Curare ☠️

Curare is one of the names South American peoples gave to the plant poisons they used to coat the tips of hunting arrows and blowpipe darts. The two main sources were Chondrodendron vines, especially C. tomentosum, and Strychnos species, especially S. toxifera ^{22Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}.

The poison is little absorbed when swallowed, so the meat of animals killed with it is harmless ^{22Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}. Hunters tested the strength of each batch by how far a struck monkey could flee, from one tree to three ^{22Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}.

Bark and root are decocted and reduced to a thick paste, and the mix of plants varies between peoples and regions.

In South America the root is used as a bitter tonic, diuretic, fever remedy and emmenagogue. A root decoction is taken for oedema, kidney stones, persistent urinary tract infections, prostatitis and testicular inflammation ^{24Reference 24FernFern, K. (n.d.). Chondrodendron tomentosum — species database entry. Useful Tropical Plants Database. https://tropical.theferns.info/viewtropical.php?id=Chondrodendron+tomentosumView study →}.

Externally the plant is applied as a poultice to bruises and to poisonous snake bites ^{24Reference 24FernFern, K. (n.d.). Chondrodendron tomentosum — species database entry. Useful Tropical Plants Database. https://tropical.theferns.info/viewtropical.php?id=Chondrodendron+tomentosumView study →}.

The Portuguese brought the root to Europe in the second half of the seventeenth century. It was sold as pareira brava, and in Brazil it was called abutua ^{23Reference 23Felter et al. · 1898Pareira (UView study →}.

It was official in the United States Pharmacopoeia. King’s American Dispensatory (1898) describes it as a tonic, diuretic and mild laxative, used for chronic inflammation of the bladder and kidney, kidney stones, leucorrhoea, dropsy, rheumatism and jaundice ^{23Reference 23Felter et al. · 1898Pareira (UView study →}.

The drug was often adulterated, most commonly by selling the weaker stem as the root ^{23Reference 23Felter et al. · 1898Pareira (UView study →}.

The French physiologist Magendie received curare samples from Alexander von Humboldt and used the poison to immobilise animals. In the mid-nineteenth century Claude Bernard and his pupil Vulpian showed that curare acts between the motor nerve and the muscle, at the motor endplate ^{22Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}.

In 1912 the German surgeon Läwen used “curarine”, a partly purified material from calabash curare, alongside anaesthesia ^{22Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}.

In 1938 the explorer Richard Gill brought back more than 11 kg of curare from the Amazon. Scientists at E. R. Squibb & Sons identified C. tomentosum as a plant source and made a stable extract of uniform strength, Intocostrin. Harold Griffith gave it in the operating room in 1942 ^{1Reference 1Elsherbini et al. · 2024The connection between DrView study →}. Gill later disputed Squibb’s claim that curare came from C. tomentosum alone ^{1Reference 1Elsherbini et al. · 2024The connection between DrView study →}.

(+)-Tubocurarine, the principal alkaloid of C. tomentosum, is a reversible competitive antagonist at the nicotinic acetylcholine receptor of the motor endplate. It produces flaccid paralysis of skeletal muscle ^{1,22Reference 1Elsherbini et al. · 2024The connection between DrView study →Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}.

Voltage-clamp work at the frog neuromuscular junction shows it binds both acetylcholine sites on the receptor with micromolar affinity, and with an association rate as fast as that of acetylcholine ^{3Reference 3Le Dain et al. · 1991In vitroKinetics of (+)-tubocurarine blockade at the neuromuscular junction — in vitroView study →}.

In a comparison under enflurane anaesthesia, ten patients each received tubocurarine 0.5 mg/kg, vecuronium 0.1 mg/kg or atracurium 0.5 mg/kg. Recovery followed a similar pattern with all three drugs ^{4Reference 4O’Hara et al. · 1986RCTReappearance of the train-of-four after neuromuscular blockade induced with tubocurarine, vecuronium or atracurium — randomised controlled trialView study →}.

Cholinesterase inhibitors such as neostigmine reverse the block ^{22Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}.

The effect appears only when the alkaloid is injected. Curare is little absorbed when swallowed, which is why game killed with it can be eaten ^{22Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}.

Gap: Every human result belongs to the purified alkaloid injected intravenously under anaesthesia, with the airway secured and breathing controlled. It paralyses the diaphragm along with every other muscle, and without ventilation the effect is fatal. No oral preparation of the plant produces it.

