Pistacia integerrima Gall: A Comprehensive Reference
1. Identity and Botanical Classification
1.1 Nomenclature
The botanical name of the plant is Pistacia integerrima, and it belongs to the family Anacardiaceae. The full scientific designation frequently encountered in pharmacological literature is Pistacia integerrima J. L. Stewart ex Brandis. Some taxonomic authorities treat it as a subspecies: Pistacia chinensis subsp. integerrima (J. L. Stewart) Rech. f.
It is commonly called "Crab's claw" in English, and "Shani" or "Shringi" in Hindi. In Sanskrit classical literature it is known as Karkatashringi or Karkatasringi. The name Karkatshringi derives from the Sanskrit words "Karkata" (crab) and "Shringi" (horn), referring to the peculiar horn-like galls formed on the twigs, leaves, or branches of the tree due to the activity of insects. Additional regional and folk synonyms include Kakarsinghi (Urdu/Hindi), Kakadshringi (Marathi), and Kakar Singhi.
1.2 Botanical Description and Natural Source
Pistacia integerrima is a dioecious, unbranched tree reaching up to 25 meters in height, with large pinnate compound leaves bearing horn-shaped galls and small reddish flowers arranged in panicles; its fruit is purple to blue and globular.
The plant is indigenous to India and is found in the outer ranges of the North-Western Himalayas at an altitude of 500 to 2,500 m. It occurs commonly in countries such as Nepal, China, Afghanistan, Pakistan, India, Armenia, and the northwestern and western Himalayas.
1.3 The Gall: Morphology, Origin, and Common Forms
The galls, which are a defense response to aphid infestations, are rich in bioactive compounds that contribute to their extensive medicinal uses. The galls are hollow, horn-shaped, bitter, and used for medicinal purposes. The leaf galls contain 20–75% tannin, making them among the most tannin-dense plant-derived structures documented in the Pistacia genus.
The leaf galls contain about 5% resin, which is used as mastic (Bombay mastic). An essential oil is obtained by steam distillation.
The galls are available and marketed in the following primary forms:
- Crude gall powder (churna): Gall powder is most commonly used in diseases such as cough, diarrhoea, and fever.
- Aqueous and ethanolic extracts: used across preclinical pharmacological studies as decoctions or standardized preparations.
- Essential oil: in Pistacia integerrima, the volatile chemical constituents are extracted by hydro distillation or liquid-liquid extraction.
- Compound Ayurvedic formulations: Karkatshringi is an important ingredient of Ayurvedic formulations like Chavyanprash, Dashmularista, and Shringyadi Churna.
2. Traditional and Historical Use
2.1 Systems of Medicine and Time Periods
Pistacia integerrima has a long history of use in such systems as Ayurveda, Unani, and Siddha, which implies its high cultural value. Traditional practice of Ayurveda in ancient India dates back to at least the first millennium BC.
It is extensively used as an herbal drug in the traditional medication systems like Ayurveda, Unani, and Siddha and folkloric practices to treat numerous diseases like asthma, diarrhoea, dysentery, fever, vomiting, skin diseases, respiratory ailments, and psoriasis, as well as hepatitis and liver disorders.
2.2 Classical Ayurvedic Applications
The galls are used in various Ayurvedic formulations such as "Dasamularista," "Chayavanaprasa," and "Shringyadi curna," which are used in the treatment of diseases like swasa (asthma), yakshma (tuberculosis), ajeerna (indigestion), hridyaroga (heart disease), jwara (fever), and yakrit roga (liver disorder).
The term Karkatshringi refers to the horn-like galls that form on the leaves due to insect infestation, and it is these galls that hold immense therapeutic value. Found predominantly in the sub-Himalayan regions of India, including Himachal Pradesh, Uttarakhand, and parts of Kashmir, this herb is deeply embedded in ancient Ayurvedic pharmacopeia for its Kapha-Vata balancing properties and anti-inflammatory, expectorant, and immunomodulatory actions.
2.3 Ethnobotanical and Folkloric Uses
In India, galls of Pistacia integerrima are valued in traditional medicine for the treatment of asthma, chronic bronchitis, phthisis, diarrhoea, fever, and other ailments of the respiratory tract, and as antispasmodic, carminative, antiamoebic, and anthelmintic.
