Last Updated: September 28 2022

Uncaria rhynchophylla (Gou-Teng or Chotoko) is an antiepileptic eastern medicine and major component of 'Yokukansan' for the treatment of agitation in elderly persons. It appears to be neuroprotective, anticonvulsive, and has antipsychotic properties like Aripiprazole.

Gou-teng is most often used for

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Sources and Composition



Uncaria rhynchophylla (of the family Rubiaceae) is a traditional chinese medicine and frequently used in Japanese (Kampo) medicine for the treatment of convulsive disorders,[1] headaches, vertigo and dizziness, epilepsy,[2] and as an antipyretic and antihypertensive medication.[2] It is known as Chotoko in Japanese medicine (and the dust from this plant, or pulvis uncariae, is called Uncariae uncis cum ramulus[3]) and Gou-teng in Chinese medicine.[4][5]

This plant is also sometimes called Cat's Claw or Fish Hook Vine (referring to the hook structures on the plant) but this is a term that is used to describe the entire genera of uncaria and, when used colloquiolly, tends to refer to the Amazonian species Uncaria tomentosa or uncaria guianensis. The reason the plants in this genera are called such is because the plants bear 'hooks' which is what the entire genera is named after (uncus is latin for hook), and this is the branch of the plant which is modified into a hook shape to allow the plant to climb upon the vines of other plants.

Uncaria rhynchophylla (Choto-ko) is a herb that has traditionally been used to treat head ailments (headache, dizziness) and for the treatment of epilepsy and hypertension. It is most well known for being a component of Yokukansan, a Kampo medicine for the treatment of agitation and well being in persons with Dementia



The components of uncaria rhynchophylla (the medicinal hooks, unless otherwise specified) include:

  • Hirsuteine (0.015% of Yokukansan or YKS;[6] 0.08% hook dry weight), the hydrogenated version known Hirsutine (0.013% of YKS;[6] 0.07% hook dry weight), and the isomer of Hirsuteine known as Geissoschizine methyl ether (0.014% of YKS;[6] 0.08% hook dry weight); the latter being structured similar to Geissoschizine (without the methyl ether) and turbinatine (Geissoschizine glycoside[7])
  • Corynoxeine (0.026% of YKS;[6] 0.25-1.43mg/g[4] or 0.40-2.47mg/g of the dried hook[8] and 0.27-0.82mg/g dry leaf[8]), Isocorynoxeine (0.009% of YKS;[6] 0.60-1.96mg/g[4] or 0.66-4.63mg/g dried hook[8] and 0.74-2.31mg/g dried leaves[8]), Cisocorynoxeine,[9] and 9-hydroxy derivatives;[4] there is also 22-O-β-D-glycopyranosyl glycoside of isocorynoxeinic acid (0.21mg/g hook dry weight or otherwise undetectable; undetectable in leaves[8]) and N-oxide derivatives of corynoxeine (0.02mg/g dry hook weight or otherwise undetectable; not in leaves[8]) and isocorynoxeine (0.08mg/g dry hook weight or less, not in leaves[8])
  • Rhynchophylline (0.027% of YKS;[6] detected in the range of 0.77-1.44mg/g[4] or 0.50-2.21mg/g dried hook[8] and 0.39-0.96mg/g dried leaves[8]) and Isorhynchophylline (0.005% of YKS;[6] 0.87-4.55mg/g dried hook and 0.81-3.95mg/g in dried leaves[8]) as well as rhynchophylline and isorhynchophylline N-oxide variants (less than 0.12mg/g and 0.15mg/g respectively in the hooks; lesser or nonexistent in the leaves[8])
  • Rhynchophyllic acid and isorhynchophyllic acids as well as their 22-O-β-glucopyranosides[4]
  • Corynoxine and corynoxine B (epimers)[4] as well as 18,19-dehydrocorynoxinic and 18,19-dehydrocorynoxinic B (epimers)[8][10]
  • Specionoxeine and isospecionoxeine[4]
  • Procyanidin B1 and B2[4]
  • Rutin[4]
  • Akuammigine (oxindole alkaloid)[11][12]
  • Vallesiachotamine[9]
  • Alkaloid glycosides such as vincoside lactam (0.21-0.37mg/g[4] or 0.8-0.42mg/g dry hook weight[8] and 2.29-3.98mg/g dry leaf weight[8]) its 11-hydroxy-2′-O-D-glucopyranosyl (0.07-0.20mg/g dried hook[8] and 0.10-0.48mg/g dried leaves[8]), and strictosidine (2.29-3.92mg/g dry leaf weight and 0.07-1.08mg/g dry hook[8])
  • (+)-catechin (2.56mg/g dried hook)[1][4] and (-)-epicatechin (1.53mg/g dried hook)[1][4]
  • Chlorogenic acid (5.66mg/g of the dried hook) and neochlorogenic acid[4]
  • trans-anethole, p-anisaldehyde, and estragole[13] (volatile oils also found in fennel)
  • The triterpenes 3-oxo-olean-12-en-28-oic acid[13] and ursolic acid[14] as well as the triterpenes with phenolic groups named Uncarinic Acids A-E[15][16] which are either isomers of 3β-hydroxy-27-feruloyloxyurs-12-en-28-oic acid (uncarinic acids C and D) or β-hydroxy-27-coumaroyloxyolean-12-en-28-oic acid (uncarinic acid E)[17]

Rhynchophylline and isorhynchophylline are relatively unique structures known as tetracyclic oxindole alkaloids, and are epimers of each other at the C7 position.[2] Corynoxeine and isocorynoxeine are also oxyindole alkaloids, but geissoschizine methyl ether and both hirsuteine and hirsutine are indole alkaloids.[18]


The components of this plant are essentially the alkaloids, which are present in very low quantities but due to their potencies at the molecular level this small quantity may be sufficient. The are broken down into either oxindole alkaloids or indole alkaloids for the most part, and the main bioactives are probably rhynchophylline (and its isomer) as well as geissoschizine methyl ether

When looking collectively at the groups of alkaloids, the oxindoles (rhynchophyllineand corynoxeine related) 0.26-1.38% dry weight while the alkaloid glycosides (vincoside lactam, its glycoside, and strictosidine) are lesser at 0.02-0.19%.[8] In the leaves, the alkaloid glycosides are much higher (3.8-7.5% dry weight) while the oxindoles are comparatively lower (0.21-0.71% dry weight); the oxindole N-oxides are trace in all aerial parts.[8] The indole alkaloids (hirustine, hirusteine, geissoschizine methyl ether) are somewhat lower than the oxinolde alkaloids.

