu extract, is responsible for the perception of a mouth-watering flavor sensation, as well as the ability to promote salivation as a sialogogue, perhaps through its astringent action or its pungent taste. Compounds that induce tingling sensations associated with topical application or chewing of jambu include spilanthol, and to a lesser degree acmellonate. Taste-activating alkamide compounds that induce a salivary response have also been identified.

4.5 Gastroprotective Mechanisms

Potential mechanisms for gastroprotective effects linked to rhamnogalacturonan, a polysaccharide isolated from A. oleracea, include protectively binding to the mucosal surface, increasing mucus synthesis, scavenging radicals, and diminishing secretions of acid and pepsin. Other research suggests rhamnogalacturonan promotes restoration of epithelial continuity via epithelial cell proliferation and enhances mucin production to promote gastric ulcer healing.

4.6 Diuretic Mechanism

The diuretic capability of A. oleracea is illustrated by its impact on ADH secretion, altering urine osmolality and the renal excretion of essential electrolytes like sodium, potassium, and chloride.

4.7 Anti-Obesity Mechanism

The plant demonstrates anti-obesity effects by impeding pancreatic lipase, which is involved in fat digestion, consequently influencing weight management.

5. Scientific Evidence by Area of Use

5.1 Oral Health, Toothache, and Local Anesthesia

Traditional basis: The most traditional use of this plant is to reduce toothache throughout India as well as South America.

Preclinical evidence: Traditional use has been applied to modern medicine research as a possible useful analgesic agent; concentrated extracts from the plant are especially effective as a means of antinociception. Currently, this research is mostly limited to data from rat subjects.

Pharmaceutical development: Researchers have developed an anesthetic mucoadhesive film containing Acmella oleracea (jambu) extract for topical use on oral mucosa. The three mucoadhesive films developed showed physical stability and visual appearances suitable for use on oral mucosa. The permeation study revealed that spilanthol from 10% JBC presented higher flux and permeability coefficient values. Moreover, 10% JBC showed better topical anesthetic efficacy than the other films (p < 0.01). The authors concluded that mucoadhesive film containing crude extract of jambu treated with activated carbon is a potential alternative for oral, topical use, encouraging future clinical studies.

Antibiofilm/cariogenic bacteria: Leaves and stem of Acmella oleracea had strong activity against Streptococcus mutans in laboratory testing. Extracts presented MIC and MBC of 125 µg/ml against S. mutans. In the antibiofilm assay, the extract at 500 µg/ml (4×MIC) presented an inhibition of 50.89% after a one-minute single application, similarly (p > 0.05) to that found after chlorhexidine gluconate 0.12% treatment.

Evidence strength: Preclinical and in vitro evidence is compelling. A registered randomized clinical trial on antiseptic and analgesic action on skin (NCT02792972) was completed, though detailed results have not been widely published in indexed literature. Current research on A. oleracea remains largely preclinical. Conducting well-designed clinical trials is imperative to validate therapeutic efficacy and safety.

5.2 Pain and Inflammation (Systemic and Musculoskeletal)

Preclinical evidence: Extracts and phytoconstituents isolated from this plant have shown different pharmacological responses, which includes anticonvulsant, analgesic, anti-inflammatory, vasodilation, diuretic, and antimalarial effects.

Chronic low back pain — human observational study (2025): In a prospective, multicenter, observational, real-world, cohort study, 103 patients with chronic low back pain (CLBP) and neuropathic pain received a standardized A. oleracea and B. serrata extract for 8 weeks as an add-on to ongoing therapy. Neuropathic pain was assessed using the painDETECT (PD-Q) and Neuropathic Pain Symptom Inventory (NPSI). PD-Q scores significantly decreased by 13.4% at Week 2, 25.5% at Week 4, and 37.1% at Week 8, and NPSI scores decreased by 15.8%, 24.4%, and 36.9%, respectively (all p < 0.0001 vs. baseline). NRS pain intensity improved by 28.0% by Week 8 (p < 0.0001). ODI scores reduced by 20.8% (p < 0.0001) and SF-12 scores improved by 4.1% (p < 0.001) compared to baseline. Use of NSAIDs and gabapentinoids decreased by 23.7% and 22.2%, respectively (p < 0.05). No serious adverse events occurred; mild and transient effects were reported in 8.7% of patients. The A. oleracea and B. serrata extract as adjunctive therapy resulted in significant improvements in neuropathic pain, functional disability, and reduced medication use, with good tolerability. However, the absence of a control group limits causal inference. Randomized controlled trials are needed to establish efficacy and confirm these preliminary observations.