P. integerrima has many ethnobotanical uses and is being used for the treatment of diarrhea, dysentery, fever, vomiting, skin diseases, respiratory ailments, and psoriasis, and is marketed in a traditional dosage form known as "habb-e-suranjan" by Hamdard Laboratories (WAQF) Pakistan.
Traditionally it is also used for rheumatic pain, analgesic, and antipyretic effects.
3. Key Constituents and Active Compounds
3.1 Primary Phytochemical Classes
The plant mainly contains alkaloids, flavonoids, tannins, saponins, and sterols in different parts including leaf, stem, bark, galls, and fruit. A number of terpenoids, sterols, and phenolic compounds have been isolated from Pistacia integerrima extracts.
The secondary metabolites like alkaloids, tannins, terpenoids, and flavonoids are reported in the galls. Besides them, minor constituents like crystalline hydrocarbon, gum mastic, resinous substance, and crystalline acids are also present.
Roots of Pistacia integerrima were found to contain terpenoids and tannins. Fruits are reported to possess tannins, essential oil, resin, pistacienoic acid, triterpene alcohol, and triterpenoic acid.
3.2 Essential Oil Constituents
The plant contains a significant amount of essential oils: alpha-pinene (25%), camphene (27%), di-limonene (4%–5%), 1,8-cineol (10%), caprylic acid (15%), alpha-terpineol (20%), and aromadendrene (4%–5%).
3.3 Phenolic and Flavonoid Constituents
Methanol extract and its ethyl acetate fraction of Pistacia integerrima were found to contain phenolics and flavonoids. Six flavonoids have been isolated from the methanolic extract of galls by column chromatographic analysis: 3,5,7,4′-tetrahydroxy-flavanone (1), naringenin (2), 3,5,4′-trihydroxy,7-methoxy-flavanone (3), sakuranetin (4), spinacetin (5), and patuletin (6).
Phytochemical analysis revealed that gallic acid and phenol content were higher in P. integerrima than in comparable species. Occurrence of gallic acid was measured at 15.41 ± 0.016 mg/g, compared to 8.65 ± 0.024 mg/g in Terminalia chebula and 6.80 ± 0.011 mg/g in Garuga pinnata.
3.4 Pistagremic Acid: The Principal Signature Triterpene
Pistagremic acid (PA) was isolated from the dried galls extract of P. integerrima. This phytoconstituent, namely pistagremic acid (PA), present in the galls of the plant, is the known natural terpene inhibitor of β-secretase. Pistagremic acid was isolated from the methanolic extract of the dried galls and subsequently identified using X-ray crystallography.
Pistagremic acid has shown significant pharmacological potential in various studies, including leishmanicidal, anticancer, antimicrobial, β-secretase inhibition, and α-glucosidase inhibition activities.
3.5 Tannins and Their Astringent Properties
The presence of tannins as major constituents is responsible for the astringent action of the gall drug. P. integerrima, which contains higher amounts of tannins than T. chebula and G. pinnata, is recommended as a potential antidiarrheal agent.
4. Established Mechanisms of Action
4.1 Respiratory / Antiasthmatic Mechanisms
Studies demonstrate the effectiveness of essential oil of Pistacia integerrima J. L. Stewart ex Brandis galls in bronchial asthma, possibly related to its ability to inhibit L-subtype Cav channel, mast cell stabilization, antioxidant, angiostatic, and through inhibition of 5-lipoxygenase enzyme.
Preclinical research demonstrates that P. integerrima extracts and isolated constituents can modulate key molecular pathways associated with asthma pathophysiology, including the inhibition of NF-κB, suppression of inducible nitric oxide synthase, modulation of mast cell stabilization, and downregulation of Th2 cytokines such as IL-4, IL-5, and IL-13.
4.2 Antidiarrheal / Antispasmodic Mechanisms
Antidiarrheal, antispasmodic, and bronchodilator activities of Pistacia integerrima are mediated through dual inhibition of muscarinic receptors and Ca²⁺ influx.
Docking models suggested that the extracts and isolated compounds exert antidiarrheal activity by inhibiting mu-opioid and delta-opioid receptors.
4.3 Anti-inflammatory and Analgesic Mechanisms
In animal studies, the antinociceptive effect of pistagremic acid was not antagonized by naloxone injection, suggesting that opioid receptors do not fully account for its analgesic effects. Pistagremic acid significantly ameliorated post-carrageenan-induced edema dose-dependently during various stages of inflammation, with the effect most dominant (60.02%) after the 3rd hour of drug administration when examined over 5 hours.