The branches/hooks of uncaria rhynchophylla contain a decent amount of the oxindole and indole alkaloids. The leaves (not usually used medicinally) have much higher levels of the alkaloid glycosides


Physicochemical Properties

Rhynchophylline and isorhynchophylline appear to be poorly soluble, limiting their usage in in vitro studies past 100µM despite usage of DMSO.[2]

Apparently ("it is traditionally known that"[5]) uncaria rhynchophylline is unstable in high temperatures; it was mentioned in the aforementioned study following hot water extraction at 60-70°C (and 2 hour evaporation at 60°C) as a reason to avoid further extraction.


Formulations and Variants

There is a formulation called Yokukansan or Choto-san in Japanese medicine (Yi-Gan San in Chinese) which contains the powder of uncaria rhynchophylla (referred to as Uncariae uncis cum ramulus) at 3g alongside the rhizome of Atractylodes lancea (4g), the mushroom Poria cocos (4g), the rhizome from Cnidium officinale (3g), the root of Angelica acutiloba (3g), the root of Bupleurum falcatum (2g), and licorice root (Glycyrrhiza uralensis at 1,500mg). This formulation is recommended for restlessness in children or for treating agitation in dementia.

Yokukansan is a compound formulation used for the treatment of aggression and enhancement of well being in elderly persons with dementia or other cognitive disorders. The role uncaria rhynchophylla plays in this formulation is thought to be the antiagressive effect (see the serotonin section) and alongside glycyrrhiza uralensis it adds some neuroprotective properties

Another formulation including uncaria rhynchophylla (synonymous with Choto-ko) is called Choto-san. This formulation also appears to be used for the treatment of cognitive decline and dementia.

Choto-san is five parts Gypsum Fibrosum to one part Ginger rhizome to three parts of each of the following: chrysanthemi flower, aurantii nobilis Pericar, ophiopogonis tuber, ginseng root, hoelen, ledebouriellae root, pinelliae tuber, and licorice root (glycyrrhiza uralensis);[19] by weight, it is 9.7% uncaria rhynchophylla[19]

Choto-san is another formulation which contains 'Choto-ko' (ie. uncaria rhynchophylla) and also serves as an anti-cognitive decline compound formulation


Molecular Targets


Ion channels

Rhynchophylline appears to have the potential to block L-type voltage gated calcium channels, and was able to attenuate the release of calcium in response to caffeine and potassium.[20] Hirsutine can suppress calcium efflux in endothelial cells that is induced by noradrenaline or potassium in the 3-30µM range (approximately 20-70%; less potent than 10µM vermapril), although direct binding to calcium channels was not investigated.[21]

Rhynchophylline does not appear to significantly interact with calcium-activated potassium channels[20] although 30μM rhynchophylline has been noted to accelerate the slow-type (C-type) inactivation of voltage-gated potassium currents in an extracellular manner, functionally changing them into something more like an A-type potassium channels (those that are rapidly inactivated).[22]

The alkaloids are known to directly interact with ion channels, particularly by inhibiting calcium channels and possibly modifying slow-type voltage gated potassium channels into ones that act similar to fast-type channels; these occur at higher than normal concentrations that are found in the blood following oral ingestion, and their physiological relevance following supplementation of uncaria rhynchophylla has not yet been proven and is doubtful





Oral administration of 1-4g/kg Yokukansan to rats (150-600mg/kg uncaria rhynchophylla) has been noted to increase plasma levels (measured one hour after ingestion) of geissoschizine methyl ether (2.1-9.0ng/mL; 5.73-24.5nM), rhynchophylline (1.8-10.8ng/mL; 4.68-28.1nM), Isorhynchophylline (0.7ng/mL at the higher dose; 1.8nM), corynoxeine (1.9-14.5ng/mL; 4.97-37.9nM), hirsutine (0.6-1.6ng/mL; 1.68-4.34nM), and hirsuteine (1.0-6.0ng/mL; 2.73-16.39nM) but not isocorynoxeine.[23]

Oral ingestion of 37.5mg/kg rhychnophylline to rats results in serum levels of rhychnophylline peaking at three hours (Tmax) to a concentration of 351.5ng/mL (Cmax) which then are normalized to baseline levels after 8 hours.[24]

The alkaloids are all detectable in serum following oral ingestion, although with the standard dose of uncaria rhynchophylla (via Yokukansan) it appears to reach the low nanomolar range. A full pharmacokinetic study of the herb by itself, rather than the context of Yokukansan, has not yet been conducted (which is important, since many of these formulations have 'support' herbs that increase bioavailability of the primary pharmacological agents such as how licorice or black pepper extract are used)



Following oral ingestion of 37.5mg/kg rhychnophylline to rats, rhychnophylline is hydroxylated at either the 10-carbon or the 11-carbon by CYP enzymes (CYP1A1/2, CYP2D, and CYP2C but not CYP3A4 are implicated) which are then both glucuronidated to form the end products of 10-Hydroxyrhynchophylline 11-O-β-D-Glucuronide and 11-Hydroxyrhynchophylline 11-O-β-D-Glucuronide.[24] Metabolism into the 11-hydroxy or the 10-hydroxy metabolite are pretty much even for both rhynchophylline[24] and its isomer which follows similar hydroxylation and glucuronidation.[25]

Hirsuteine and hirsutine both follow similar hydroxylation (via CYP2C) and glucurondation following oral ingestion to rats.[26]

All alkaloids studied appear to undergo hydroxylation by CYP enzymes (thought to be CYP2C) followed by glucuronidation by Phase II enzymes; at this moment in time no alternate metabolic pathway is detectable



In an in vitro model or blood brain barrier (BBB) permeability, it appears that geissomethyl ether can cross the BBB with a permeability rate of 27.3%; higher than the other uncaria rhynchophylla alkaloids.[23]

In rats treated with Yokukansan (4g/kg; 600mg/kg uncaria rhynchophylla) there is a detectable brain concentration of hirsuteine (3.9ng/g), corynoxeine (1.7ng/g), and geissoschizine methyl ether (5.9ng/g) whereas no other metabolites were detected at this oral dose and only geissoschizine methyl ether was detected at an oral dose of 1g/kg Yokukansan (150mg/kg uncaria rhynchophylla) at 1.6ng/g.[23] Following oral ingestion of rhychnophylline at 37.5mg/kg, it can reach brain concentrations of 0.650+/-0.018ng/g after three hours;[24] since rhychnophylline reached 351.5ng/mL in plasma at this time, it appears to have very poor transportation into the brain.[24]