Dysmenorrhea — human retrospective study (2025): A study evaluated a food supplement with Acmella oleracea and Boswellia serrata for dysmenorrhea symptom management in women with inadequate NSAID response. This single-center retrospective study included 33 women aged 20–35 with dysmenorrhea-related symptoms who had experienced insufficient relief from NSAIDs alone. The combination showed potential for supplementary pain management; the primary active compound spilanthol has been found to exhibit analgesic effects by modulating the central pain pathway and reducing the release of pro-inflammatory mediators.

Chemotherapy-induced neuropathic pain — preclinical (2025): Chemotherapy-induced neuropathic pain is a major side effect of antineoplastic treatment. A 2025 study investigated the neuroprotective potential of Acmella oleracea L. extracts containing the N-alkylamide spilanthol, phenolic acids, and glycosylated flavonoids. This study remains preclinical.

Intestinal mucositis — preclinical: Daily administration of spilanthol significantly lowered the severity of intestinal mucositis, reducing histopathological changes and increasing the villus height in the animals treated with spilanthol at a dosage of 30 mg/kg (p < 0.0044) compared to a group exposed only to 5-FU. A decrease of myeloperoxidase activity was also observed in the animals treated with 30 mg/kg of spilanthol (p < 0.05). The data demonstrated that spilanthol effectively reduced inflammation in a mouse model of intestinal mucositis induced by 5-FU. In murine models of 5-fluorouracil-induced intestinal mucositis, spilanthol from A. oleracea reduced inflammation. However, human data are lacking.

Evidence strength: Preclinical evidence (animal models) is strong and mechanistically characterized. The 2025 observational study in CLBP and the 2025 retrospective dysmenorrhea study are the most substantive human data, but both carry methodological limitations (no control arm; retrospective design; combination formulation). Overall, human clinical evidence is preliminary.

5.3 Skin Aging and Cosmetic Applications

Myorelaxant ("botulinum toxin-like") mechanism: Spilanthol, notably in the form of an Acmella oleracea extract, was observed to be able to effectively inhibit contractile activity in subcutaneous face muscles, leading to its commercial exploitation as a "natural Botox" alternative.

In vivo clinical data on wrinkles: The in vivo smoothing efficacy of Acmella oleracea extract has been demonstrated on the fine lines and wrinkles present around the eye area, often known as "crow's feet" wrinkles. With 5% Acmella oleracea extract, more than 83% of volunteers benefitted from a reduction in crow's feet wrinkles.

Anti-wrinkle serum study (International Journal of Cosmetic Science, 2021): A serum containing 15% of emollients and 1% of emulsifier was tested in vivo in 16 healthy adults (12 women and four men). Screening of skin irritation effects revealed the absence of potential irritancy of the investigated serum, suggesting overall satisfying skin tolerability and preliminary safety. Silicone skin replica image analysis demonstrated noticeable reduction/improvement in all measured skin wrinkle parameters after only 2 weeks of test serum application in periorbital and perioral areas, indicating rapid and beneficial effects on facial expression lines and wrinkles.

Anti-inflammatory mechanism in skin: When administered topically in mice, spilanthol has been demonstrated to inhibit mitogen-activated protein kinase signaling and improve allergic inflammation in 2,4-dinitrochlorobenzene-induced atopic dermatitis.