4.4 Alpha-Glucosidase Inhibition (Anti-Diabetic)
Strong α-glucosidase inhibitory potential of pistagremic acid was predicted using its molecular docking simulations against yeast α-glucosidase as a therapeutic target, and significant experimental α-glucosidase inhibitory activity confirmed the computational predictions. PA showed potent enzyme inhibitory activity both against yeast (IC₅₀: 89.12 ± 0.12 μM) and rat intestinal (IC₅₀: 62.47 ± 0.09 μM) α-glucosidases.
4.5 Beta-Secretase (BACE1) Inhibition
A triterpenic compound named pistagremic acid (PA) was isolated from Pistacia integerrima, and the β-secretase inhibition study found PA to be significantly active against β-secretase enzyme (BACE1) with an IC₅₀ value of 350 ± 2 nM, compared to a standard inhibitor with IC₅₀ = 290.71 ± 1 nM. The selectivity of this compound was also evaluated against acetylcholinesterase and butyrylcholinesterase enzymes; PA was found to be inactive against them and showed selectivity towards β-secretase enzyme (BACE1).
4.6 Phosphodiesterase-1 (PDE1) Inhibition
Pistacia integerrima galls and some of its active constituents — naringenin (1) and 3,5,7,4′-tetrahydroxy-flavanone (2) — are able in vitro to inhibit PDE1 activity (59.20 ± 4.95%, 75.90 ± 5.90%, and 65.25 ± 5.25%, respectively) and demonstrate in silico an interesting interaction with this enzymatic site. PDE1 inhibition is mechanistically relevant to bronchodilation and smooth muscle relaxation, consistent with the herb's traditional respiratory uses.
4.7 Xanthine Oxidase Inhibition (Anti-Gout)
Researchers examined whether polyphenolic constituents of this plant could counter hyperuricemia, measuring radical scavenging activity by DPPH and xanthine oxidase (XO) inhibitory activity in vitro, as well as using a fructose-induced hyperuricemic animal model to assess the serum uric acid-lowering effect. Ethyl acetate and n-BuOH fractions had the highest DPPH radical scavenging activity, with IC₅₀ values of 6 and 7.6 μg/ml, respectively — less potent than quercetin (IC₅₀ 0.95 μg/ml) and ascorbic acid (IC₅₀ 1.76 μg/ml).
5. Scientific Evidence by Area of Use
Important note on evidence level: The overwhelming majority of evidence for Pistacia integerrima gall is preclinical (in vitro and animal studies). The outstanding activity as an antiglycating agent is considered the most promising and so far unique activity, but in-depth research and clinical trials on human subjects to investigate P. integerrima pharmacological activity, clinical efficacy, and safety are recognized as crucial next steps. No large, well-controlled randomized clinical trials in humans have been published as of the date of this article.
5.1 Respiratory System: Asthma and Bronchitis
Pistacia integerrima J. L. Stewart ex Brandis, commonly known as Kakarsinghi, has traditionally been used in South Asia to treat respiratory conditions, including cough, bronchitis, and asthma, a practice prevalent in Ayurveda, Unani medicine, and local folklore.
Preclinical evidence: The essential oil of galls (EOPI) was tested using in vitro studies such as antioxidant activity, mast cell degranulation, angiogenesis, isolated guinea pig ileum preparation, and soybean lipoxidase enzyme activity. In vivo studies included lipopolysaccharide-induced bronchial inflammation in rats and airway hyperresponsiveness in ovalbumin-sensitized guinea pigs. The presence of rich content of phenolic chemical constituents contributes to the antiasthmatic activity of Pistacia integerrima Stewart ex Brandis galls, thus supporting the veracity of the claims made in the traditional literature.
Clinical suggestion: Clinical studies indicate that galls may effectively prevent respiratory attacks and enhance chest expansion and respiratory rate when used in polyherbal preparations. However, these clinical observations stem from small, uncontrolled or observational formats; no adequately powered randomized controlled trials have been reported in indexed literature.
Evidence strength: Moderate-to-strong preclinical evidence; clinical evidence is preliminary and insufficient to draw conclusions without further controlled trials.
