Prickly ash

Prickly Ash (Zanthoxylum spp.): A Comprehensive Reference

1. Identity: Botanical Names, Natural Sources, and Common Forms

1.1 Botanical Classification and Species

Zanthoxylum is a genus of aromatic shrubs and trees in the Rutaceae (citrus) family, known for their tingling, numbing effect when chewing or applied topically. The Zanthoxylum genus (Rutaceae) consists of 250 species worldwide, including 45 species and 13 varieties in China. Although the common name "prickly ash" is applied to multiple species, the term most frequently refers to a cluster of medicinally important plants whose identities differ by geography and tradition.

The two North American species of greatest medicinal importance are:

• Zanthoxylum americanum Mill. (Northern Prickly Ash) — a woody shrub native to North America. Northern Prickly Ash is native to southern Canada and northern, central and western parts of the United States.
• Zanthoxylum clava-herculis L. (Southern Prickly Ash, Hercules' Club) — a spiny tree or shrub native to the southeastern United States. Southern Prickly Ash is native to central and southern United States.

Zanthoxylum (also referred to in the literature as Xanthoxylum), a member of the Yellow Wood family (Rutaceae), is a widely distributed genus of plants. Two species of Zanthoxylum are indigenous to the mainland of the United States — Z. americanum Mill. (Northern Prickly Ash) and Z. clava-herculis L. (Southern Prickly Ash).

Additional medicinally important species include:

• Zanthoxylum bungeanum Maxim. (Chinese Prickly Ash / Sichuan Pepper, "Hua Jiao") — commonly known as Chinese prickly ash, is a well-known spice and traditional Chinese medicine ingredient with a rich history of use in treating inflammatory conditions. Dry Z. bungeanum pericarps, named Pericarpium Zanthoxyli ('Huajiao'), are listed in the Pharmacopoeia of the People's Republic of China as an important medicine to treat diseases.
• Zanthoxylum rhetsa (Roxb.) DC. (Indian Prickly Ash) — an aromatic tree, known vernacularly as "Indian Prickly Ash." Rutaceae, is an aromatic tree with its native range Tropical Asia to N. Australia.
• Zanthoxylum zanthoxyloides (Lam.) Zepern. & Timler (Fagara, West African Prickly Ash) — widely used in West and Central Africa for numerous traditional purposes, including management of sickle cell disease.
• Zanthoxylum heitzii — a Central and West African species used traditionally against sickle cell disorder.

1.2 Common Names and Synonyms

Along with the related Zanthoxylum americanum, Z. clava-herculis is sometimes called "toothache tree" or "tingle tongue" because chewing on the leaves, bark, or twigs causes a tingling numbness of the mouth, tongue, teeth and gums. Other common names include Clavalier, Pepperwood, Toothache Bark, Xanthoxylum, and Yellow Wood. The genus name is sometimes spelled Xanthoxylum.

1.3 Botanical Description

Z. clava-herculis grows to 10–17 m tall and has distinctive spined thick, corky lumps 2–3 cm long on the bark; leaves are glabrous and leathery, pinnately compound, 20–30 cm long with 7–19 leaflets, each leaflet 4–5 cm long. The flowers are dioecious, in panicles up to 20 cm long, each flower small, 6–8 mm in diameter, with 3–5 white petals; the fruit is a two-valved capsule 6 mm in diameter with a rough surface, and containing several small black seeds.

1.4 Common Forms and Preparations

Various plant parts are used medicinally across traditions:

• Bark and root bark — the most commonly employed part in North American herbal medicine. Preparations include decoctions, tinctures, and dried powder in capsule form.
• Berries (fruits/pericarps) — used both medicinally and as a culinary spice, especially in Asian traditions. The pericarps of Zanthoxylum species are commonly used as spices for their special flavor and are a therapeutically efficacious traditional medicine; the therapeutic efficacy is mainly because of the presence of volatile oils in their pericarps.
• Tincture — an alcohol-based liquid extract. Historical texts describe preparation with ethanol or whiskey.
• Decoction and infusion — hot-water preparations of the bark or berries.
• Topical preparations — liniments and poultices applied externally for joint and skin conditions.
• Essential oil — extracted from the pericarps, primarily for research and flavoring purposes.

