Hi , i just want to know how much gramine is dangerous?

Nobody knows even if it's harmful to humans at all, let alone in what amounts. More research is needed, it's only because it is poisonous to sheep that it is assumed it is harmful to humans too.

Erspamer, V. (1954). "Pharmacology of Indolealkylamines". Pharmacological Reviews 6 (4): 425–487. PMID 13236482.

And by way of comparison...

Did you read this thread: Gramine?

Anyway, welcome to the forum.

Generally, you don't want any gramine in your spice.

I thought that was a myth?
When sheep got hit by sheep staggers people made all kinds of guesses about the cause, several of which started to be stated as fact (like gramine) then it was tested.
Researchers bred Phalaris grass into three lines, one making just DMT, one making just ß-carbolies, and one making just gramine. They fed each grass to a different group of sheep to see which group got sick and... none of them did. Its not the alkaloids.
And yes in college I tried to locate those three varieties, but sadly failed, lol

Uuum it's interesting ... Do you have any resource for your words?

Gramine is horrible for medow voles...

http://www.ncbi.nlm.nih.gov/pubmed/7020159
Some hematological and histopathological effects of the alkaloids gramine and hordenine on meadow voles (Microtus pennsylvanicus).
Goelz MF, Rothenbacher H, Wiggins JP, Kendall WA, Hershberger TV.
Abstract
Meadow voles (Microtus pennsylvanicus) were used to evaluate the relative toxicity of the alkaloids, gramine and hordenine, which are present in reed canarygrass (Phalaris arundinacea) and to assess their effects on the quality of this grass as a forage. One hundred and twenty meadow voles, 31 days of age, were fed gramine (0, 0.125, 0.25, or 0.5% of a nutritionally complete diet) or hordenine sulfate (0, 0.15, 0.31, or 0.62% of the diet) for 21 days. The effects of treatment on growth, mortality, hematology, blood chemistry, and histology of body organs were examined. Approximately one-third of the voles died when fed either 0.25 or 0.50% gramine. Voles that survived on gramine diets had kidney lesions, glycosuria, higher intakes (P less than 0.05), and lower weight gains (P less than 0.01) than control animals. Voles fed 0.25 and 0.50% gramine had increased circulating reticulocyte levels (P less than 0.01) and those fed 0.125% gramine had higher alkaline phosphatase activity (P less than 0.05) than the control voles. Hordenine did not affect vole diet intake, weight gain, or rate of mortality. Voles fed hordenine developed kidney lesions and glucose was detected in the urine of 62% of these animals. Gramine was more toxic than hordenine on a molar equivalent basis. http://www.ncbi.nlm.nih.gov/pubmed/7020159

-eg

Experimental evidence that tryptamine alkaloids do not cause Phalaris aquatica sudden death syndrome in sheep.

Abstract
The acute toxicity for sheep of 3 alkaloids that occur in Phalaris acquatica was examined by intravenous and oral administration. The lowest tested dose rates that produced clinically observed signs were, for 5-methoxy dimethyltryptamine, 0.1 mg/kg body weight intravenously and 40 mg/kg orally; for gramine, 10 mg/kg intravenously and 500 mg/kg orally; and for hordenine, 20 mg/kg intravenously and 800 mg/kg orally. All induced the clinical signs observed in the nervous form of phalaris toxicity, but none induced the cardiac, sudden death, syndrome.
http://www.ncbi.nlm.nih.gov/pubmed/3421887

---

Abstract
BACKGROUND: A mixture of plant species adds biochemical diversity to pastures that may enhance productivity while decreasing reliance on herbicides and insecticides. All plants contain secondary metabolites (PSMs) that interact in plant communities in a variety of ways. Our objective was to determine if PSM diversity enhanced food intake when sheep were allowed to select from foods that varied in concentrations of tannins, saponins, and alkaloids. We hypothesized that intake of foods containing alkaloids would increase when sheep were offered supplemental foods with tannins and saponins. The alkaloid gramine is proteinaceous in nature, tannins bind to proteins in the gut, which enhances excretion of proteins, so we hypothesized tannins would bind to gramine and enhance its excretion from the body. The alkaloid ergotamine is steroidal, saponins have a high affinity for binding to lipid and steroidal compounds in the gut and then being excreted, so we hypothesized saponins would bind to ergotamine and enhance its excretion from the body.