Evidence strength: Topical cosmetic studies demonstrate measurable outcomes in small human cohorts. However, these studies are typically funded by or carried out in the context of commercial cosmetic development, are very small in sample size, and do not meet the evidentiary bar of independent randomized clinical trials. The preclinical data on myorelaxation and anti-inflammatory skin effects are robust.

5.4 Sexual Function

Traditional basis: Acmella is known in Indian medicine as an aphrodisiac and is used as a therapy for impotency.

Premature ejaculation — human pilot study (2023): In a study on patients with premature ejaculation, researchers evaluated the clinical action of a nano-formulation containing an ethanolic extract of A. oleracea inflorescences. Major constituents in the extracts were identified based on gas chromatographic analysis. Participants used a spray preparation based on the A. oleracea extract for 12 weeks, during which they were instructed to apply the product 5 minutes prior to sexual intercourse. During spray treatment, the A. oleracea nanoformulation increased participants' IELT values (293 s) compared to baseline values (193 s), confirming clinical action in men with premature ejaculation. Participants demonstrated good tolerance to the spray and had no systemic side effects or incidence of local effects. Compared with baseline values, participants recorded an increase in IELT when using this spray, although these time increases were proved to be statistically non-significant, which may be attributable to the small number of participants included in the study.

Animal hormonal evidence: An animal study found that an S. acmella ethanolic flower extract rich in alkylamides affected male sexual functioning by increasing levels of testosterone, follicle-stimulating hormone, and luteinizing hormone, with the effect being significant and lasting at high doses.

Evidence strength: The available human evidence consists of a single small pilot study. Animal data on hormonal modulation are preliminary. No conclusions about clinical efficacy for sexual function can be drawn from current evidence.

5.5 Antimicrobial and Antifungal Activity

Broad-spectrum antibacterial: The methanol extract from the leaves exhibited antibacterial activity against E. coli, S. epidermidis, MRSA, and P. aeruginosa, as well as antifungal activity against C. albicans, with MIC values ranging from 125 to 1000 µg/mL. When assessing adhesion inhibition against S. aureus, P. aeruginosa, and their mixed biofilms, the extract showed inhibition rates of 44.71%, 95.5%, and 51.83%, respectively. It demonstrated significant growth inhibition of 77.17% for S. aureus and 62.36% for P. aeruginosa.

Anthelmintic activity: Research confirms that Acmella oleracea contains important bioactive compounds responsible for broad-spectrum anthelmintic activity.

Evidence strength: Antimicrobial and antifungal activities are documented in vitro. No clinical (human) trials have evaluated antimicrobial applications directly. The antibiofilm data against S. mutans in oral health contexts are methodologically meaningful as proof-of-concept.

5.6 Immunomodulatory Activity

In terms of immune response, Acmella oleracea serves an immunomodulatory role, curtailing the secretion of inflammatory cytokines such as TNF-α and IL-6. Isolated spilanthol displays immunomodulatory properties in vitro causing dose-dependent reduction in macrophage activation and nitric oxide (NO) production, as well as inhibition of cytokine production and NF-κB activation.

Evidence strength: All immunomodulatory data are from in vitro cell studies and animal models. No human clinical trials have assessed immune modulation specifically. Evidence is preclinical and preliminary.

5.7 Cardiovascular — Antihypertensive and Vasorelaxant

The antihypertensive action of A. oleracea is facilitated through the induction of vasorelaxation. Evidence indicates that affinin/spilanthol activates vascular endothelial cannabinoid receptors (CB1 and eCB), as well as endothelial TRPA1 and TRPV1 channels. In silico analyses showed that affinin is able to bind with high affinity to these molecular targets. Effects of oral administration of 100 mg/kg of hydroethanolic flower extract over 60 days were studied in male spontaneously hypertensive (SHR) and Wistar rats.

Evidence strength: Antihypertensive and vasorelaxant activity are characterized mechanistically in preclinical models. No human cardiovascular trials exist.

5.8 Gastroprotection

It is used in the treatment of anaemia, cancer, constipation, diuresis, fever, flatulence, inflammation, liver abscess, peptic ulcer, and ulcer in traditional ethnopharmacological records. The polysaccharide rhamnogalacturonan has been the subject of mechanistic research, as described in Section 4.3, but all gastroprotective evidence remains preclinical.

