Dragon's Blood: Taspine, Toxicity and Safety Unknowns

Table of Contents

1. What Taspine Is
2. How Much Taspine the Sap Contains
3. Taspine Kills Cells in the Laboratory
4. Blood-Vessel Growth and Taspine Derivatives
5. Mutagenicity Tests on the Sap
6. A Related Croton Sap in Mice
7. Acute Toxicity Figures for the Leaf Extract
8. Effects on Blood-Vessel and Stomach Muscle in Rats
9. What the Drug's Safety Record Does and Does Not Cover
10. The Safety Unknowns
11. Key Research Papers
12. Connections

What Taspine Is

Taspine is an alkaloid, a nitrogen-containing plant compound of the kind that includes many potent natural drugs and poisons. It is not unique to Croton lechleri: Chinese researchers have isolated it from a different medicinal plant, sold as Radix et Rhizoma Leonticis (Hong Mao Qi), and studied it as a possible anti-cancer lead.

In dragon's blood research taspine has played two roles:

• The proposed healing agent. A 2002 paper in the Journal of Natural Products described taspine as the component earlier work had found responsible for the latex's wound-healing activity.
• A cytotoxic compound. Later studies found that it stops cancer cells growing at very low concentrations, interferes with their internal skeleton, and suppresses the growth of new blood vessels.

The two roles are compatible in principle, since a compound can be useful at one dose and harmful at another, but no study in our pack establishes where those boundaries lie in people.

How Much Taspine the Sap Contains

The 2002 survey, led by researchers at Washington University in St. Louis, analysed latex and leaf samples of Croton lechleri from 22 sites across northern Peru and Ecuador.

• The leaves contained up to six alkaloids: isoboldine, norisoboldine, magnoflorine, thaliporphine, glaucine and taspine.
• The latex contained only taspine.
• Taspine's mean concentration across the range was 9% of the latex by dry weight.
• Three chemical types (chemotypes) of the tree were defined by their leaf alkaloids, each with its own geographic distribution.

Nine percent is a large share for a biologically active alkaloid. Because the figure is an average across many sites, any single bottle of sap may contain more or less, and no product standard for taspine content appears in the research in our pack.

Taspine Kills Cells in the Laboratory

A 2012 study from the University of Padua, published in the Journal of Ethnopharmacology, compared Croton lechleri sap and isolated taspine with two established chemotherapy drugs on human cancer cell lines.

• The sap inhibited proliferation of melanoma cells (SK23) from 1 µg/mL; about ten times higher concentrations were needed for two colon cancer lines (HT-29 and LoVo).
• Taspine at 0.1 µg/mL inhibited proliferation of the melanoma and HT-29 cells, with a stronger effect on melanoma cells after 48 hours.
• Under the microscope, the sap at 1 µg/mL caused a loss of microtubule structure (the protein scaffolding cells use to divide), while taspine at 0.5 µg/mL increased acetylated tubulin and changed cell shape.
• At 50 µg/mL the sap caused a dramatic drop in cells in the normal growth phases and a large increase in dying cells.

Other extracts of the tree behave similarly. A 2012 Mexican study found a methanol extract of the leaves toxic to cervical cancer (HeLa) cells, with a half-maximal concentration of 17 µg/mL, while reporting no toxic effects on the normal human cells tested. A 2024 Bulgarian and Portuguese study of twig extracts found dose-dependent toxicity to both malignant melanoma cells and normal human skin cells (keratinocytes), with one ethanol extract more selective for the cancer cells.

The 2024 result is relevant to topical use: extracts from the tree harmed normal human skin cells in culture as well as cancer cells. How that translates to sap applied to a wound has not been studied.

Blood-Vessel Growth and Taspine Derivatives

Research on taspine from the Chinese source plant adds another dimension:

• A 2008 study in Cancer Letters found that taspine inhibited the growth of new blood vessels (angiogenesis) in chick-embryo membranes and in tumours grown on them at 0.5 to 2 µg per egg. In human lung cancer cells and human umbilical-vein cells it reduced secretion of the blood-vessel growth signals VEGF and bFGF, and it inhibited vessel-cell migration in a dose-dependent way.
• A 2014 study in Breast Cancer tested a taspine derivative, coded HMQ1611 and made to be more active and soluble. It reduced the adhesion, migration and invasion of a human breast cancer cell line and lowered two tissue-dissolving enzymes, MMP-2 and MMP-9.

Researchers studying cancer regard these as promising properties for a drug lead. For wound healing they cut the other way, because closing a wound requires new blood vessels and migrating cells. Whether taspine at the amounts reaching a wound from applied sap has any such effect is unknown.

Mutagenicity Tests on the Sap

A 2004 study from the University of Caxias do Sul in Brazil, published in the Journal of Ethnopharmacology, tested Croton lechleri sap in two directions at once.

Protective findings

• Significant antioxidant activity in yeast cells exposed to the oxidising agent apomorphine, under all conditions studied.
• Against hydrogen peroxide, antioxidant activity only in yeast cells in a resting (stationary) growth phase.
• Protection of maize seedlings from apomorphine toxicity.