2. Traditional and Historical Use

2.1 North American Indigenous and Settler Use

In North American herbalism, Zanthoxylum americanum and Z. clava-herculis have deep roots in both Native American and early European settler medicine. Often referred to as "toothache tree" or "pepperwood," it was used to treat mouth and gum pain, tooth infections, sore throats, and cold-induced ailments. Traditional healers would chew the bark or berries to numb oral tissues or apply them to aching joints to increase circulation and reduce pain.

Along with the related Zanthoxylum americanum, Z. clava-herculis is sometimes called "toothache tree" or "tingle tongue" because chewing on the leaves, bark, or twigs causes a tingling numbness of the mouth, tongue, teeth and gums. It was used for such medicinal purposes by both Native Americans and early settlers to treat toothache.

Many eastern Native American tribes, and practitioners at the end of the 19th century, continued the traditional uses of prickly ash, primarily as a digestive aid, to strengthen the nervous system, and for cholera. The bark was also widely used by herbalists to treat rheumatic conditions.

2.2 Eclectic Medical Tradition (19th Century)

The Eclectic physicians of the 19th century adopted Zanthoxylum as a key remedy for chronic rheumatism, digestive sluggishness, and pelvic congestion, particularly in women's health. Historical texts, including King's American Dispensatory (1898), recorded the plant's reputation as "powerfully sudorific and diaphoretic," and noted that it could "excite copious salivation" both by direct oral contact and when taken internally. King's American Dispensatory describes that physiologically, prickly ash acts upon the secretions, the nervous and circulatory systems. It was also employed for paralysis of the oral musculature, dropsy, and as a tincture prepared from the berries or root in alcohol.

People have taken northern prickly ash for blood circulation problems and resulting conditions including leg pain (intermittent claudication) and Raynaud's syndrome, as well as joint pain, cramps, low blood pressure, fever, swelling (inflammation), toothache, sores, ulcers, and cancer (as an ingredient in the Hoxsey formula).

2.3 Traditional Chinese Medicine

Zanthoxylum bungeanum, or Chinese prickly ash, holds a rich history spanning over two millennia in traditional Chinese medicine. This herb has been extensively used orally and topically to address various ailments, including gastrointestinal discomfort, arthritis, and bruises. Its significance extends beyond China, finding a place in traditional medical practices in countries such as India and Nepal.

In Traditional Chinese Medicine, Zanthoxylum bungeanum — better known as Sichuan pepper or Hua Jiao — has been used for centuries to warm the middle burner (digestive organs), disperse cold, kill parasites, and alleviate abdominal pain. As a traditional herbal medicine, Z. bungeanum has been widely used to treat many diseases, especially digestive disorders, toothache, stomach ache, and diarrhea.

2.4 Indian and South Asian Traditions

Z. rhetsa has been predominantly used by Indian tribes for the treatment of many infirmities like diabetes, inflammation, rheumatism, toothache, and diarrhea. The Kannikar tribes from Tamil Nadu utilized a paste made from the prickly thorns of Z. rhetsa to treat breast pain and to increase lactation in breastfeeding mothers. The plant shoots are consumed as a vegetable by the Adi tribes of Arunachal Pradesh, India. Various parts of Z. rhetsa are traditionally used as an aromatic, astringent, antimicrobial, antiseptic and antidiabetic agent, as well as used to treat snake bites, inflammatory dermatosis, cholera, rheumatism, and toothache.