5.2 Gastrointestinal System: Diarrhoea and Dysentery
Animal study (2021): The main goal of one investigation was to assess the antidiarrheal effect of Pistacia integerrima extracts/fractions and four isolated flavonoid compounds in mice. An in vivo assay involving castor-oil-induced diarrhea was used to evaluate the antidiarrheal potential of extracts/fractions at 100, 200, and 400 mg/kg p.o., as well as isolated compounds at 5, 10, and 20 mg/kg p.o. Pretreatment of mice with extracts/fractions significantly attenuated castor-oil-induced diarrhea in a dose-dependent manner. Among all crude extracts, the ethyl acetate extract was the most effective with 100% protection against diarrhea, followed by chloroform (75% protection) at 400 mg/kg p.o.
All isolated compounds exhibited strong antidiarrheal activity; isolated compounds 1 and 4 demonstrated 100% protection against diarrhea. Docking models suggested that the extracts and isolated compounds exert antidiarrheal activity by inhibiting mu-opioid and delta-opioid receptors, affording a strong pharmacological basis for the traditional use of P. integerrima galls in the treatment of diarrhea.
P. integerrima, which contains higher amounts of tannins than T. chebula and G. pinnata, is recommended as a potential antidiarrheal agent.
Evidence strength: Preclinical (animal and in silico) evidence is robust; no human clinical trials on file.
5.3 Analgesic and Anti-Inflammatory Activity
Animal study (2010): A study evaluated the possible analgesic and anti-inflammatory effects of Pistacia integerrima extracts. Analgesia was determined using acetic acid-induced abdominal constriction and formalin-induced paw licking in mice, with antinociceptive effect observed by thermally induced algesia. Pistacia integerrima gall extracts showed highly significant protection (P < 0.0001) against chemically induced pain in a dose-dependent manner.
Pistagremic acid animal study (2014): Results illustrated significant inhibition of noxious stimulation in the acetic acid-induced writhing test, with a maximum effect of 68% at 10 mg/kg i.p. In the tail immersion test, pretreatment with PA demonstrated marked activity during various assessment times in a dose-dependent manner, with maximum pain inhibition of 59.46% at 10 mg/kg i.p. after 90 minutes of PA treatment. Similarly, PA provoked dose-dependent antipyretic effect in febrile mice, with a maximum of 60.04% activity at 10 mg/kg i.p.
Evidence strength: Consistent in vivo animal data; no human trials.
5.4 Hyperuricemia and Gout
In vitro / animal study (published in Journal of Ethnopharmacology, 2008): Ethyl acetate and n-BuOH fractions had the highest DPPH radical scavenging activity; the 50% inhibitory concentration (IC₅₀) was 6 and 7.6 μg/ml, respectively — less than quercetin (IC₅₀ 0.95 μg/ml) and ascorbic acid (IC₅₀ 1.76 μg/ml). Xanthine oxidase inhibitory activity was also demonstrated in vitro, and a fructose-induced hyperuricemic animal model showed serum uric acid-lowering effects, providing pharmacological basis for the traditional use of the plant in gout.
Evidence strength: Preliminary in vitro and animal data; no human clinical trials.
5.5 Diabetes / Glycaemic Regulation
Pistacia integerrima is traditionally used as a folk remedy for various pathological conditions including diabetes. In order to identify the bioactive compound responsible for its folk use in diabetes, a phytochemical and biological study was conducted.
Six flavonoids were isolated from galls by column chromatographic analysis. These isolated compounds were tested against α-glycosidase. The maximum antagonistic effect was noted against compound 6 (patuletin, 97.65%), followed by compound 5 (spinacetin, 90.42%) and compound 1 (90.01%) at the same concentration (0.2 μg).
Evidence strength: In vitro and computational evidence only; no clinical data in humans.
5.6 Antimicrobial Activity
Pistacia integerrima extracts show significant antimicrobial activity against certain bacteria, such as the causative agents of prevalent infections. The gall powder is also reported to be effective against Staphylococci, Pseudomonas, and Escherichia coli bacteria. Ethanol and aqueous fractions of leaf galls were evaluated for antibacterial activity using the agar-well diffusion method, and the objective was to explore antimicrobial properties of n-hexane, ethyl acetate, chloroform, and methanol fractions with phytochemical profiling.
Evidence strength: In vitro only; no human clinical data.