Mutagenic findings

• In the Ames test, which uses strains of Salmonella bacteria to detect substances that cause mutations, the sap was mutagenic for strain TA1535 when a liver-enzyme mix was added to mimic metabolism, and weakly mutagenic for strain TA98. These strains detect base-pair substitutions and frameshift mutations respectively.
• The sap was also mutagenic in a yeast strain, for both locus-specific reversion and frameshift mutations.

A positive Ames result does not prove a substance causes cancer in people, but it is one of the standard early warnings toxicologists use.

The picture is complicated by a 2013 Italian study of the tree's stem-bark essential oil, a different product from the latex. In the Ames test with strain TA98, the oil reduced mutations caused by heterocyclic amines (mutagens formed in cooked meat) by 21% to 34% with metabolic activation, and by 39% to 40% against two of them without it. Different parts and preparations of the same tree can therefore behave differently.

A Related Croton Sap in Mice

The strongest animal safety signal concerns Croton palanostigma, a related species whose dark red sap is also sold as dragon's blood. A 2013 study from São Paulo State University gave mice a single dose of the sap by stomach tube at 300, 1,000 or 2,000 mg/kg.

• Chemistry: taspine was the main compound identified in the crude sap.
• DNA damage: all three doses produced genotoxic effects in white blood cells and liver cells, measured by the comet assay 24 hours after dosing.
• Chromosome damage: the two higher doses produced clastogenic or aneugenic effects (broken or mis-sorted chromosomes) in bone-marrow cells, measured by the micronucleus test.
• Cell toxicity: the ratio of young to mature red blood cells indicated no bone-marrow cytotoxicity.

The authors noted that dragon's blood had "scarce data about its safe use in humans" and concluded that their data suggest caution in human use of Croton palanostigma sap because of a possible cancer risk. This was a different species, at high single doses, in mice. Whether Croton lechleri sap does the same has not been tested in the studies in our pack, but the shared taspine content makes the question relevant.

Acute Toxicity Figures for the Leaf Extract

The 2012 Mexican study also measured acute toxicity in mice for its methanol extract of Croton lechleri leaves (not the latex):

• LD50 (the dose that killed half the animals) of 356 mg/kg by injection into the abdomen;
• LD50 of 500 mg/kg by mouth.

The authors described this as "moderate toxic effects in vivo". In the same study, daily abdominal injections of 1, 10 and 50 mg/kg in mice carrying human cervical-cancer tumours slowed tumour growth by 38%, 48% and 59%. The leaves differ chemically from the latex (they contain up to six alkaloids, while the latex contains only taspine), so these numbers cannot be applied directly to the sap.

Effects on Blood-Vessel and Stomach Muscle in Rats

A 2009 study from the University of Padova, published in Phytomedicine, tested the sap on isolated rat tissues:

• From 10 to 1,000 µg/mL, the sap caused concentration-dependent constriction of rat tail arteries, whether or not the lining of the vessel was intact, and also in arteries already constricted by other agents.
• Blocking alpha-1 adrenergic, muscarinic, serotonin 5-HT2A and capsaicin (vanilloid) receptors, or L-type calcium channels, did not stop the effect. The mechanism remains unidentified.
• On rat stomach muscle the sap slightly increased tension, and pre-treatment increased the contraction caused by carbachol, a drug that mimics the nerve messenger acetylcholine.

The authors described this as the first experimental evidence that the sap constricts smooth muscle. The study used isolated animal tissue, so its relevance to people taking the sap by mouth, or to people with high blood pressure or vascular disease, has not been studied.

What the Drug's Safety Record Does and Does Not Cover

Crofelemer, the purified proanthocyanidin from the same latex, has a reassuring record in the people it was tested in:

• In the ADVENT trial it was minimally absorbed, well tolerated, and had a safety profile comparable to placebo.
• The US LiverTox database reports occasional serum enzyme elevations during therapy, but no cases of clinically apparent acute liver injury.

That record does not extend to the crude latex. The drug is a defined substance from which taspine and the other non-proanthocyanidin components were removed, studied at a fixed dose with monitoring. A 2013 review also noted that long-term safety data on crofelemer were still lacking.

The 2003 review's statement that the sap "has shown low toxicity" predates the 2004 mutagenicity study and the 2013 mouse genotoxicity study, so readers can weigh it in that light.

The Safety Unknowns

These questions have no published answers in our citation pack:

1. How much taspine reaches the bloodstream when the sap is swallowed?
2. How much crosses broken skin when the sap is applied to a wound?
3. Is Croton lechleri sap genotoxic in animals, as Croton palanostigma sap was?
4. What is a safe amount, if any, for repeated oral use?
5. What happens in pregnancy and breastfeeding? No data exist on either.
6. Does the sap interact with other medicines, including antiretrovirals, blood-pressure drugs or chemotherapy?
7. How common are skin irritation and allergic reactions with topical use?
8. How much does taspine content vary between commercial products?
9. Does the vessel-constricting effect seen in isolated rat arteries occur in people?
10. What are the long-term effects of crofelemer itself, beyond the 48-week safety study?