Most alkaloids (at the practically relevant low nanomolar concentrations in the blood) do not reach the brain, but geissoschizine methyl ether appears to be pretty well absorbed while hirsuteine and corynoxeine are present. Rhychnophylline (and it is assume isorhychnophylline) appear to have poor transportation into the brain



Rhychnophylline and its metabolites (the glucuronidated forms) can be detected in bile after oral ingestion, and after six hours accounts for around 5.9% of the ingested dose;[24] these end products are pretty much identical to those of isorhynchophylline[25] which reaches 10% after 12 hours.[25]

The overall amount of rhychnophylline fecally excreted after 24 hours is about five-fold higher than that in the urine,[24] and 12.6% of the ingested dose of rhychnophylline is excreted in the urine (so about 63% of the oral dose was detected in the feces after 24 hours, and around 25% still within tissue after 24 hours).[24] These numbers are similar to its isomer, since 71.6% and 13.8% of isorhynchophylline is detectable in the feces and urine, respectively, after 24 hours.[25] Hirsiteine and hirsutine (free and conjugated forms) have about 14% and 26% of the total ingested dosage get urinated out, whereas 35% and 46% are fecally excreted (and after 24 hours, 52% and 28% still remaining in tissue).[26]

Some unconjugated and unmetabolized rhychnophylline can be detected in both urine and the feces[24] although the fecal excretion of isorhynchophylline is mostly (80%) unconjugated and unmetabolized which is thought to be due to poor intestinal absorption.[25] Hirsuteine and hirsutine also have unmetabolized forms detectable in the urine and feces.[26]

Urinary and fecal elimination are involved in handling these alkaloids, with about one part urinary excretion to five parts fecal excretion. The gluruconide metabolites are the most prominent end product, although there is a small amount of unchanged alkaloids in the urine


Cardiovascular Health


Cardiac Tissue

Isorhynychophylline appears to have anti-arrythmic properties in rats and guinea pigs where arrythmia is induced by oubain or calcium chloride.[27]

Isolated hirsutine is able to preserve cardiomyocytes from damage from a lack of oxygen (hypoxia; reduced viability to 45.1+/-2.1% of control) at 1μM (76.8+/-2.1% viability) and 10μM (85.6+/-3.1 viability) although the protective effect at 100nM was not significant but still redued LDH leakage somewhat (indicating minor protective effects on the cell membrane).[28] This protective effect was thought to be secondary to stimulating superoxide dismutase (SOD) activity, which was reduced to 65.7U/mg protein after hypoxia, to 77.4-102U/mg in the range of 0.1-10μM.[28]

The alkaloids are technically cardioprotective. Practical significance of this information is not known due to higher than normal concentrations being required



A hot water extract of uncaria rhynchophylline (2.5:1 concentration) is able to relax precontracted endothelial vessels (noradrenaline) whether the vessel has its endothelium intact (18.67-80.13% relaxation at 40-400µg/mL) or if it is denuded (0.43-18.55% at the same concentration range; 59.75% at 4mg/mL), conferring EC50 values of 94µg/mL and 2.4mg/mL.[5] This relaxing effect was not reversed with washout, and the lower concentrations (endothelium intact) were fully blocked with NMMA suggesting the involvement of nitric oxide;[5] acetylcholine receptors did not appear to be involved.[5]

Geissoschizine methyl ether (GME) appears to be able to relax adrenaline precontracted endothelium with an EC50 of 744nM, a potency about 14-fold greater than that of hirsutine (10.6µM) and 10-fold greater than hirsuteine (7.6µM).[29] Other individual alkaloids were weaker, having EC50 values of 10.47µM (isorhynchophylline), 31.1µM (rhynchophylline), 34.2µM (Isocorynoxeine), and 37.1µM (Corynoxeine); similar to the hot water extract, the low concentrations of all alkaloiids are fully inhibited by L-NAME (nitric oxide inhibitor) while higher concentrations are not.[29]

The alkaloids in uncaria rhychnophylla appear to reduce blood pressure by one of two mechanisms, either blocking calcium channels (to prevent their contractile effects) or by releasing nitric oxide to cause relaxation. The concentrations required for blocking calcium channels is much higher than is seen following ingestion of this plant, and the lower concentration of geissoschizine methyl ether and hirsuteine (fully mediated by nitric oxide) are likely relevant to oral ingestion of the plant

Corynoxeine (5-50µM) appears to reduce the proliferation of vascular smooth muscle cells (VSMCs) in response to platelet derived growth factor (PDGF) by 25-88% and the DNA synthesis from PDGF by 32.8-76.9%;[30] this is thought to be associated with inhibiting ERK1/2 activity since there was no influence on MEK, PLCγ1, or Akt activation and the receptor for PDGF was unaffected.[30]

Higher than normal concentrations of corynoxeine may reduce VSMC proliferation, which is a mechanism thought to reduce atherosclerotic progression


Red Blood Cells

Secondary to its antioxidant properties, Uncaria rhynchophylla is able to reduce lipid peroxidation to the red blood cell membrane in the concentration range of 250-1,000µg/mL (full protection at 1,000µg/mL) and 571mg/kg oral uncaria rhynchophylla to rats is able to prevent 20-30% of lipid peroxidation to red blood cells when the blood cells are tested ex vivo (extracted at 120-240 minutes after ingestion).[19]

The antioxidant properties appear to be protective of red blood cells, and this appears to occur in rats following oral ingestion of the basic plant extract





Both (+)-catechin and (-)-epicatechin from this plant can inhibit MAO-B with IC50 concentrations of 88.6µM and 58.9µM and Ki values of 74µM and 21µM, respectively.[1] Despite the low potency from the catechins, a 50% methanolic extract of uncaria rhynchophylla has been able to inhibit MAO-B with an IC50 value of 30µg/mL[31] which suggests other bioactives since (+)-catechin and (-)-epicatechin are only present up to 0.25% and 0.14% of the hook's dry weight respectively.[4]

While the catechins are likely inactive in practical situations (too high of a concentration), the overall methanolic extract did seem to be active at a lower concentration. It is possibly active in the body, but requires further evidence to confirm


