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Dragon's Blood

Scientific Name(s): Croton lechleri Muell. -Arg.
Common Name(s): Blood of the dragon, Crofelemer, Drago, Dragon's blood, Sangre de drago, Sangre de grado, SP-303

Medically reviewed by Drugs.com. Last updated on Jul 1, 2019.

Clinical Overview

Use

A variety of traditional uses are associated with dragon's blood as C. lechleri sap, such as bleeding control, wound healing, and treatment of GI problems and cancer. However, evidence from clinical trials is insufficient to support these uses. Crofelemer (Fulyzaq) has been approved by the US Food and Drug Administration (FDA) for symptomatic relief of noninfectious diarrhea in patients with HIV/AIDS who are receiving antiretroviral therapy.

Dosing

The traditional oral dosage is 5 to 10 drops of the sap in water, once to twice per day for 5 days. For HIV/AIDS-related diarrhea, crofelemer 125 mg twice daily in adults. Safety and efficacy in children have not been established.

Pharmacokinetic data indicate that systemic absorption of oral crofelemer is minimal, regardless of concomitant food intake.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

No major toxic effects have been reported from consumption of C. lechleri extract. Systemic absorption of crofelemer is minimal, and studies report low levels of GI-related adverse effects (eg, abdominal pain, flatulence, dyspepsia).

Toxicology

Weak to no mutagenicity has been reported for the sap of C. lechleri; however, the chemical constituent taspine is considered cytotoxic.

Scientific Family

  • Euphorbiaceae (spurge)

Botany

The genus Croton comprises approximately 750 species of trees and shrubs commonly found in tropical and subtropical regions. The C. lechleri tree stands 10 to 20 m high, and the trunk is covered with smooth, mottled bark. When the bark is cut or damaged, it oozes a red, sap-like resin, which makes the tree appear to be bleeding. The plant bears heart-shaped leaves 15 to 30 cm in size, as well as 3-celled fruits from small flowers borne on tall, thin spikes.1, 2

A number of other sources of "dragon's blood" are documented, including the genera Dracaena, Daemonorops, and Pterocarpus, as well as mercury sulfide.3 Synonyms include Oxydectes lechleri and Croton draco.

History

Dragon's blood is mentioned in early Greek, Roman, and Arabic records; however, the source of the preparation varies. As "sangre de grado" (blood of the dragon), its recorded use has been extensive among Latin American countries since the 1600s: both the bark and resin have been used internally and externally to stop bleeding, heal wounds, and treat GI problems (including piles and hemorrhoids).3, 4 The sap has also been used in childbirth and as a remedy for cancer.3, 5, 6, 7

Chemistry

Reviews of the chemical constituents of C. lechleri have been published.2, 3

Among other alkaloids, taspine has been isolated from C. lechleri sap, and sinoacutine has been isolated from the leaves.2, 8, 9 Proanthocyanidins (or oligomers) and flavonols are the major phenolic constituents of the sap of C. lechleri, including galloepicatechin, gallocatechin, epicatecin, and catechin.7, 10, 11, 12, 13 Diterpenes and steroidal compounds have also been described.2 The bark essential oil consists primarily of sequiterpenes and monoterpenes.14

Uses and Pharmacology

Antibacterial and Antiviral effects

Animal data

Several phenolic compounds and diterpenes, as well as the essential oil from the plant, have demonstrated antibacterial activity.12, 14, 15

Antiviral effects have also been seen with C. lechleri extracts and may be related to viral penetration of the cell membrane. Crofelemer demonstrates broad in vitro activity against DNA and RNA viruses, including respiratory syncytial virus, influenza A, parainfluenza virus, herpesvirus types 1 and 2, and hepatitis A and B.13, 16, 17 The constituent taspine inhibited RNA-directed DNA polymerase activity from certain virus types, including leukemia and sarcoma virus.3, 18

Clinical data

Limited clinical studies have been conducted to evaluate antiviral effects. In a 1997 phase 2 clinical study, a 15% crofelemer ointment was not superior to oral acyclovir therapy in the treatment of genital herpes simplex virus infections.2

Cancer

Animal data

C. lechleri extracts increased apoptosis in Helen Lake tumor cells and other human cancer cell lines, and they have inhibited tumor growth in mice.3, 6, 7, 19 Thaspine (taspine), a topoisomerase inhibitor, alone induced apoptosis in mouse models of colon cancer.9 An inhibitory effect against mutagens has been demonstrated in vitro.7

Conversely, leukemic cells from children were exposed to C. lechleri extracts and showed both resistance to the extract and increased survival times.20

Clinical data

Clinical studies evaluating the effect of C. lechleri in cancer are lacking.