Because of these gaps, the evidence does not establish that the crude sap is safe for internal use. The gaps matter most for prolonged or repeated oral use, for pregnancy and breastfeeding, and for people already taking other medicines, for whom no interaction data exist. Questions about any of these situations are for a clinician.

Key Research Papers

1. Milanowski DJ, Winter RE, Elvin-Lewis MP, et al. Geographic distribution of three alkaloid chemotypes of Croton lechleri. Journal of natural products. 2002;65(6):814-9. PubMed PMID: 12088421
2. Montopoli M, Bertin R, Chen Z, et al. Croton lechleri sap and isolated alkaloid taspine exhibit inhibition against human melanoma SK23 and colon cancer HT29 cell lines. Journal of ethnopharmacology. 2012;144(3):747-53. PubMed PMID: 23123266
3. Alonso-Castro AJ, Ortiz-Sánchez E, Domínguez F, et al. Antitumor effect of Croton lechleri Mull. Arg. (Euphorbiaceae). Journal of ethnopharmacology. 2012;140(2):438-42. PubMed PMID: 22301443
4. Tzintzarov A, Boyadzhieva SS, Coelho JAP, et al. Novel Insights into the Biological Activity of Croton lechleri Twigs Extracts and Advancements in Their Sustainable Recovery. Molecules (Basel, Switzerland). 2024;29(17). PubMed PMID: 39275010
5. Zhang Y, He L, Meng L, et al. Suppression of tumor-induced angiogenesis by taspine isolated from Radix et Rhizoma Leonticis and its mechanism of action in vitro. Cancer letters. 2008;262(1):103-13. PubMed PMID: 18180095
6. Zhan Y, Wang N, Liu C, et al. A novel taspine derivative, HMQ1611, suppresses adhesion, migration and invasion of ZR-75-30 human breast cancer cells. Breast cancer (Tokyo, Japan). 2014;21(3):334-40. PubMed PMID: 22875642
7. Lopes MI, Saffi J, Echeverrigaray S, et al. Mutagenic and antioxidant activities of Croton lechleri sap in biological systems. Journal of ethnopharmacology. 2004;95(2-3):437-45. PubMed PMID: 15507372
8. Rossi D, Guerrini A, Paganetto G, et al. Croton lechleri Müll. Arg. (Euphorbiaceae) stem bark essential oil as possible mutagen-protective food ingredient against heterocyclic amines from cooked food. Food chemistry. 2013;139(1-4):439-47. PubMed PMID: 23561129
9. Maistro EL, Ganthous G, Machado Mda S, et al. Dragon's blood Croton palanostigma induces genotoxic effects in mice. Journal of ethnopharmacology. 2013;147(2):406-11. PubMed PMID: 23528364
10. Froldi G, Zagotto G, Filippini R, et al. Activity of sap from Croton lechleri on rat vascular and gastric smooth muscles. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2009;16(8):768-75. PubMed PMID: 19406630
11. Risco E, Ghia F, Vila R, et al. Immunomodulatory activity and chemical characterisation of sangre de drago (dragon's blood) from Croton lechleri. Planta medica. 2003;69(9):785-94. PubMed PMID: 14598201
12. Macarthur RD, Hawkins TN, Brown SJ, et al. Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study. HIV clinical trials. 2013;14(6):261-73. PubMed PMID: 24334179
13. Crofelemer. 2012;. PubMed PMID: 31643647
14. Yeo QM, Crutchley R, Cottreau J, et al. Crofelemer, a novel antisecretory agent approved for the treatment of HIV-associated diarrhea. Drugs of today (Barcelona, Spain : 1998). 2013;49(4):239-52. PubMed PMID: 23616951
15. Jones K. Review of sangre de drago (Croton lechleri)--a South American tree sap in the treatment of diarrhea, inflammation, insect bites, viral infections, and wounds: traditional uses to clinical research. Journal of alternative and complementary medicine (New York, N.Y.). 2003;9(6):877-96. PubMed PMID: 14736360

PubMed Topic Searches

1. PubMed: Taspine (all studies)
2. PubMed: Croton lechleri mutagenicity
3. PubMed: Croton genotoxicity
4. PubMed: Taspine and angiogenesis

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Connections

• All Herbs
• Dragon's Blood (Croton lechleri) — the main topic page
• Dragon's Blood: Benefits Deep Dive — the evidence ledger
• Crofelemer: From Sap to Licensed Drug — the purified drug
• Wound Healing and Insect Bites — the taspine wound hypothesis
• Four Plants, One Name — Croton palanostigma and the other sources
• Comfrey — a wound herb whose internal use raised toxicity concerns
• Melanoma — the cancer cell type most sensitive to taspine in the lab
• Breast Cancer — the taspine-derivative cell study
• HIV/AIDS — where the purified drug was tested
• Skin, Wound and Topical Herbs — the parent category

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