Curine, a bisbenzylisoquinoline also called bebeerine, has anti-inflammatory activity in mice. The material studied came from the related C. platyphyllum. Taken by mouth, curine reduced paw swelling and vascular permeability, and in vitro it inhibited prostaglandin E2 production without changing COX-2 expression. Its effects resembled those of indomethacin ^{7Reference 7Leite et al. · 2014AnimalCurine, an alkaloid isolated from Chondrodendron platyphyllum, inhibits prostaglandin E2 in experimental models of inflammation and pain — mouse in vivoView study →}.

In mice with LPS-induced pleurisy, curine reduced neutrophil recruitment and lowered TNF-α, IL-1β, IL-6, MCP-1 and leukotriene B4 ^{8Reference 8Ribeiro-Filho et al. · 2019AnimalCurine inhibits macrophage activation and neutrophil recruitment in a mouse model of lipopolysaccharide-induced inflammation — in vivoView study →}.

Five bisbenzylisoquinolines, including cycleanine and chondocurine, suppressed nitric oxide production by activated mouse macrophages in vitro ^{9Reference 9Kondo et al. · 1993In vitroInhibitory effect of bisbenzylisoquinoline alkaloids on nitric oxide production in activated macrophages — in vitroView study →}.

Gap: The best-characterised work used curine from C. platyphyllum, a different species. Effects in C. tomentosum are inferred from shared chemistry, and no human data exist.

In ovalbumin-sensitised mice, oral curine reduced eosinophil recruitment and activation and airway hyper-responsiveness, and lowered IL-13 and eotaxin. The effect resembled that of the calcium-channel blocker verapamil and was linked to reduced calcium influx ^{11Reference 11Ribeiro-Filho et al. · 2013AnimalCurine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma — in vivoView study →}.

In mast-cell-dependent models, curine reduced scratching, paw swelling, anaphylaxis and production of cysteinyl leukotrienes and PGD2. It acted as a mast-cell stabiliser, comparable to cromoglycate ^{12Reference 12Ribeiro-Filho et al. · 2014AnimalCurine inhibits mast cell-dependent responses in mice — in vivoView study →}.

A review summarises curine’s anti-allergic effects in skin, lung and whole-body allergy models at non-toxic oral doses ^{10Reference 10Ribeiro-Filho et al. · 2015ReviewAnti-allergic properties of curine, a bisbenzylisoquinoline alkaloid — reviewView study →}.

This is preclinical work from one research group, using curine from C. platyphyllum. No clinical asthma or allergy trial exists for this plant.

In mice, curine reduced acetic-acid-induced writhing and carrageenan-induced pain sensitivity, and reduced the inflammatory but not the neurogenic phase of the formalin test. The pattern resembled indomethacin rather than morphine, which points to an effect through reduced prostaglandin E2 ^{7Reference 7Leite et al. · 2014AnimalCurine, an alkaloid isolated from Chondrodendron platyphyllum, inhibits prostaglandin E2 in experimental models of inflammation and pain — mouse in vivoView study →}.

This is one animal study, and the effect follows from the anti-inflammatory action.

The potency data for this plant’s alkaloids come from other members of the moonseed family. Isochondodendrine, isolated from the root bark of Epinetrum villosum, was the most potent antiplasmodial alkaloid in that plant, with an in vitro IC50 of 0.10 µg/mL and a selectivity index of 175 against human colon cancer cells ^{13Reference 13Otshudi et al. · 2005In vitroBiologically active bisbenzylisoquinoline alkaloids from the root bark of Epinetrum villosum — in vitroView study →}.

In a screen of 53 bisbenzylisoquinolines, more than half were at least 100 times more toxic to Plasmodium falciparum than to human cells, and (–)-cycleanine was among the most selective ^{14Reference 14Angerhofer et al. · 1999In vitroAntiplasmodial and cytotoxic activity of natural bisbenzylisoquinoline alkaloids — in vitroView study →}.

Docking studies suggest curine binds Plasmodium prolyl-tRNA synthetase and dihydrofolate reductase ^{15Reference 15Suresh et al. · 2023Bisbenzylisoquinolines from Cissampelos pareira L. as antimalarial agents: molecular docking and molecular dynamics — in silicoView study →}.