Glutaminergic Neurotransmission

The alkaloids from uncaria rhynchophylla have once failed to show any binding affinity for NMDA receptors at a concentration up to 100µM and failed to significantly inhibit calcium influx by glutamate by more than 20% at 100µM,[32] this study tested isorhynchophylline but not rhynchophylline, and elsewhere both of these alkaloids (in Xenopus oocytes expressing NMDA receptors) reduced NMDA-evoked currents by 25.5-54.9% and 33-60.3% at 3-100µM respectively;[2] the IC50 values were measured at 48.3μM (range of 35.4–65.8μM) and 43.2μM (range of 26.0–72.0μM) respectively in the presence of 100µM NDMA and were neither voltage dependent, use dependent, or altered by NMDA modulators such as spermine, dithiothreitol, zinc, or alterations of pH.[2] NDMA antagonism has been noted with the plant extract elsewhere[33] and in vitro with the methanolic extract of the plant 1-10μg/mL is able to inhibit currents evoked by both glutamate (16.5-27.2%; not concentration dependent) and NMDA (37.3-45%; concentration dependent) in hippocampal cells[34] which is replicated with the alkaloids.[35]

The study that noted inhibitory effects against NMDA currents by rhynchophylline and isorhynchophylline failed to find an inhibitory effect against kainate or AMPA mediated currents[2] and the methanolic extract has similarly failed to inhibit these currents;[34] if anything, 1-10μg/mL of the methanolic extract had a mild (10-20%) enhancement of AMPA currents.[34]

Although one study failed to find an effect, it appears that the alkaloids in this plant are NMDA receptor inhibitors. While the IC50 values are too high for what is normally found in the brain, it is possible that mild inhibition (less than 20%) may occur with high doses. Kainate receptors are unaffected, and low concentrations of the methanolic extract may weakly enhance AMPA receptors


GABAergic Neurotransmission

GABAA signalling is known to be theapeutic for epilepsy[36] and during a seizure the sensitivity of these receptors seems to be reduced[37] since repetitive activation of mossy fibers releases zinc into the synapse which blocks GABAA signalling.[38] The receptor level does not appear to be influenced (in a rat model of kainic acid induced seizures) and uncaria rhynchophylline does not modify GABAA receptor levels either over the short term[39] or after six weeks of oral ingestion.[40]

No known interactions with GABAergic neurotransmission


Cholinergic Neurotransmission

An ethyl acetate extraction of uncaria rhyncophylla appears to inhibit acetylcholinesterase in the concentration range of 600µg/mL by 25.9+/-0.43%;[13] the most effective molecule appeared to be trans-anethole (8.2-39.2% inhibition at 30-150µg/mL) but was significantly weaker than tacrine as reference drug (94.1% inhibition at 30µg/mL).[13]

Geissoschizine methyl ether appears to have more potency as an acetylcholinesterase inhibitor, with an IC50 of 3.7+/-0.3µM (noncompetitive inhibition) whereas other tested alkaloids (Hisuteine, histine, vallesiachotamine, corynoxeine, cisocorynoxeine, and isorhynchophylline) were not significantly effective.[9]

There is a possibly relevant inhibition of acetylcholinesterase with geissoschizine methyl ether

The decrease in acetylcholinesterase associated with cognitive function can be attenuated with oral ingestion of a dose of uncaria rhynchophylline sufficient to attenuate amnesia.[41]

The alterations in cholinergic neurotranmission seen with neurotoxicity are attenuated when said neurotoxicity is attenuated from this herb


Serotonergic Neurotransmission

Geissoschizine methyl ether is an alkaloid in uncaria rhynchopylla which acts on the 5-HT1A receptors. It is able to outcompete 8-OH-DPAT binding to the receptor with an IC50 and Ki value of 904nM and 517nM (respectively) and activated the receptor in the contration range of 0.1–100μM (although it had 40% the potency as serotonin itself);[6] this has been noted elsewhere, where a Ki value of 800nM was reported for 5-HT1A receptors[42] and an EC50 in activating them was measured at 4.6+/-7μM, reaching maximal activation (Emax) of 85+/-3% the potency of 1μM serotonin.[43]

There appears to be affinity for 5-HT2C (Ki 900nM)[42] which was later found to be inhibition, possessing an IC50 of 5.07+/-0.41μM[43] although higher concentrations (20μM) have weak activating abilities suggesting it is a partial agonist.[43]

There appears to be affinity for 5-HT2A (Ki 1.4μM)[42] which was later noted to be inhibition; IC50 value of 4.87+/-0.44μM[43] and again higher concentrations (20μM) were noted to be weak agonists (and thus it was a partial agonist).[43]

5-HT7 is also inhibited with an IC50 of 610+/-290nM (blocking serotonin binding)[43] and 340nM (blocking LSD binding)[44] while the ability of geissoschizine methyl ether to block serotonin induced cAMP production is slightly weaker (IC50 6µM).[44]

Corynoxeine, isocorynoxeine, rhynchophylline, and isorhynchophylline fail to interact with the 5-HT1A receptor up to 100µM while hirsuteine and hirsutine were weakly effective (blocked 40% of 8-OH-DPAT binding at 100µM while geissoschizine methyl ether was absolute at 10µM).[6] When testing the overall Yokukansan plant up to 200µg/mL (where uncaria rhynchophylla is thought to mediate the serotonin like effects) there was no influence on 5-HT2B receptors nor the serotonin transporter.[6]

When looking at the level of the receptors, geissoschizine methyl ether is a potent agonist of the 5-HT1A receptors while it is inhibitory at the 5-HT2A, 5-HT2C, and 5-HT7 receptors at the same concentration range, with the possibility of being a partial agonist at higher doses. This profile is very similar to the anti-psychotic drug Aripiprazole

The major traditional combination therapy that uncaria rhynchophylla is a part of (Yokukansan) is known to be recommended for reducing aggression in elderly persons with dementia; aggression is known to be associated with dysfunctions in serotonin signalling[45][46] and Yokukansan has been implicated in modifying the serotonin system (partial agonist of 5-HT1A with no influence on 5-HT2A[47]) which has reduced aggressive symptoms in rodents, yet has its anti-aggressive effects blocked by inhibiting this receptor.[48]