5.7 Hepatoprotective Activity
The compounds isolated from the ethyl acetate fraction of methanol extract were subjected to determination of antioxidant activity by DPPH free radical activity, reducing power assay, and scavenging of hydroxyl radicals. There is a close relationship between antioxidant and hepatoprotective activity, so the isolated compounds were subjected to in vitro hepatoprotective studies using paracetamol-induced hepatotoxicity in primary rat hepatocytes, assessed by determining changes in hepatocyte viability and parameters including glutamic transaminase, glutamic pyruvic transaminase, and total protein. The fractions showed significant protective effect by restoring altered parameters in the selected in vitro model.
Khan et al. (2004) observed hepatocurative properties of Pistacia integerrima extracts in CCl₄-induced hepatic injury in rats.
Evidence strength: In vitro and animal data only.
5.8 Anticancer and Multidrug-Resistance Reversal Activity
Crude extract from Pistacia integerrima and its fractions were tested for cytotoxic activity against the MCF-7 human breast cancer cell line. The crude stem extract exhibited antitumour as well as antifungal potential activities; the crude extract inhibited MCF-7 cell viability in a dose-dependent manner, from poor toxicity (1.6%) at 10 μg/ml to moderate toxicity (55.4%) at 100 μg/ml, with an IC₅₀ value of 90.9 μg/ml. The ethyl acetate and chloroform fractions at a concentration of 200 μg/ml showed approximately 100% and 97.4% inhibition against the MCF-7 cell line, respectively.
Reversal of multidrug resistance in mouse lymphoma cells by extracts and flavonoids from Pistacia integerrima was also investigated.
Evidence strength: In vitro cell-line and mouse studies only; no human clinical evidence exists.
5.9 Neurological: BACE1 Inhibition and Potential in Alzheimer's Disease
A new triterpenic compound pistagremic acid (PA) was isolated from Pistacia integerrima, and the β-secretase inhibition study found PA significantly active against BACE1 with an IC₅₀ value of 350 ± 2 nM. BACE1 is a key enzyme in the amyloid cascade associated with Alzheimer's disease, making this observation of potential interest to neuropharmacological research. This remains entirely exploratory and no human data exist.
5.10 Anticonvulsant Activity
Screening of Pistacia integerrima extracts for their anticonvulsant activity was performed in acute zebrafish and rodent models of epilepsy, reported in the International Journal of Nutrition, Pharmacology, Neurological Diseases, 2015. Evidence is preclinical only.
5.11 Leishmanicidal Activity
Pistagremic acid showed significant leishmanicidal activity (IC₅₀: 6.71 ± 0.09 µM) against Leishmania major (DESTO) promastigotes in comparison to the standard compound amphotericin B (IC₅₀: 0.21 ± 0.06 µM). While substantially less potent than the clinical standard, this finding is noteworthy for natural compound drug discovery. Evidence is in vitro only.
5.12 Antioxidant Activity
The antioxidant properties owing to the presence of flavonoids and phenolic compounds safeguard cells against oxidative stress and damage. Multiple studies have confirmed antioxidant capacity through DPPH radical scavenging, reducing power, and hydroxyl radical scavenging assays. All antioxidant evidence is in vitro.
6. Body Systems and Health Areas Associated with Pistacia integerrima Gall
- Respiratory system: Phytochemical studies have identified various bioactive compounds in Kakarsinghi, including flavonoids, terpenoids, and phenolic acids, which exhibit antioxidant, anti-inflammatory, immunomodulatory, and bronchodilatory properties.
- Gastrointestinal system: Antidiarrheal, antispasmodic, antidysenteric, and antiemetic uses are extensively documented in both traditional records and preclinical studies.
- Metabolic system: α-Glucosidase inhibition and xanthine oxidase inhibition relevant to diabetes and gout/hyperuricemia respectively.
- Hepatic system: Hepatoprotective and hepatocurative activity in animal models of liver injury.
- Immune / Infectious disease: Antimicrobial activity against bacteria and fungi; leishmanicidal activity in vitro.
- Musculoskeletal system: Analgesic and anti-inflammatory applications for rheumatic and general pain.
- Nervous system: BACE1 inhibition relevant to Alzheimer's disease research; anticonvulsant effects in animal models.
- Oncology (exploratory): In vitro cytotoxic and multidrug-resistance reversal activity.