Diarrhea

Animal data

Crofelemer is an antidiarrheal agent that inhibits both the cyclic adenosine monophosphate–stimulated cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion (Cl–) channel and the calcium-activated Cl– channels (CaCC) at the luminal membrane of enterocytes. The CFTR Cl– channel and CaCC regulate Cl– and fluid secretion by intestinal epithelial cells. Crofelemer acts by blocking Cl– secretion and the accompanying high volume water loss in diarrhea, normalizing the flow of Cl– and water in the GI tract.13, 21, 22, 23 Experiments in mice have shown an action of C. lechleri sap on smooth muscle cells.24 In neonatal calves with experimentally induced enterotoxigenic Escherichia coli diarrhea, crofelemer increased fecal dry matter.25

A rat study of crofelemer for the severe diarrhea associated with dacomitinib, a tyrosine kinase inhibitor for cancer treatment, found no benefit for diarrhea and may have worsened GI toxicity.26

Clinical data

Crofelemer has been approved by the FDA for symptomatic relief of noninfectious diarrhea in patients with HIV/AIDS who are receiving antiretroviral therapy.23, 27 Clinical studies have been conducted in acute infectious diarrhea, diarrhea in patients with HIV, and diarrhea-predominant irritable bowel syndrome (IBS).13, 21, 23

In a phase 2 randomized, double blind, placebo-controlled study in patients with HIV-associated diarrhea (N = 51), administration of crofelemer 500 mg every 6 hours for 4 days resulted in a reduction in mean stool weight versus placebo (P = 0.14); however, reduction in stool frequency was insignificant.28

In a larger study (N = 374), crofelemer 125 mg twice daily for 4 weeks resulted in a reduction in daily watery stools (P = 0.04) and in daily stool consistency versus placebo (P = 0.02).29

In a trial evaluating crofelemer versus placebo in the treatment of travelers' diarrhea (N = 184), partial or complete resolution of symptoms occurred on day 1 among a significantly greater number of patients treated with crofelemer 125 and 250 mg 4 times daily than among the placebo group (P = 0.04 and 0.003 respectively); however, these results were not observed with crofelemer 500 mg.13, 16, 23, 30

Other, limited studies of infectious diarrhea suggest improvements in primary end points.13, 16 A multicenter, randomized, double-blind, placebo-controlled trial evaluated the efficacy of various doses of crofelemer in 241 adult men and women with diarrhea-predominant IBS. No improvement in stool consistency, frequency, or urgency was found over placebo at 12 weeks. However, improvements in pain-free days were observed in patients receiving crofelemer 500 mg twice daily (P = 0.03), particularly among female patients (P = 0.008).13, 16, 31

GI effects

Animal data

Reductions in the size of induced gastric ulcers in rats were achieved when sap from C. lechleri and Croton palanostigma was added to the rats' drinking water for 7 days. A decrease in bacterial counts of ulcers in the sap-drinking rats versus controls was also reported.2

Clinical data

Clinical data regarding the use of C. lechleri sap for gastric ulcers are lacking.

Wound-healing effects

Animal data

Anti-inflammatory actions of the taspine alkaloid from dragon's blood were first documented in 1979.32 Later studies confirmed these actions, leading to further studies in the area of wound healing. In one study, taspine was found to be the active cicatrizant principle by an in vivo test in mice; increased migration of human fibroblasts was suggested as the probable mechanism in this acceleration of the wound-healing process.33 Another report evaluating taspine's wound-healing properties demonstrated positive results (with higher dosing, these were seen earlier rather than later), using such parameters as wound tensile strength and histology; taspine also stimulated chemotaxis for fibroblasts. Data from the report suggest that taspine promotes early phases of wound healing in a dose-dependent manner.34 Another chemical constituent, a dihydrobenzofuran lignan also involved in wound healing actions, was isolated in 1993.35 Additionally, an in vitro study evaluating the effect of C. lechleri sap demonstrated inhibition of cutaneous neurogenic inflammation.36

Clinical data

Clinical data regarding the use of C. lechleri sap for wound healing are lacking.

Other uses

Immunomodulatory, weak antioxidant, and analgesic/anti-inflammatory properties have been described for C. lechleri sap, based largely on in vitro studies.3, 14, 37

Dosing

The traditional oral dosage is 5 to 10 drops of the sap in water, once to twice per day for 5 days.2 For HIV/AIDS-related diarrhea, crofelemer 125 mg twice daily in adults. Safety and efficacy in children have not been established.38

Pharmacokinetic data indicate that systemic absorption of oral crofelemer is minimal, regardless of concomitant food intake.13, 21

Pregnancy / Lactation

Fetal Risk Recommendation: No Human Data—Probably Compatible. For more information on pregnancy and lactation, see the professional Crofelemer drug information monograph.