Both acute administration and continual ingestion over four weeks of 75-150mg/kg uncaria rhynchophylla in socially isolated rats appears to reduce the aggressive effects of social isolated in a dose-dependent manner, with 75-150mg/kg being as effective as 500-1,000mg/kg Yokukansan.[6] Isolated geissoschizine methyl ether (75-300µg/kg; equivalent to 53-212mg/kg Yokukansan) failed to reduce aggression acutely (but was effective after two weeks) and enhanced social behaviour at all times;[6] both uncaria rhynchopylla and isolated geissoschizine methyl ether had their effects blocked by a 5-HT1A receptor antagonist.[6]

Due to being a partial agonist of the 5-HT1A receptors, geissoschizine methyl ether appears to confer antiaggressive properties in the oral dose that is found in the uncaria rhynchophylla plant and traditional medicine Yokukansan


Adrenergic Neurotransmission

Geissoschizine methyl ether has failed to show affinity for adrenergic α1 receptors at concentrations below 10µM,[42] although a screening study in rat prostate cells noted that rhynchophylline and corynoxeine (as well as their isomers) had affintiy to adrenergic α1 receptors in a similar manner to tamsulosin, suggesting inhibition.[49] In regards to the a2 receptors, a few alkaloids show inhibitory activity against the α2A subset in particular (with no affinity for α1 receptors, α2B or α2C recepors, nor β-adrenergic receptors) with IC50 values of 2.4μg/mL (geissoschizine methyl ether), 32μg/mL (hirsuteine), and 17μg/mL (hirsutine).[50]

The α2A adrenergic receptor in particular appears to be inhibited by geissoschizine methyl ether and its related indole alkaloids (hirsutine and hirsuteine); geissoschizine methyl ether may be active centrally whereas the others may be active peripherally


Dopaminergic Neurotransmission

Geissoschizine methyl ether has once failed to show affinity for D2 receptors at concentrations lesser than 15µM (via displacing the ligand spiperone)[42] although at the D2L it can activate signalling with an EC50 of 4.4+/-3.6µM reaching max potency at 50+/-15% the equivalent of dopamine; these were slightly lesser than the drug Aripiprazole with an EC50 value of 7.64+/-0.33µM but an Emax of 68.6+/-13.7%; again similar to aripiprazole, geissoschizine methyl ether had an atypical ability to only activate 53.9% of cells (in a manner blocked by haloperidol) and appeared to at higher concentraitons (20μM) showed slight inhibitory potential.[43]

Geissoschizine methyl ether appears to have very high affinity for the D2 receptor, but is only a partial agonist of this receptor (half as potent as dopamine itself) and may be weakly suppressive at higher doses; it seems selective, and again is similar to the antipsychotic Aripiprazole



When looking at the overall plant extract, uncaria rhynchophylline appears to be neuroprotective against NMDA-mediated excitotoxicity[33] at concentrations as low as 20µg/mL of the water extract[32] or 1ug/mL of the methanolic extract;[34] Yokukansan overall is neuroprotective[51] and this is thought to be primary due to uncaria rhynchophylline and (licorice) since the protection from atractylodis lanceae is weak and the others inactive.[32]

5-10µM of a few alkaloids (Hirsuteine, hirsutine, geissoschizine methyl ether, and rhynchophylline) in primary neurons is able to attenuate glutamate-induced neuronal death by about half at the higher concentration; this was not associated with inhibiting NMDA receptors in these primary neruons.[32] This study noted that the potency at 20µg/mL was comparable between uncaria rhynchophylline and glycyrrhiza uralensis (licorice),[32] and elsewhere in PC12 cells (not expressing the main NMDA receptor subunits) 200μg/mL of uncaria rhynchophylline were found to be more protective associated with a preservation of glutathione.[52] Corynoxeine has been twice found to not be neuroprotective[18][32] while other alkaloids (rhynchophylline, isorhynchophylline, isocorynoxeine) are only significantly neuroprotective against glutamate in the 100-1,000µM range[18] and despite protection occurring at 10µM in primary neurons[32] hirsutine and hirsuteine have failed to reduce glutamate toxicity in cerebellar granule cells.[18]

The indole alkaloids (but not oxyindole alkaloids) appear to be neuroprotective against glutamate, and it seems that this may be independent of possibly blocking the receptors (but associated with preserving glutathione in the cells)



When looking at individual alkaloids, hirsutine is able to suppress the inflammatory response in the hippocampus from LPS as assessed by nitric oxide and IL-1β production.[53] In primary microglial cultures, LPS stimulation is also inhibited by rhynchophylline in the range of 3-30µM in a concentration dependent manner (as assessed by nitrite and PGE2; COX2 induction required 10µM) and attenuated inflammatory changes in NF-kB, TNF-α, and IL-1β levels.[54] Corynoxeine and isocorynoxeine, as well as vinctoside lactam, are in ths above concentration range as well (IC50 13.7-19µM) while 18,19-dehydrocoynoxeine and its epimer are not (IC50 greater than 100µM).[10]

In N9 micrglia, rhynchophylline and isorhynchophylline can suppress LPS activation of these glial cells in the concentration range of 0.3-30μM (16.6-58.7% for rhynchophylline and 18.9-63.2% for its isomer), with 1-3μM being as effective as 10μM resveratrol as reference.[55] IC50 values were attained for inhibiting the secretion of TNF-α (12.1 and 2.3μM, respectively) and IL-1β secretion (6.1 and 3.3μM) associated with inhibiting ERK and p38 phosphorylation.[55]

The alkaloids appear to have general antiinflammatory properties against LPS stimulation of microglia, with the effective concentrations perhaps low enough to be effective following oral ingestion

The microglial inflammation (assessed via immunoreactivity) in response to kainate induced seizures in rats appears to be reduced with oral ingestion of 500-1,000mg/kg uncaria rhynchophylline (7.86:1 concentrated water extract) for three days, with both doses being equally effective and neither dose being significantly different than the control group (ie. full statistical prevention of neuroinflammation from kainate).[56] Expression of nNOS and iNOS were also fully prevented with both doses relative to kainate control, being comparable to the group not given kainate,[56] and elsewhere other inflammatory biomarkers (AP-1 and NF-kB activity) were significantly decreased by both uncaria rhynchophylline and isolated rhynchophylline in response to kainate while MAPKs are unaffected (by both kainate and uncaria rhynchophylline).[57]

This is thought to underlie the anti-epileptic effects of uncaria rhynchophylline since biomarker proteins, S100B proteins (released from damaged astrocytres and involved in the pathology of seizures[58]) are not increased in rats given both kainate and uncaria rhynchophylline,[39] suggesting the astrocytes (mediators of neuroinflammation) are not being damaged.