5.9 Cytotoxic and Anticancer Activity

In vitro, a hydroethanolic extract of S. acmella produced cytotoxic effects in tumor cell cytoskeletons. Spilanthol can exert a variety of biological and pharmacological effects including analgesic, neuroprotective, antioxidant, antimutagenic, anti-cancer, anti-inflammatory, antimicrobial, antilarvicidal and insecticidal activities.

Evidence strength: In vitro only. No human cancer data exist. This area requires extensive further research before any claims can be substantiated.

6. Body Systems and Health Areas Associated with Toothache Plant

• Oral and dental health: The flowers have been used for their numbing and pain-relieving properties, and the plant has been noted to relieve stomatitis, have taste-activating properties, and to induce a salivary response.
• Musculoskeletal and pain management: Multiple pharmacological actions include local anaesthetic, analgesic, antinociception, and anti-inflammatory effects.
• Integumentary (skin): Anti-wrinkle, myorelaxant, and anti-inflammatory effects at the skin level, as reviewed in Section 5.3.
• Immune system: Immunomodulatory activity via NF-κB and cytokine regulation, as reviewed in Section 5.6.
• Cardiovascular system: Vasorelaxant and antihypertensive activity mediated via TRP channels and cannabinoid receptors, as reviewed in Section 5.7.
• Genitourinary system: Experimental studies suggest diuretic and aphrodisiac effects.
• Gastrointestinal system: Gastroprotective polysaccharide mechanisms and traditional use for flatulence, dysentery, and peptic ulcer, as noted in ethnobotanical records.
• Reproductive system: Traditional aphrodisiac use and emerging research on premature ejaculation, as detailed in Section 5.4.
• Infectious disease (antimicrobial): Broad-spectrum in vitro antibacterial and antifungal activities, as detailed in Section 5.5.

7. Dosage Forms and Dosages Reported in Studies

No universally established standard dosage exists for Acmella oleracea as a dietary supplement, and no major regulatory body has issued a formal monograph specifying a therapeutic dose. The following dosages are reported in the scientific literature:

• Intestinal mucositis (preclinical, mice): Daily administration of spilanthol at a dosage of 30 mg/kg significantly lowered the severity of intestinal mucositis (p < 0.0044).
• Antihypertensive (preclinical, rats): Oral administration of 100 mg/kg of hydroethanolic flower extract was administered over 60 days in spontaneously hypertensive and Wistar rats.
• Premature ejaculation (human pilot): Participants used a spray preparation based on the A. oleracea extract for 12 weeks, instructed to apply the product 5 minutes prior to sexual intercourse.
• Topical cosmetic (anti-wrinkle): Formulations at 5% Acmella oleracea extract were tested in cosmetic evaluations, with more than 83% of volunteers showing reduction in crow's feet wrinkles.
• Mucoadhesive oral film: Formulations containing 10% or 20% of crude jambu extract were developed as mucoadhesive films for topical use on oral mucosa.
• EFSA/JECFA safe intake reference: EFSA and JECFA reviewed a feeding study in rats and both authorities recognized that the no adverse effect level (NOAEL) for spilanthol was 572 mg/kg b.w./day, yielding a safe dose of spilanthol of 1.9 mg/kg b.w./day, or 133.5 mg/70-kg-male/day, 111 mg/58-kg-female/day, or 38 mg/20-kg-child/day.
• Topical cosmetic concentration (per patent US7531193B2): When spilanthol is used in pure form, the concentration of spilanthol in the composition is between 0.005 and 10% of the weight of the composition.

8. Safety Considerations

8.1 Regulatory Safety Assessment

EFSA and JECFA reviewed a feeding study in rats and both authorities recognized that the no adverse effect level for spilanthol was 572 mg/kg b.w./day, yielding a safe dose of spilanthol of 1.9 mg/kg b.w./day, or 133.5 mg/70-kg-male/day, 111 mg/58-kg-female/day, or 38 mg/20-kg-child/day.