2.5 African Traditions

Z. zanthoxyloides and Z. clava-herculis are traditionally used for healing diseases of the circulatory and respiratory systems, malaria, and diabetes. In Côte D'Ivoire, Z. gilletii is widely used to treat malaria, skin infections, and hypertension. In other parts of Africa, decoctions from different parts of Z. gilletii are also used either alone or in combination to treat oral diseases and erectile dysfunction, female reproductive issues, rheumatism, and many kinds of pains. Z. chalybeum bark and seeds are boiled and consumed to relieve pain associated with surgeries and other forms of pain, and to treat malaria and amoebiosis, while burnt ashes from the bark and seeds are used to treat rheumatism. West African practitioners have long used Z. zanthoxyloides (Fagara) specifically for sickle cell disease crisis management.

3. Key Constituents and Active Compounds

3.1 Overview of Phytochemical Classes

Characteristic secondary metabolites of Zanthoxylum species include lignoids, alkaloids, amides, flavonoids, terpenes, sterols, and coumarins. Alkaloids are abundant in the trunk and root bark, and are typically of the isoquinoline and quinolone types.

Over 500 compounds have been isolated from Zanthoxylum species. To date, over 140 compounds have been isolated and identified from Z. bungeanum alone, including alkaloids, terpenoids, flavonoids, and free fatty acids.

Several classes of phytochemicals have been detected in Zanthoxylum species, such as terpenes, flavonoids, coumarins, phenolic acids, and alkaloids, the most reported among all the classes.

3.2 Alkaloids

Alkaloids are among the most pharmacologically studied constituents of the genus. The principal alkaloids of the North American species are:

• Chelerythrine — the benzophenanthridine alkaloid chelerythrine is the major active natural product found in Z. clava-herculis, exhibiting anti-bacterial activity against Staphylococcus aureus. It is a potent, selective, and cell-permeable protein kinase C inhibitor.
• Nitidine — another benzophenanthridine alkaloid found in North American prickly ash species; studied for anticancer and anti-malarial activities.
• Berberine, Laurifoline, Magnoflorine, Tembetarine, Candicine — both Z. americanum and Z. clava-herculis have shown to contain the alkaloids candicine, chelerythrine, laurifoline, magnoflorine, nitidine, and tembetarine.
• Skimmianine — an acridone alkaloid found across multiple Zanthoxylum species.

The alkaloid columbamine, a berberine-class compound, was isolated from the bioactive chloroform fraction of Z. rhetsa bark alongside tetrahydrofuran lignans (yangambin and kobusin) and the triterpenoid lupeol.

Alkaloids such as berberine, chelerythrine, and columbamine isolated from Z. schreberi bark demonstrated strong inhibitory activity against both acetylcholinesterase and butyrylcholinesterase.

3.3 Amides (Alkylamides / Sanshools)

The amide class — particularly the sanshools — is responsible for the genus's most distinctive sensory and neurophysiological properties.

Sanshools and hydroxyl sanshools, from the same family as piperine and capsaicin, are commonly found alkylamides in Sichuan pepper. They are responsible for the numbing, tingling and buzzing mouth sensation after consuming Sichuan pepper flavored dishes or food products. The unique sensation is different from the pungency caused by capsaicin, piperine, or isothiocyanates.

Hydroxy-α-sanshool (HAS), having four double bonds in the cis-configuration, is the active ingredient most responsible for the unique tingling sensation evoked by the pericarps of Z. bungeanum. HAS was first isolated from the pericarps of Z. bungeanum and identified by Yasuda et al. (1982).

The discovery of the first amide compound, α-sanshool, by researcher Crombie L. from the bark of Zanthoxylum clava-herculis dates back to 1954.

3.4 Coumarins and Furanocoumarins

Z. americanum contains a number of coumarins that distinguish it from Z. clava-herculis. These coumarins include a series of pyranocoumarins from the bark: dipetaline, alloxanthoxyletin, xanthoxyletin, and xanthyletin, in addition to a number of furanocoumarins isolated from the berries: isoimperatorin, cnidilin, imperatorin, psoralen, and xanthotoxin.

The presence of light-mediated compounds, such as psoralen, 8-methoxypsoralen and imperatorin in extracts of different organs was confirmed by RP-HPLC. A high furanocoumarin content was detected in fruit and leaf, and low furanocoumarin levels were found in bark and wood.