Compounds isolated from various parts of P. integerrima have been documented as analgesic, anti-inflammatory, muscle relaxant, antipyretic, and in reducing and inhibiting gastrointestinal motility. They also exhibit in vitro antioxidant, antimicrobial, multidrug-resistance reversal, α-glucosidase inhibition, β-secretase, and phosphodiesterase-1 inhibitory properties.
7. Dosage Forms and Dosages Reported in Studies
No official pharmacopeial monograph (such as the European Pharmacopoeia, WHO monograph, or USP) specifying dosage for Pistacia integerrima gall has been located in indexed literature. The following dosages are drawn exclusively from preclinical study protocols as explicitly reported in those publications.
- Antidiarrheal (animal study, ACS Omega 2021): Extracts/fractions were evaluated at 100, 200, and 400 mg/kg p.o., and isolated compounds at 5, 10, and 20 mg/kg p.o. in mice.
- Antinociceptive / anti-inflammatory / antipyretic (pistagremic acid, animal study 2014): Maximum effect (68% inhibition of writhing) was observed at 10 mg/kg i.p.
- Gastrointestinal motility (pistagremic acid, animal study): Pistagremic acid was assessed at 10, 50, and 100 mg/kg i.p. in the charcoal screening model.
- Acute toxicity (pistagremic acid, animal study): Pretreatment of PA exhibited substantial safety in the acute toxicity test up to the dose of 500 mg/kg p.o.
- Gall powder in traditional Ayurvedic practice: Gall powder (churna) at approximately 1–3 grams is referenced in classical Ayurvedic texts and contemporary Ayurvedic practice guides; however, no standardized, peer-reviewed clinical dosing study verifying this range in humans has been indexed in PubMed.
8. Safety Considerations
8.1 Toxicological Studies
The goals of one formal investigation were to evaluate acute (single-dose) and sub-acute (repeated-dose) toxicity profiles of methanolic extract of Pistacia integerrima J. L. Stewart ex Brandis in Wistar rats of both sexes, observing physiological changes, mortality, changes in body weight, histopathology of body organs, hematology, and biochemistry of the animals. The methanolic extract of PI was devoid of toxicity; hence, it can be used for various Ayurvedic preparations and treatments of diseases.
Results revealed that pretreatment of pistagremic acid exhibited substantial safety in the acute toxicity test up to the dose of 500 mg/kg p.o. However, when studied in the charcoal meal GI transit test, PA caused significant (p < 0.05) attenuation of GIT motility and an increase in intestinal transit time, comparable to atropine (a muscarinic receptor blocking agent). This antimotility effect is pharmacologically expected given the herb's antidiarrheal mechanism, but implies that high doses could theoretically cause constipation or impaired bowel motility.
8.2 Anacardiaceae Family Considerations
Kakarsingi, scientifically known as Pistacia integerrima, belongs to the family Anacardiaceae, which includes other notable plants like cashews and poison ivy. Members of this family are known to contain urushiol-type alkylphenols in some species, which can cause contact dermatitis; however, no peer-reviewed study has specifically documented contact sensitization from Pistacia integerrima gall preparations in humans.
8.3 Inclusion in Multi-Ingredient Ayurvedic Preparations
Galls of Pistacia chinensis subsp. Integerrima (J. L. Stewart) Rech. f. form a component of Divya-Swasari-Vati, a calcium-enriched Ayurvedic prescription medicine comprising nine botanical drugs along with seven mineral ashes (Bhasmas). The botanical drugs in this preparation include roots of Glycyrrhiza glabra and Anacyclus pyrethrum; fruits of Cressa cretica, Piper longum, and Piper nigrum; rhizomes of Zingiber officinale; bark of Cinnamomum verum; and flower buds of Syzygium aromaticum. Findings about safety for this multi-ingredient preparation do not isolate the individual contribution of the gall.
8.4 Absence of Human Clinical Safety Data
The available literature emphasizes the need for further research to explore the pharmacological actions of P. integerrima. No peer-reviewed clinical pharmacokinetic, drug-interaction, or long-term human safety study for Pistacia integerrima gall in isolation has been indexed as of the date of this article. The safety profile is considered favorable based on available animal toxicology and its long history of use in Ayurvedic medicine, but human clinical safety data are absent.
References
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