8.2 Buccal and Transmucosal Permeation

Boonen et al. (2010) evaluated the transmucosal behavior of spilanthol administered in a gel formulation of S. acmella ethanolic extract using porcine buccal mucosa in an in vitro Franz diffusion cell configuration. They demonstrated the promising local and systemic functionality of spilanthol in permeating the mucosa in a formulation-dependent manner, increasing penetration with both local and systemic effects on the mucosa after topical administration. The implication is that topically applied formulations can produce systemic as well as local exposure.

8.3 Reproductive and Developmental Toxicity (Preclinical)

In zebrafish embryonic development studies, teratogenic effects were observed including tail deformation, cardiac and yolk edema, scoliosis, and growth retardation; these alterations were more prominent in groups born from progenitors exposed to the highest concentrations (100 and 200 µg/L), but only the occurrence of yolk and cardiac edema had a statistically significant difference compared to the control group. Overall, data showed that treatment caused no detrimental changes in progenitors regarding their gonads or fertility, but caused some potentially teratogenic activity in embryos, which may be due to the action of spilanthol's metabolites.

In vivo, potential teratogenic activity in embryos may be due to various spilanthol metabolites. These findings are based on a zebrafish model and their relevance to human pregnancy is not established. However, they indicate a need for caution with use during pregnancy until further data are available.

8.4 Acute Toxicity (Preclinical)

Treatment with hydroethanolic flower extract (EHFAo) in zebrafish caused significant behavioral changes and death at high doses. The calculated median lethal dose (LD₅₀) was 148.42 mg/kg, and the calculated median lethal concentration (LC₅₀) was 320 µg/L. In the histopathological study, tissue alterations compromising normal functioning occurred with oral doses of 88.915, 199.53, and 281.83 mg/kg, with the intestine being the most affected. When treatment was performed by immersion, the most affected organ was the gills. These results are from an animal model and are not directly translatable to human oral supplement dosing.

8.5 Potential Cardiac Effects

One publication noted the ability of spilanthol to generate arrhythmia when injected into isolated rabbit hearts, a finding noted in patent literature reviewing the pharmacology. This was an isolated tissue (ex vivo) preparation and does not represent a clinical observation, but it has been cited as a pharmacological caution.

8.6 Androgen-Sensitive Conditions

An animal study found that an S. acmella ethanolic flower extract rich in alkylamides affected male sexual functioning by increasing levels of testosterone, follicle-stimulating hormone, and luteinizing hormone, with the effect being significant and lasting at high doses. Memorial Sloan Kettering Cancer Center has flagged this as a consideration for patients with androgen-sensitive prostate cancer, based on this preclinical androgenic activity.

8.7 Allergic Potential

Toothache plant is a member of the Asteraceae family, which includes asters, daisies, and cornflowers. Individuals with known hypersensitivity to plants in the Asteraceae/Compositae family may theoretically be at risk of cross-reactive allergic responses, though no clinical cases have been indexed in the reviewed literature.

8.8 Human Tolerability Data

In the clinical pilot study on premature ejaculation, participants demonstrated good tolerance to the topical spray and had no systemic side effects or incidence of local effects. In the observational back pain cohort study (n = 103), no serious adverse events occurred; mild and transient effects were reported in 8.7% of patients. Overall, Spilanthes acmella is described in review literature as a well-known plant in the Indian traditional system of medicine with multiple pharmacological action and minor side effects, though this characterization is based on traditional use and limited clinical data rather than large-scale clinical trials.

8.9 Overall Evidence Limitations

Despite promising findings, current research on A. oleracea remains largely preclinical. The majority of pharmacological data come from in vitro cell studies and rodent or zebrafish models. Human clinical trials are few, small, often lack control groups, and in several cases combine A. oleracea with other botanical extracts, making it difficult to attribute observed effects to this plant alone. Conducting well-designed clinical trials is imperative to validate the therapeutic efficacy and safety of A. oleracea.