3.5 Lignans

Previous phytochemical work on Z. americanum and Z. clava-herculis has yielded both a number of identical chemical constituents in addition to some distinctive chemical classes. For instance, both species have shown to contain the 3,7-dioxabicycle[3,3,0]octane lignans: asarinin and sesamin.

3.6 Volatile Oils and Terpenes

Volatile oils are a complex blend of substances (from a dozen to several hundred constituents) present at different concentrations. Generally, two or three major constituents are present in high concentrations (>30%), while other constituents are present only at trace levels. Monoterpenes, sesquiterpenes, and their oxygenated derivatives are the most common constituents.

Sabinene, terpinen-4-ol, pinenes, terpinenes, and cymene have been isolated as major volatile constituents from carpel and seed. Important phytochemicals like caryophyllene oxide, β-caryophyllene, β-copaene and spathulenol are present in the leaves.

3.7 Polyphenols and Flavonoids

The antioxidant and anti-inflammatory property of Sichuan pepper extract is largely related to its polyphenols content. These polyphenols have exhibited considerable promise, as evidenced by preclinical studies in animal models, suggesting their therapeutic potential in human inflammatory diseases such as ulcerative colitis, arthritis, asthma, chronic obstructive pulmonary disease, cardiovascular disease, and neurodegenerative conditions.

4. Mechanisms of Action

4.1 Neurophysiological Effects: Ion Channel Modulation

The mechanism underlying prickly ash's most iconic property — the numbing and tingling sensation — has been investigated in considerable detail, though conflicting models have been proposed.

Conflicting theories have been proposed to explain the sensory mechanism of sanshools. One study showed evidence of activation of TRPV1 and TRPA1 channels from hydroxyl-α-sanshool. TRPV1 is associated with burning and painful sensations caused by capsaicin, and TRPA1 is activated by pungent stimulants including cinnamaldehyde and isothiocyanate.

In vitro, HAS has been shown to activate TRPV1 and TRPA1 in sensory neurons by influx of Ca2+ in cells. Subsequently, Bautista et al. (2008) reported the activation of somatosensory neurons including small- and large-diameter cells, elicited through the unique ability of HAS to inhibit two-pore potassium channels (KCNK3, KCNK9, and KCNK18).

A competing theory holds that it is caused by modulating two-pore potassium channels instead of activating TRPA1 or TRPV1 channels. The numbing sensation in Sichuan pepper is primarily initiated by unsaturated amides, primarily sanshool compounds, and the varying intensity of this sensation is attributed to the distinct interactions of sanshools with membrane ion channels, including TRPV1, TRPA1, and KCNK.

Behavioral assays and nerve fiber recordings revealed that sanshool inhibits Aδ mechanosensory nociceptors and the activity of multiple voltage-gated sodium channel subtypes, playing an important role in anesthetic effect.

4.2 Anti-inflammatory Mechanisms

Network pharmacology investigations reported that the analgesic effect of Z. bungeanum is mediated through three key signaling pathways: mitogen-activated protein kinase, phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin, and IκB kinase-nuclear factor κB-cyclooxygenase 2.

In a rat model of type 2 diabetes mellitus, Zanthoxylum alkylamides (ZA), a mixed extract containing hydroxyl-γ-sanshool, hydroxyl-β-sanshool, and hydroxyl-α-sanshool, demonstrated the ability to control inflammation and address protein metabolism disorders. The PI3K/Akt/forkhead box O signaling pathway and the TNFα/NF-κB pathway are implicated in this process.

4.3 Protein Kinase C Inhibition

Chelerythrine is a benzophenanthridine alkaloid; it is a potent, selective, and cell-permeable protein kinase C inhibitor. This mechanism has been studied in relation to antimicrobial and potential anticancer activities.