No antiplasmodial testing has been done on C. tomentosum material.

Cycleanine isolated from Triclisia subcordata inhibited ovarian cancer cell lines at 7–14 µM and triggered apoptosis through caspase-3/7 activation and PARP cleavage ^{16Reference 16Uche et al. · 2016In vitroCytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordata — in vitroView study →}. A modelling study proposed PARP1 as a direct target ^{17Reference 17Nwaefulu et al. · 2022The impact of cycleanine in cancer research: a computational study — in silicoView study →}.

Curine from C. platyphyllum caused G1 arrest and apoptosis in HL-60 leukaemia cells and was cytotoxic to K562 cells ^{18Reference 18Dantas et al. · 2015In vitroEffects of curine in HL-60 leukemic cells: cell cycle arrest and apoptosis induction — in vitroView study →}. (–)-Curine from Cyclea wattii killed liver cancer cells whatever their p53 status ^{19Reference 19Gong et al. · 2017In vitroGong, S., et al. (2017). (–)-Curine induces cell cycle arrest and cell death in hepatocellular carcinoma cells in a p53-independent way — in vitro. Biomedicine & Pharmacotherapy. https://pubmed.ncbi.nlm.nih.gov/28292017/View study →}.

Gap: All in vitro, with alkaloids from other plants, no tumour model and no clinical work.

Curine relaxes vascular smooth muscle by blocking calcium channels. In rat aorta it inhibited contractions to high potassium and to Bay K8644. In A7r5 vascular smooth-muscle cells it reduced the L-type calcium current and shifted its inactivation toward more negative potentials, independently of cAMP and cGMP ^{20Reference 20Medeiros et al. · 2011In vitroCurine, a bisbenzylisoquinoline alkaloid, blocks L-type Ca²⁺ channels and decreases intracellular Ca²⁺ transients in A7r5 cells — in vitro/ex vivoView study →}. The same calcium-channel block has been linked to curine’s anti-allergic effects ^{11Reference 11Ribeiro-Filho et al. · 2013AnimalCurine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma — in vivoView study →}.

This is a single line of ex vivo and in vitro work, with no whole-animal blood-pressure or human data.

In vitro, curine and cycleanine were among eleven bisbenzylisoquinolines tested against Trypanosoma cruzi, the parasite of Chagas disease. Both were active, and curine reached an LC50 of about 10 µM. The alkaloids were mixed inhibitors of trypanothione reductase, an enzyme the parasite depends on ^{21Reference 21Fournet et al. · 1998In vitroTrypanocidal bisbenzylisoquinoline alkaloids are inhibitors of trypanothione reductase — in vitroView study →}.

These are enzyme and parasite assays on purified alkaloids, not tests of the plant.

Paralysis. (+)-Tubocurarine is a potent skeletal-muscle relaxant ^{3,22Reference 3Le Dain et al. · 1991In vitroKinetics of (+)-tubocurarine blockade at the neuromuscular junction — in vitroView study →Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}. It causes flaccid paralysis and, at sufficient dose, death by respiratory arrest. The diaphragm is a skeletal muscle, and the person stays conscious while breathing stops, which is why the drug was only ever used with airway management ^{22Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}.

Route. Curare does little when swallowed, because its charged alkaloids are poorly absorbed from the gut, and meat from curare-killed game is eaten safely ^{22Reference 22Bowman · 2006ReviewNeuromuscular block — reviewView study →}. This is a pharmacokinetic fact, not a safety margin. It does not show that oral herbal doses are safe, and any injection or contact with broken skin is dangerous.

Histamine release. In 21 surgical patients, injected tubocurarine raised plasma histamine in proportion to the dose, and the rise tracked the fall in blood pressure ^{5Reference 5Moss et al. · 1981Role of histamine in the hypotensive action of d-tubocurarine in humansView study →}. In rats it released histamine directly from mast cells ^{6Reference 6Kubota · 1986In vitroEffects of tubocurarine on plasma histamine concentration in the rat; correlation with histamine release from isolated mast cells — animal/in vitroView study →}. Flushing and bronchospasm are also attributed to this release.

No herbal safety data. There are no toxicology or safety studies of oral herbal preparations of this plant, and no established therapeutic dose.