Category C. There are no adequate, well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed.

C. lechleri sap has been traditionally used as a vaginal bath before childbirth and for healing after an abortion; however, clinical data are insufficient to support these uses.2, 3, 5

Interactions

Case reports for interactions with C. lechleri extracts are lacking.

In vitro studies have shown that crofelemer has the potential to inhibit cytochrome P450 isoenzyme 3A (CYP3A) and transporters MRP2 and OATP1A2 at expected concentrations in the gut. Because of the minimal absorption of crofelemer, the drug is unlikely to inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 systemically. Studies in healthy volunteers found no clinically relevant interactions of crofelemer with nelfinavir, zidovudine, or lamivudine.21, 38

Adverse Reactions

No major toxic effects have been reported from consumption of C. lechleri extract, and studies evaluating crofelemer report low levels of GI-related adverse effects (eg, abdominal pain, flatulence, dyspepsia).13, 21 Combined data from HIV studies using crofelemer also report increased bilirubin; however, the clinical relevance of this finding is unclear because systemic absorption of crofelemer is minimal.39

Toxicology

Weak to no mutagenicity in Salmonella and yeast tests has been reported for the sap of C. lechleri,2, 37 and no mutagenicity of the plant essential oil was observed.14 Because the constituent taspine may be cytotoxic, it should not exceed 5,000 ppm.2, 33, 40 The acute oral median lethal dose of crofelemer in rats was determined to be greater than 300 mg/kg.2 Chronic mouse skin carcinogenesis models found no evidence of mutagenicity in topical sap applications.2