4.4 Anticholinesterase Activity

Alkaloids such as berberine, chelerythrine, and columbamine demonstrated strong inhibitory activity against both acetylcholinesterase and butyrylcholinesterase, with IC50 values of 0.11, 1.03 and 3.75 µM and 6.40, 3.53, and 2.05 µM, respectively. The finding suggests that these compounds should be subjected to in vivo studies to assess their potential for managing Alzheimer's disease.

4.5 Anti-sickling Mechanisms

Researchers have identified several types of coumarins and various alkaloids that reduce platelet sticking. Among the agents known to possess anti-sickling inhibitory activity at low concentrations are the aqueous extract of the roots of Zanthoxylum xanthoxyloides (anti-sickling ether fraction), vanillic acid, parahydroxybenzoic acid, and paraflurobenzoic acid. The burkinabins (A, B, and C) isolated from the root bark of Z. zanthoxyloides have also been identified as constituents with anti-sickling properties.

5. Scientific Evidence by Area of Use

Note: As with many traditional medicinal plants, the large majority of evidence for prickly ash is preclinical (in vitro and animal models). Robust, large human clinical trials are absent for most indications. This section characterizes evidence strength explicitly.

5.1 Oral and Dental Pain (Topical Analgesic)

Traditional basis: The bark, leaves, and twigs were chewed by Native Americans and early settlers to numb the mouth, tongue, teeth, and gums to treat toothaches.

Scientific basis: The mechanism is reasonably well-characterized at the molecular level. Bian et al. demonstrated that the ethyl ether extract of different prepared products of Z. bungeanum had an infiltration anesthetic effect, and the vinegar product has a significantly anesthetic effect comparable to the positive control lidocaine hydrochloride. This was an in vitro / preclinical study. HAS was shown to cause calcium influx in sensory neurons by activating TRPV1 and TRPA1; subsequently, researchers found that HAS activates neurons by stimulating large-diameter myelinated neurons through a unique mechanism.

Evidence strength: The numbing mechanism is biologically plausible and has preclinical support, but no controlled human clinical trials specifically quantifying its efficacy for dental pain have been identified in the peer-reviewed literature. People use northern prickly ash for infections, sore throat, toothaches, wounds, and other conditions, but there is no good scientific evidence to support these uses.

5.2 Anti-inflammatory and Analgesic Effects

Scientific evidence: The extracts and compounds of Z. bungeanum have been shown to possess wide-ranging biological activity, such as anti-inflammatory and analgesic effects, antioxidant and anti-tumor effects, antibacterial and antifungal effects, as well as regulatory effects on the gastrointestinal system and nervous system.

It has been demonstrated that Zanthoxylum species significantly alleviate pain induced by formalin and capsaicin in animal models. Hydroxy-α-sanshool (HAS) exerts analgesic effects by inhibiting the excitation of voltage-gated Na+ channels on Aδ mechanical pain receptors.

Polyphenols of Z. bungeanum have exhibited considerable promise, as evidenced by preclinical studies in animal models, suggesting their therapeutic potential in human inflammatory diseases such as ulcerative colitis, arthritis, asthma, chronic obstructive pulmonary disease, cardiovascular disease, and neurodegenerative conditions. However, further research is necessary to fully elucidate their mechanisms of action and develop safe and effective therapeutic applications.

Evidence strength: Predominantly in vitro and animal model data. No confirmed large-scale human RCTs for chronic inflammatory conditions have been identified in peer-reviewed sources.

5.3 Antimicrobial Activity

Antifungal: Leaf, fruit, stem, bark and root of Zanthoxylum americanum were investigated for antifungal activity with 11 strains of fungi representing diverse opportunistic and systemic pathogens, including Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. All extracts demonstrated a broad spectrum of antifungal activity and inhibited at least eight fungal species in a disk diffusion assay (600 µg/disk). Antifungal activity was light-dependent, with fruit and leaf extracts most active in general. A high positive correlation was observed between total furanocoumarin content and fungal inhibition zones (r²=0.902, p<0.001). This is an in vitro study.