The neuroinflammation indued by kainate is essentially fully prevented with oral dosing of uncaria rhynchophylla, which is thought to be due to the antiinflammatory effects since the kainate receptor is not blocked (see the glutaminergic neurotransmission section)



75-300µg/kg of isolated geissoschizine methyl ether acutely or daily for two weeks does not seem to alter locomotion or physical symptoms of otherwise healty rats[6] although higher doses has been noted to suppress spontaneous motor activity (30mg/kg),[42][59] convulsion,[60] and head twitching (10-30mg/kg);[42] the lack of activity is thought to be more relevant since the 75-300mg/kg dosage correlates to 9-36mg/kg uncaria rhynchopylla,[6] and in mice oral ingestion of 500-2,000mg/kg of the water extract of the plant failed to significantly modify locomotion.[59]


Anxiety and Stress

The water extract of uncaria rhychnophylla at 100-200mg/kg orally for one week prior to an elevated maze plus test in rats caused anxiolytic effects either comparable or nonsignificantly greater than the reference drug (buspirone at 1mg/kg) in a manner that is wholly mediated via 5-HT1A receptors (fully blocked by WAY 100635; flumazenil ineffective);[61] the comparable efficacy was noted after a week of ingestion, although a single dose appeared to also be effective.[61]

The 5-HT1A activation (from geissoschizine methyl ether) appears to confer anxiolytic properties of potency comparable to the reference drug of buspirone (Buspar)


Memory and Learning

In rats given the amnesiac drug scopolamine, 250mg/kg of the ethyl acetate extract can preserve 78.2% of amnesia as assessed by a passive avoidance task;[13] this was thought to be related to trans-anethole which was similar in potency to tacrine (both at 2.5mg/kg oral intake) despite trans-anethole being much weaker at inhibiting acetylcholinesterase.[13]

200-400mg/kg of the 70% aqueous ethanolic extract of uncaria rhynchophylline, but not 100mg/kg, is able to preserve cognition in a rat model of Alzheimer's disease (galactosamine induced cognitive dysfunction) when consumed over eight weeks;[41] this is associated with a preservation in glutathione and acetylcholine concentrations.[41]

The neuroprotective effects may confer some anti-amnesiac effects


Epilepsy and Convulsion

One of the foremost usages of uncaria rhynchophylline in traditional medicines is for treating convulsions and epilepsy. Kainic acid injections (caused temporal lobe seizures in rats and mice with a similar phenotype to epileptic seizures in humans,[62] and thus is a research model for epileptic seizures), and the process of epileptic seizures tends to be associated with glial cell (astrocyte) proliferation,[63] neuronal losses (hippocampal),[64] and a phenomena known as mosst fiber sprouting[65] where unmyelinated axons in the hippocampus being hyperexcited and is vital to the pathophysiology of epileptic seizures.

Injections of uncaria rhynchophylline are known to significantly attenuate kainic acid induced seizures (250-1,000mg/kg of the hook extract) when given 15 minutes prior to seizure induction[66][67] and three days injections with the last dose preceding kainic acid by 30 minutes appears to be able to reduce epileptic (facial myoclonia, wet dog shakes, paw tremor) by 54-65% (uncaria rhynchophylline at 1,000mg/kg) or 65-70% (rhynchophylline at 250µg/kg), the former of which was comparable in potency to the reference drug valproate (250mg/kg) while rhynchophylline was more protective.[57] 1,000mg/kg of a 70% ethanolic extract fed to rats for two weeks prior to seizures was able to statistically normalize wet dog shakes induced by kainic acid[39] and efficacy has been noted elsewhere with oral ingestion of uncaria rhynchophylla (1,000mg/kg of the ethanolic extract) for six weeks in rats.[40]

Oral ingestion of uncaria rhynchophylline has been confirmed to reduce seizures in rats, and it appears to be quite effective as it significantly attenuates physical symptoms (potency similar to valproate) and nearly normalizes biochemical markers of inflammation associated with kainic acid

Intraperitoneal injections of the plant (1,000mg/kg of a water extract) to rats 15 minutes prior to an injection of kainic acid (to induce a seizure) noted that, when measured three hours after seizure induction, in both the frontal cortex and hippocampus the seizure reduced levels of two proteins (MIF and cyclophilin A) while administration of the herb or isolated rhynchophylline (250µg/kg) was able to increase them both beyond control levels.[68] It also seems that while S100B proteins (their induction from astrocytes, when damaged, mediates epileptic changes in the brain[58]) are increased during seizures and greatly reduced with oral intake of uncaria rhynchophylline (1,000mg/kg oral intake) in the hippocampus by 63.5% (CA1), 77% (CA3), and 85.5% (Hilus area) relative to kainic acid control.[39][40]

Oral intake of the 70% ethanolic extract (1,000mg/kg for two weeks) is able to abolish the kainic acid induced spikes in activity, and significantly attenuated cell death and glial cell proliferation in the hippocampus[40][39] associated with a reduction of mossy fiber sprouting (49.8+/-2.7% increase in kainic acid control; 17.3+/-1.1% in the group fed uncaria).[40]

There appears to be reduced signalling magnitudes in the hippocampus and less mossy fiber activation, and due to there also being no proliferation of glial cells nor release of proteins from these glial cells (which are involved in the pathology of seizures) it suggests that antiinflammatory effects on the level of the microglia may underlie the antiepileptic effects


Stroke and Ischemia

Intraperitoneal injections of uncaria rhychnophylla at 250-1,000mg/kg (70% methanolic extract; 0.074% rhychnophylline) at the time of cerebral ischemia and again 90 minutes later appeared to cause 70.5-75.6% neuronal preservation in the hippocampus with no dose dependence and associated with less inflammatory biomarkers (PGE2, TNF-α, COX2 induction).[69] There was no dose-dependence noted, but the lowest dose (100mg/kg) was ineffective.