Index Terms

  • Croton draco
  • Oxydectes lechleri

References

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3. Gupta D, Bleakley B, Gupta RK. Dragon's blood: Botany, chemistry and therapeutic uses. J Ethnopharmacol. 2008;115(3):361-380.18060708
4. Cobb C, Goldwhite H, Fetterolf M. The Chemistry of Alchemy: From Dragon's Blood to Donkey Dung, How Chemistry Was Forged. Amherst, NY: Prometheus Books; 2014.
5. Duke JA. Handbook of Medicinal Herbs. 2nd ed. Boca Raton, FL: CRC Press; 2002.
6. Alonso-Castro AJ, Ortiz-Sanchez E, Dominguez F, et al. Antitumor effect of Croton lechleri Mull. Arg. (Euphorbiaceae). J Ethnopharmacol. 2012;140(2):438-442.22301443
7. Gonzales GF, Valerio LG Jr. Medicinal plants from Peru: a review of plants as potential agents against cancer. Anticancer Agents Med Chem. 2006;6(5):429-444.17017852
8. De Marino S, Gala F, Zollo F, et al. Identification of minor secondary metabolites from the latex of Croton lechleri (Muell-Arg) and evaluation of their antioxidant activity. Molecules. 2008;13(6):1219-1229.18596648
9. Fayad W, Fryknas M, Brnjic S, Olofsson MH, Larsson R, Linder S. Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters. PLoS One. 2009;4(10):e7238.19798419
10. Cai Y, Evans FJ, Roberts MF, Phillipson JD, Zenk MH, Gleba YY. Polyphenolic compounds from Croton lechleri. Phytochemistry. 1991;30(6):2033-2040.
11. Cai Y, Chen ZP, Phillipson JD. Diterpenes from Croton lechleri. Phytochemistry. 1993;32(3):755-760.
12. Cai Y, Chen ZP, Phillipson JD. Clerodane diterpenoids from Croton lechleri. Phytochemistry. 1993;34(1):265-268.
13. Cottreau J, Tucker A, Crutchley R, Garey KW. Crofelemer for the treatment of secretory diarrhea. Expert Rev Gastroenterol Hepatol. 2012;6(1):17-23.22149578
14. Rossi D, Bruni R, Bianchi N, et al. Evaluation of the mutagenic, antimutagenic and antiproliferative potential of Croton lechleri (Muell. Arg.) latex. Phytomedicine. 2003;10(2-3):139-144.12725567
15. Chen ZP, Cai Y, Phillipson JD. Studies on the anti-tumour, anti-bacterial, and wound-healing properties of dragon's blood. Planta Med. 1994;60(6):541-545.7809208
16. Crutchley RD, Miller J, Garey KW. Crofelemer, a novel agent for treatment of secretory diarrhea. Ann Pharmacother. 2010;44(5):878-884.20388859
17. Ubillas R, Jolad SD, Bruenig RC, et al. SP-303, an antiviral oligomeric proanthocyanidin from the latex of Croton lechleri (Sangre de Drago). Phytomedicine. 1994;1(2):77-106.23195881
18. Sethi M. Inhibition of RNA-directed DNA polymerase activity of RNA tumor viruses by taspine. Can J Pharm Sci. 1977;12(1):7-9.
19. Montopoli M, Bertin R, Chen Z, Bolcato J, Caparrotta L, Froldi G. Croton lechleri sap and isolated alkaloid taspine exhibit inhibition against human melanoma SK23 and colon cancer HT29 cell lines. J Ethnopharmacol. 2012;144(3):747-753.23123266
20. Styczynski J, Wysocki M. Alternative medicine remedies might stimulate viability of leukemic cells. Pediatr Blood Cancer. 2006;46(1):94-98.16047362
21. Clay PG, Crutchley RD. Noninfectious diarrhea in HIV seropositive individuals: a review of prevalence rates, etiology, and management in the era of combination antiretroviral therapy. Infect Dis Ther. 2014;3(2):103-122.25388760
22. Tradtrantip L, Namkung W, Verkman AS. Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol. 2010;77(1):69-78.19808995
23. Frampton JE. Crofelemer: a review of its use in the management of non-infectious diarrhoea in adult patients with HIV/AIDS on antiretroviral therapy. Drugs. 2013;73(10):1121-1129.23807722
24. Froldi G, Zagotto G, Filippini R, Montopoli M, Dorigo P, Caparrotta L. Activity of sap from Croton lechleri on rat vascular and gastric smooth muscles. Phytomedicine. 2009;16(8):768-775.19406630
25. Teixeira AG, Stephens L, Divers TJ, Stokol T, Bicalho RC. Effect of crofelemer extract on severity and consistency of experimentally induced enterotoxigenic Escherichia coli diarrhea in newborn Holstein calves. J Dairy Sci. 2015;98(11):8035-8043.26298758
26. Van Sebille Y, Gibson R, Bowen J. Is crofelemer an effective intervention for dacomitinib-induced gastrointestinal toxicity? Asia-Pac J Clin Oncol. 2014;10(suppl 8):208-209.
27. Hornby PJ. Drug discovery approaches to irritable bowel syndrome. Expert Opin Drug Discov. 2015;10(8):809-824.26193876
28. Holodniy M, Koch J, Mistal M, et al. A double blind, randomized, placebo-controlled phase II study to assess the safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS. Am J Gastroenterol. 1999;94(11):3267-3273.10566728
29. Macarthur RD. Management of noninfectious diarrhea associated with HIV and highly active antiretroviral therapy. Am J Manag Care. 2013;19(12 suppl):s238-s245.24495294
30. DiCesare D, DuPont HL, Mathewson JJ, et al. A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J Gastroenterol. 2002;97(10):2585-2588.12385443
31. Mangel AW, Chaturvedi P. Evaluation of crofelemer in the treatment of diarrhea-predominant irritable bowel syndrome patients. Digestion. 2008;78(4):180-186.19092244
32. Perdue GP, Blomster RN, Blake DA, Farnsworth NR. South American plants II: taspine isolation and anti-inflammatory activity. J Pharm Sci. 1979;68(1):124-126.758452
33. Vaisberg AJ, Milla M, Planas MC, et al. Taspine is the cicatrizant principle in Sangre de Grado extracted from Croton lechleri. Planta Med. 1989;55(2):140-143.2748730
34. Porras-Reyes BH, Lewis WH, Roman J, Simchowitz L, Mustoe TA. Enhancement of wound healing by the alkaloid taspine defining mechanism of action. Proc Soc Exp Biol Med. 1993;203(1):18-25.8386382
35. Pieters L, de Bruyne T, Claeys M, et al. Isolation of a dihydrobenzofuran lignan from South American dragon's blood (Croton spp.) as an inhibitor of cell proliferation. J Nat Prod. 1993;56(6):899-906.8350090
36. Pereira U, Garcia-Le Gal C, Le Gal G, et al. Effects of sangre de drago in an in vitro model of cutaneous neurogenic inflammation. Exp Dermatol. 2010;19(9):796-799.20698880
37. Lopes MI, Saffi J, Echeverrigaray S, Henriques JA, Salvador M. Mutagenic and antioxidant activities of Croton lechleri sap in biological systems. J Ethnopharmacol. 2004;95(2-3):437-445.15507372
38. Fulyzaq (crofelemer) [prescribing information]. Raleigh, NC: Salix Pharmaceuticals Inc; December 2012.
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