Antibacterial (MRSA): The bark extract of southern prickly ash, Zanthoxylum clava-herculis, has shown antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), a bacterium that has developed resistance to a number of conventional antibiotics that can result in an infection that may be life-threatening for some. This activity is attributed to chelerythrine. These are in vitro findings; no clinical trials exist for MRSA treatment.

Antimalarial: Four alkaloids — bis-dihydrochelerythrinyl ether, skimmianine, buesgenine, and chelerythrine — isolated from roots, root-bark, and stem-bark exhibited anti-plasmodial activity against chloroquine-sensitive (3D7) strains of P. falciparum, with IC50 values of 4.3, 0.7, 2.0, and 0.4 µg/mL, respectively. Nitidine from Z. gilletii stem bark also exhibited anti-plasmodial activity against P. falciparum strain FcB1 with IC50 <5 µg/mL by halting DNA synthesis in the parasite. These are all in vitro findings.

Evidence strength: Antimicrobial activities are well-documented in vitro and represent one of the more extensively studied areas. However, all data to date are preclinical; no human clinical trials have been conducted for infectious disease treatment using prickly ash.

5.4 Sickle Cell Disease (Antisickling Activity)

This is one of the most clinically relevant areas of research for prickly ash species, particularly those used in African traditional medicine.

Few reports have shown that extracts from Zanthoxylum or Fagara genus demonstrated anti-sickling property. One study investigated the in vitro antisickling and antioxidant properties of extracts from Zanthoxyllum heitzii.

Results showed that treatment of sickling cells with extracts at different concentrations demonstrated a decrease in the percentage of sickling cells in both induced and non-induced sickling cells. The fruits extract of Z. heitzii demonstrated the best anti-sickling property. The same extract at 250 µg/mL showed the best membrane cell stability compared to others. All extracts revealed antioxidant and anti-radical activities. The fruit extract of Z. heitzii demonstrated the most significant antisickling effect with a potential for use in the clinical management of SCD.

Doctors in Nigeria use Fagara (Zanthoxylum zanthoxyloides) to reduce the painful crisis of sickle cell anemia. This herb has a variety of unusual properties that reduce platelet and blood cell sticking.

Another promising traditional anti-sickle cell herb gaining attention is Fagara (Zanthoxylum macrophylla, previously Fagara zanthoxyloides and Fagara macrophylla). Fagara is a prickly-ash relative. The root bark from this plant has been shown to dramatically reduce sickle cell formation. Fagara constituents thought to inhibit sickling include burinabins A, B, and C.

Evidence strength: Primarily in vitro. The anti-sickling effects of Zanthoxylum species are documented in multiple in vitro studies, and there is substantial traditional use in West and Central Africa. However, rigorous randomized clinical trial data confirming efficacy and safety in humans with sickle cell disease remain lacking as of the available literature.

5.5 Anticancer Properties

In HCT-116 colorectal cancer cells, hydroxy-γ-sanshool (HRS) significantly inhibited mRNA and protein levels of Cyclin D1, CDK4, PCNA, and increased mRNA and protein levels of P21, P53, Fas, and Caspase 8. Inhibitors of P53 and Caspase 8 proteins significantly mitigated HRS-induced cell cycle arrest and apoptosis. The study provides evidence that HRS induced human colorectal cancer cell apoptosis by up-regulating P53 and Caspase 8. This is an in vitro study.

Solvent fractions and purified compounds from Z. rhetsa bark were tested for cytotoxic potential against human dermal fibroblasts (HDF) and mouse melanoma (B16-F10) cells, using the MTT assay. All solvent fractions and purified compounds were found to be non-cytotoxic to HDF cells. However, the chloroform fraction and kobusin exhibited a cytotoxic effect against B16-F10 melanoma cells. This is also in vitro evidence.

Evidence strength: Entirely preclinical. There are no human clinical trials evaluating prickly ash or its isolated compounds as cancer therapeutics. The anticancer findings are in vitro and require extensive further development before any clinical conclusions can be drawn.