There may be some anti-ischemic properties pending future research; potency and practical significance is currently unknown



Oral ingestion of Yokukansan (850mg/kg), uncaria rhynchophylla 150mg/kg), or isolated geissoschizine methyl ether (150μg/kg) appears to attenaute physical symptoms of morphine withdrawal; while active, licorice sourced from glycyrrhiza uralensis and its bioactive (glycyrrhizin at 9.6mg/kg) appeared to be slightly more bioactive (suggesting both herbs contribute to the effects of Yokukansan).[50]

The above effects were thought to be due to interactions with α2-adrenergic signalling, since Yokukansan (12.5-200μg/mL) showed binding affinity and antagonism on this receptor (and both α1 nor β-adrenergic receptors) and specifically the α2A subset (no influence on α2B or α2C).[50] The antagonism was traced back to glycyrrhiza uralensis (IC50 36.3μg/mL) and uncaria rhynchophylla (IC50 131μg/mL) with most potency from 18β-glycyrrhetinic acid (47μg/mL) and geissomethyl ether (2.4μg/mL) respectively.[50]


Inflammation and Immunology



In isolated RAW264.7 macrophages, uncaria rhynchophylla is able to suppress NF-kB activation (Akt and all three MAPKs were also suppressed) from LPS stimulation in the concentration range of 500-2,000µg/mL with near full reduction in nitrite production at the highest concentration but more modest inhibition of IL-1β secretion.[70]

Possible antiinflammatory effects at the level of the macrophage, although nothing remarkable was noted (moderate to low potency and higher than ideal concentrations required)


Dendritic Cells

In isolated dendritic cells, Uncarinic acid C (URC) is able to enhance the expression of a wide variety of receptors (CD1a, CD38, CD40, CD54, CD80, CD83, CD86, HLA-DR and DC-Lamp) in the concentration range of 0.1-10µM, and in mature dendritic cells 100nM of URC can enhance the production of IL-12p70 to near six-fold of control (10nM inactive and 1µM less active) while blocking TLR4 signalling suppressed this by 65-80% (blocking TLR2 slightly suppressed signalling).[15]

Monocytes and immature dendritic cells tend to express the TLR2 and TLR4 receptors to high levels, but this is reduced following maturation; the reduction seen with URC (100-500nM) is less than that with LPS, causing a relatively higher level of TLR4 mRNA in matured dendritic cells.[15] This activation of dendritic cells via TLR2/TLR4 receptors has been noted with ursolic acid[14] and uncarinic acid D[16] as well, and in a manner that is synergistic with IFN-γ.[71]

This promotion of Th1 cell production is said to be IL-12 dependent[16] and blocking IL-12p70 (downstream of TLR2/TLR4) prevents the above from occurring.[15][14]

It seems that the triterpenoids in this plant can act on the surface receptors on the dendritic cells (TLR4 and a bit of TLR2) to stimulate their activity, which causes a shift in the T-cell profile form Th2 towards Th1. This is IL-12 dependent, and it appears to be very potent (occurring to a comparable level to LPS in the nanomolar range)


T Cells

In dendritic cells which were primed with URC during the maturation process, there is a promotion of Th1 cell production with nonsignificant increases in IFNγ production relative to LPS control[15] but the cytotoxicity of these T-cells (CD8+) towards T2 tumor cells was enhanced.[15] This increase in Th1 cell population has been noted with ursolic acid as well, when it primed dendritic cells.[14]

The T-cells that are primed by the actions of uncarinic acids on dendritic cells appear to have enhanced cytotoxicity towards tumor cells; characteristic of Th1 cells



Atopic dermatitis (an eczematous skin disorder with dry and itchy skin) is known to be influenced by T-cells, with Th1 cells positively mediating the allergic response to chronic dermatitis while Th2 cells mediate the acute response (usually referred to as allergic dermatitis or contact dermatitis).[72]

In a mouse model of atopic dermatitis (DNFB induced contact hypersensitivity in NC/Nga mice[73]), a water extract of uncaria rhynchophylla (2.35% yield) at 100-300mg/kg orally for six weeks following sensitization with DNFB was able to attenuate the formation of skin lesions relative to control (48-53% after 3 weeks and 53-55% after 5) with no apparent dose dependence and a potency nonsignificantly greater than 3mg/kg prednisone (24% and 32% at the two time points).[74] Uncaria rhynchophylla failed to reduce the increase in IgE and IL-4 seen with sensitization, but prevented the increase in IFN-γ (and adding IFN-γ itself to DNFB mice was sufficient to cause a response), suggesting that it suppressed Th1 mediated allergic responses but not Th2.[74]

It appears that uncaria rhynchophylla may have a role in the treatment and prevention of chronic atopic dermatitis due to suppressing the hyperactivity of Th1 cells, although preliminary evidence suggests that contact dermatitis is not affected


Interactions with Oxidation



In a DPPH asasy, uncaria rhynchophylla appears to have antioxidant effects with an IC50 of 14.3µg/mL; it was more efficient than Yokukansan (206.2µg/mL) and Yokukansan with uncaria rhynchophylla removed (244.3µg/mL) and appeared to outperform the reference of Vitamin E (IC50 24.5µM).[75]

Appears to, in general, be a potent antioxidant compound via directly reducing other molecules



Superoxide (O2-) can be nonenzymatically reduced with uncaria rhynchophylla at an IC50 value of 18.3µg/mL, and it appears to be the most potent herb in Yokukansan since the mixture has an IC50 value of 67.7µg/mL and removing uncaria rhynchophylla from the mix weakens it to 92.4µg/mL.[75] The potency of this plant is similar to Quercetin (18.7µM) but greater than both epicatechin (175.2µM) and caffeic acid (141.7µM).[75]

The plant overall appears to be comparable in antioxidant potency as quercetin ex vivo, which suggests that a bioactive is significantly more potent


Hydroxyl Radical

As assessed by deoxyribose degradation (a model of assessing hydroxl radical antioxidative effects) in the presence of EDTA; uncaria rhynchophylla appeared to inhibit oxidation (IC50 of 2.2mg/mL; similar potency to quercetin at 1.9mM) in a manner that was enhanced with removal of EDTA (to an IC50 of 1.3mg/mL);[75] this is thought to be due to the ability of uncaria rhynchophylla to chelate minerals and prevent the complexation of ferrozine-iron with an IC50 of 1.3mg/mL..[75]

Moderate hydroxyl radical scavenging properties but also a present metal chelating property


Lipid Peroxidation

In rat brain homogenate, assessing the anti-lipid peroxidative effects of uncaria rhynchophylla (via TBARS formation), it appears to suppress lipid peroxidation with an IC50 of 19.1µg/mL and is the causative agent of Yokukansan since the mixture had an IC50 of 124.7µg/mL and removing uncaria rhynchophylla from said mixture increaesd the IC50 to 368.6µg/mL;[75] the effects of the plant were more potent than Vitamin E as a referece (153.7µM) but not quercetin (3.1µM).[75]

Appears to also reduce lipid peroxidation when tested outside the body, which may persist to oral ingestion (see the cardiovascular health section on red blood cells)


Interactions with Cancer Metabolism



The uncarinic acids (C-E) are able to inhibit phospholipase Cγ1 with an IC50 value in the range of 9.5−44.6μM (most potency from uncarinic acid E)[17] while A-B are comparable to the weaker ones (35.66-44.55μM[76]); inhibition of this phospholipase is thought to be a good target for antiproliferative therapy as it is elevated in cancer cells[77][78] and mediates proliferation.