References

• Pharmacological and phytochemical review of Acmella oleracea: a comprehensive analysis of its therapeutic potential — Discover Applied Sciences, Springer Nature, 2024
• Dubey S et al. Phytochemistry, Pharmacology and Toxicology of Spilanthes acmella: A Review — Advances in Pharmacological and Pharmaceutical Sciences, PMC, 2013
• Spilanthes acmella (Jambu) — Memorial Sloan Kettering Cancer Center Integrative Medicine
• Acmella oleracea — Wikipedia (citing EFSA/JECFA data)
• Spilanthol — Wikipedia
• Khiangte L et al. Chemical composition and broad-spectrum anthelmintic activity of a cultivar of toothache plant, Acmella oleracea, from Mizoram, India — PMC, 2020
• Development and Evaluation of a Novel Mucoadhesive Film Containing Acmella oleracea Extract for Oral Mucosa Topical Anesthesia — PMC, 2016
• Spilanthol Inhibits Inflammatory Transcription Factors and iNOS Expression in Macrophages and Exerts Anti-inflammatory Effects in Dermatitis and Pancreatitis — PMC, 2019
• Acmella oleracea (L) R. K. Jansen Reproductive Toxicity in Zebrafish: An In Vivo and In Silico Assessment — PMC, 2019
• Acute Toxicity of the Hydroethanolic Extract of the Flowers of Acmella oleracea L. in Zebrafish: Behavioral and Histopathological Studies — PMC, 2020
• Pharmacological Characteristics of the Hydroethanolic Extract of Acmella oleracea Flowers: ADME/Tox In Silico and In Vivo Antihypertensive and Chronic Toxicity Evaluation — PMC, 2023
• Clinical Safety of a Pharmaceutical Formulation Containing an Extract of Acmella oleracea (L.) in Patients With Premature Ejaculation: A Pilot Study — American Journal of Men's Health, PMC, 2023
• Efficacy and Safety of Acmella oleracea and Boswellia serrata Extract as Add-On Therapy for Chronic Low Back Pain: An Observational, Real-World Cohort Study — Pharmaceuticals, PMC, 2025
• Acmella oleracea and Boswellia serrata for Symptom Relief and Reduced Analgesic Use in Women with Dysmenorrhea — PMC, 2025
• 'All-natural' anti-wrinkle emulsion serum with Acmella oleracea extract: A design of experiments (DoE) formulation approach, rheology and in vivo skin performance/efficacy evaluation — International Journal of Cosmetic Science, PubMed, 2021
• Spilanthol, the Principal Alkylamide from Acmella oleracea, Attenuates 5-Fluorouracil-Induced Intestinal Mucositis in Mice — PubMed, 2018
• Acmella oleracea for pain management — Fitoterapia, ScienceDirect, 2019
• Distinct mechanisms underlying local antinociceptive and pronociceptive effects of natural alkylamides from Acmella oleracea — Fitoterapia, ScienceDirect, 2018
• Spilanthol content of Acmella oleracea subtypes and their bactericide and antibiofilm activities against Streptococcus mutans — South African Journal of Botany, ScienceDirect, 2021
• Endothelial TRP channels and cannabinoid receptors are involved in affinin-induced vasodilation — Fitoterapia, ScienceDirect, 2021
• Amazon Rainforest Hidden Volatiles — Part I: Unveiling New Compounds from Acmella oleracea (L.) R.K. Jansen Essential Oil — PMC, 2024
• Botany, Ethnopharmacology, Phytochemistry, and Biological Activities of Acmella oleracea: A Comprehensive Review — PMC, 2025
• NCT02792972: Antiseptic and Analgesic Action Acmella Oleracea Skin: Randomized Clinical Trial — ClinicalTrials.gov
• Neuroprotective Potential of Acmella oleracea Aerial Parts and Root Extracts: The Role of Phenols and Alkylamides Against Neuropathic Pain — Nutrients, MDPI, 2025
• Acmella oleracea — Herb Society of America, Pioneer Unit