5.6 Gastrointestinal Effects

Z. bungeanum has been widely used to treat many diseases, especially digestive disorders, toothache, stomach ache, and diarrhea. The fruit is traditionally associated with treating diabetes, diarrhea, microbial diseases, toothache, and removal of intestinal worms.

Regarding antispasmodic effects, traditionally, different parts of Z. fagara are used in Brazil to suppress muscle spasm and modulate muscle tone and contraction. Crude ethanol extract of the stem bark showed good antispasmodic activity in rat ileum in vitro. Methanol extracts of Z. armatum fruit, bark, and leaves also potently relaxed precontracted rabbit jejunum strips, intestine, trachea, and thoracic aortic rings, indicating spasmolytic potentials.

Evidence strength: In vitro and animal data; no human clinical trials specifically examining prickly ash for gastrointestinal indications have been identified.

5.7 Neurological and Metabolic Effects

Among the alkaloids in Z. bungeanum, HAS has been extensively studied for its anti-inflammatory effects. HAS exhibits a neuroprotective effect on H2O2-stimulated PC12 cells without inducing cytotoxicity in normal PC12 cells.

Amides present in Z. bungeanum are the likely material basis for an irritating sensation in the mouth. In addition, these amides can play a therapeutic role in Alzheimer's disease, Parkinson's, and depression by exerting antioxidant and anti-inflammatory effects. The main targets are the TRPV1, TRPA1, and PI3K/AKT signalling pathways.

Experiments using a rat model of type 2 diabetes mellitus found that Zanthoxylum alkylamides (ZA) could effectively alleviate T2DM by enhancing protein metabolism. Zanthoxylum amide (mainly HAS, hydroxy-β-sanshool and hydroxy-γ-sanshool) exhibits substantial hypoglycemic effects by modulating glucose and lipid metabolism disorders in animal models with diabetes.

Evidence strength: Cell-based and animal model evidence only. These are preliminary findings requiring human clinical validation.

5.8 Peripheral Circulation

Northern prickly ash has a longstanding traditional use for peripheral circulatory insufficiency, including Raynaud's syndrome and intermittent claudication. People take northern prickly ash for blood circulation problems and resulting conditions including leg pain (intermittent claudication) and Raynaud's syndrome. However, no randomized controlled trials have been identified in the peer-reviewed literature that specifically test Zanthoxylum americanum or Z. clava-herculis for these conditions in human subjects.

6. Body Systems and Health Areas of Association

Based on the accumulated traditional use and preclinical research evidence, the following body systems are most associated with prickly ash preparations across the genus:

• Oral and Dental: Topical numbing and pain relief; the most historically and biochemically supported application.
• Nervous system: Local anesthesia-like effects via ion channel modulation; preliminary neuroprotective data for HAS in cell models.
• Musculoskeletal / Rheumatic: Anti-inflammatory and antispasmodic uses; preclinical support via NF-κB, COX-2 pathway inhibition in animal models.
• Cardiovascular / Circulatory: Traditional use for peripheral circulation, Raynaud's syndrome, intermittent claudication; antiplatelet properties of alkaloids and coumarins documented in vitro.
• Gastrointestinal: Carminative, antispasmodic, and digestive uses across multiple traditions; supported by in vitro antispasmodic data.
• Immune / Antimicrobial: Antifungal, antibacterial (including MRSA), antimalarial, and antiparasitic activities demonstrated in vitro.
• Hematological: Anti-sickling effects on sickle cell hemoglobin S demonstrated in vitro; traditional use in West and Central Africa.
• Oncological: In vitro cytotoxic and pro-apoptotic activity for multiple cancer cell lines; no human clinical data.
• Metabolic / Endocrine: Preliminary hypoglycemic effects of sanshool derivatives in diabetic animal models.
• Dermatological: Traditional topical use; in vitro selective cytotoxicity toward melanoma cells; light-dependent furanocoumarin content may have photosensitizing implications.