The uncarinic acids (triterpenes with phenolic acid moieties) appear to be potent inhibitors of phospholipase Cγ1 which is thought to be an antiproliferative mechanism


Proliferation and Angiogenesis

In cancer cells that normally overexpress phospholipase Cγ1 (colonic HCT-15, breast MCF-7, lung A549, and bladder HT-1197) uncarinic acids can suppress their proliferation with an IC50 of 0.5−6.5μg/mL; the most potency (IC50 of 500nM) being uncarinic acid E on colon cancer cells.[17]

In cancer cells that overexpress phospholipase Cγ1, it appears that the triterpenes can suppress their proliferation via inhibiting phospholipase Cγ1

When looking at angiogenesis, a 70% ethanolic extract of the root in HUVEC cells noted that concentrations as low as 100ng/mL enhanced cell proliferation (21.1%) reaching up to 45.5% at 10μg/mL; this proliferative effect was blocked with antibodies against VEGF and bFGF.[79] HUVEC cell migration was also enhanced 9.7-fold to at 25μg/mL, and uncaria rhynchophylla was noted to increase VEGF and bFGF mRNA expression and secretion in the concentration range of 1-100μg/mL (bFGF influenced more potently).[79]

This angiogenic property of the 70% ethanolic extract was confirmed in mice injected with 25μg of the extract where it promoted blood vessel formation with similar potency to 100ng bFGF.[79]

Something in the plant appears to be highly angiogenic, which in theory is good for wound healing but not for proliferation of tumor cells. Practical significance of this data is not known, but the potency suggests that it is relevant to supplementation (assuming the same bioactives are in the roots as well as hooks)


Colon Cancer

A methanolic extract of uncaria rhynchophylla has been noted to have mild (15.8%) inhibitory properties against HT-29 cell proliferation at the concentration of 500μg/mL[80] although in another type of colon cancer cell (HCT-15) that overexpress Cγ1 the Uncarinic acids have reduced proliferation with IC50 values of 1.4μg/mL (Uncarinic acids A and B), 1.9μg/mL (Uncarinic acid C), 2.5μg/mL (Uncarinic acid D), and 500ng/mL (Uncarinic acid E).[17]

Potential antiproliferative effects due to the phospholipase Cγ1 inhibition, but in cells where this is not overexpressed it does not appear to by as potent. Practical significance of this data and its usage towards cancer prevention uncertain


Interactions with Disease States


Alzheimer& #039;s Disease

When tested alongside protein fibrils associated with Alzheimer's disease (Aβ1-40 and Aβ1-42) at 10µg/mL, uncaria rhynchophylla is able to prevent formation of fibrils with 38.9-50.3% inhibition and can destabilize preexisting fibrils with 77.2-87.7% potency with both values referring to Aβ1-40 (Aβ1-42 slightly more resistant);[3] these effects were also noted with curcuma longa, Cinnamomum cassia, and Paeonia suffruticosa with slightly less potency.[3] When looking at Tau proteins, rhynchophylline and its isomer do not alter total concentrations of it in vitro at 100µM[81] although isorhynchophylline has once been implicated in inducing autophagy of α-synuclein (protein) in neuronal cells in a manner that is independent of mTOR but dependnet on Beclin-1.[82]

In neurons incubated alongside Aβ25–35 to assess the neurotoxicity in PC12 cells from said protein, coincubation with alkaloids from uncaria rhynchophylla noted that the basic extract (particularly molecules in the butanolic fraction) were protective in the 10-50µg/mL (but not 1µg/mL) range partially preserved cell viability, and pure rhynchophylline or its isomer (100µM) partially attenuated the effects.[81] Isolated isorhynchophylline also has protective effects against Aβ25–35 in PC12 cells in a concentration dependent manner between 1-50µM, and reduced the increase in oxidation (ROS) from 234% of control down to 132-186% and the increase in lipid peroxidation (MDA) from 177% of control down to 124-139% (1µM not significantly protective) while preserving glutathione concentrations and reducing apoptosis rates.[83]

There appear to be mechanisms which suggest that this herb is protective/therapeutic for Alzheimer's disease, but at this moment in time not enough information is given and the bioactives that are being investigated do not appear to accumulate in the brain to sufficient quantities. Further research is required, possibly with geissoschizine methyl ether


Parkinson& #039;s Disease

A hot water extract of uncaria rhynchophylla (4.07% yield) given intraorally to rats cerebrally lesioned with 6-OHDA (a dopaminergic and oxidative toxin that is a rat model for Parkinson's disease[84][85]) at the oral dose of 5mg/kg, but not 50mg/kg, was able to very mildly reduce apomorphine induced rotations and TH positive neurons.[86]

Lacklustre data on the interactions of uncaria rhynchophylla and Parkinson's disease



Geissoschizine methyl ether has been reported to have third-generation like antipsychotic effects very similar to Aripiprazole, since both drugs have an activating effect on 5-HT1A and D2L receptors and inhibitory potential on 5-HT2A, 5-HT2C, and 5-HT7 receptors; all of which are very similar potency as assessed by IC50, EC50, and Emax values.[43] Furthermore, both aripiprazole and geissoschizine methyl ester are weak partial agonist of the 5-HT2A and 5-HT2C receptors.[43]

A molecule in uncaria rhynchophylla known as geissoschizine methyl ether has similar potency and a similar pharmacological profile as the antipsycotic drug Aripiprazole, and at least in rats (assessed by aggression as a biomarker of 5-HT1A activity) it seems to be active following oral administration


Safety and Toxicology



2,000mg/kg of the water extract of uncaria rhychnophylla to rats for one week does not cause any apparent clinical toxicity.[61]

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