7. Dosage Forms and Reported Dosages

The following dosages are drawn from traditional herbal texts and herbal practice references, not from human clinical trials (which generally do not exist for standardized doses):

• Dried bark: 1–3 g, three times daily.
• Dried berries: 1–5 g, three times daily.
• Decoction of bark: 1 teaspoon per cup, simmered for 20 minutes, three times daily.
• Infusion of berries: 2 teaspoons per cup, infused for 15 minutes, three times daily.
• Tincture: 1:5 preparation in 60% ethanol, 2–4 mL three times daily.
• Topical cream (Z. bungeanum fruit extract): It is possibly safe to apply small amounts of Chinese prickly ash fruit extract 2% cream to the skin around the eyes for up to 30 days.
• In vitro antisickling studies: The fruits extract of Z. heitzii demonstrated the best anti-sickling property at a concentration of 250 µg/mL in cell-based assays.
• Anti-cancer cell line studies: HRS was applied at concentrations of 0, 50, 90, or 130 µM for 24 hours in colorectal cancer cell models.

The appropriate dose of Chinese prickly ash depends on several factors such as the user's age, health, and several other conditions. At this time there is not enough scientific information to determine an appropriate range of doses for Chinese prickly ash.

8. Safety Considerations and Drug Interactions

8.1 Pregnancy and Lactation

It is unsafe to use southern prickly ash if pregnant, as it might start the menstrual period, which could harm the pregnancy. It is also best to avoid southern prickly ash if breastfeeding, as it might cause colic in a nursing infant.

The use of Z. americanum and Z. clava-herculis is contraindicated during pregnancy as they have actions as an emmenagogue. Northern prickly ash bark is possibly unsafe when taken by mouth during pregnancy.

8.2 Anticoagulant and Antiplatelet Interactions

It is contraindicated for those on anticoagulant therapy. Chinese prickly ash might slow blood clotting. There is some concern that it might increase the risk of bleeding during and after surgery. It should be stopped at least 2 weeks before a scheduled surgery.

8.3 Cardiovascular and Antihypertensive Drug Interactions

Caution is advised for people taking antihypertensive drugs and muscle relaxants such as scopolamine, as Zanthoxylum species may potentiate the effect of the drug.

Overdose may lead to increased blood pressure, cardiac function, and salivation.

8.4 Acid-Related Drug Interactions

Southern prickly ash may increase stomach acid. By increasing stomach acid, southern prickly ash might decrease the effectiveness of antacids. A minor interaction is also noted with H2-blockers and proton pump inhibitors used to decrease stomach acid.

8.5 Alcohol-Related Drug Interactions

An alcohol extract of Zanthoxylum may result in a disulfiram-like reaction when taking disulfiram or metronidazole drugs.

8.6 Iron Absorption

Taking iron supplements with prickly ash may decrease iron absorption.

8.7 Liver Considerations

There is some concern that southern prickly ash might affect the liver. Individuals with pre-existing liver disease are generally advised to exercise caution.

8.8 Furanocoumarin-Related Photosensitivity

Z. americanum berries contain furanocoumarins including psoralen and 8-methoxypsoralen. Antifungal activity was light-dependent, with fruit and leaf extracts most active in general. The presence of light-mediated compounds, such as psoralen, 8-methoxypsoralen, and imperatorin in extracts of different organs was confirmed. Since psoralens are well-established photosensitizers, preparations high in furanocoumarin content (particularly berry-derived extracts) could theoretically increase photosensitivity, though this has not been directly studied in clinical prickly ash supplementation.

8.9 Animal Toxicity

The consumption of these species has resulted in toxic reactions in cattle and fish.

8.10 General Oral Safety

When taken by mouth, there is not enough reliable information to know if northern prickly ash is safe or what the side effects might be. The toxic dose varies depending on the individual's health and the form of the plant used, but ingestion of large quantities can lead to gastrointestinal distress and other adverse effects. Long-term safety data are limited, and prolonged use may cause unknown cumulative effects.

References

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