RESULTS: We found that sheep fed either gramine or ergotamine in combination with tannin- or saponin-containing foods had higher intakes of food than sheep offered only foods with gramine or ergotamine.

CONCLUSION: These findings are consistent with the hypothesis that animals can neutralize the negative effects of alkaloids by ingesting tannins and saponins. Our results show that PSMs can complement one another to increase a herbivore's intake of unpalatable plant species, with the potential to maintain healthy animals and bio-diverse landscapes. Copyright © 2008 Society of Chemical Industry
http://onlinelibrary.wil....1002/jsfa.3158/abstract



Though I can recall shulgin mentioning an endophytic fungi living in palatial which produces lysergamides, and that these lysergamide compounds may also contribute to "sheep staggers syndrome"

---

INTRODUCTION

Phalaris staggers is an incoordination syndrome that is associated with the ingestion of phalaris (Phalaris aquatica) which contains dimethyltryptamine alkaloids (Finnie et al 2011).

The risk of stock developing phalaris staggers is a function of soil cobalt levels, levels of soil ingestion and levels of phalaris dominance and palatability. Cases can occur at all times of the year but peak in late autumn and winter. Cattle are less susceptible than sheep but when they are affected it causes a larger problem. Phalaris staggers affect the nerves that control prehension of food and swallowing, so affected cattle are unable to eat normally and suffer a high degree of weight loss. Symptoms of staggers can be induced by normal mustering stress up to two months after leaving a phalaris paddock. There is currently no cure.

Oral cobalt is commonly used as a preventative agent against phalaris staggers (Radostits 2007). Preventative levels of dietary cobalt in sheep are double those required to maintain adequate levels of Vitamin B12 in blood. Therefore, cases of phalaris staggers do not necessarily indicate Vitamin B12 deficiency.

'Phalaris staggers' is a completely separate syndrome to 'phalaris acute sudden death'. The sudden death syndrome is proposed to occur as a result of ingesting of a compound in phalaris that decreases nitrogen metabolism, resulting in peracute ammonia poisoning (Bourke 2005). The sudden death syndrome occurs in autumn to early winter within 36 hours of introducing stock onto phalaris pastures. It takes sheep 24 hours to develop effective nitrogen metabolism on phalaris. If affected sheep are found alive still able to stand unassisted, and are treated with 200 ml of vinegar orally, the recovery rate is around 75%. Cobalt has no preventive effect on this sudden death syndrome.

http://www.flockandherd....halaris-staggers-II.html

---

https://books.google.com...mine%20sheep&f=false

Gramine and sheep

---

This is all I could dig up regarding gramine toxicity in animals.

-eg

There has always been a claim that it acts as a NRI but i never found any study that backs up this claim.

However theres studys that point in the direction that it might actually be healthy in the right amounts :



Source: https://www.ncbi.nlm.nih...pmc/articles/PMC3653934/

Other studys however draw a different picture :



Source : https://www.ncbi.nlm.nih.gov/pubmed/19131120/

Its definitely too unexplored to draw any conclusions.

There seems to be enough information in this thread to update the Gramine wiki entry a bit. I've a few other things to do first, however.

Nice references, good finds.

http://www.ncbi.nlm.nih.gov/pubmed/7020159
Some hematological and histopathological effects of the alkaloids gramine and hordenine on meadow voles (Microtus pennsylvanicus).

http://www.ncbi.nlm.nih.gov/pubmed/3421887
Experimental evidence that tryptamine alkaloids do not cause Phalaris aquatica sudden death syndrome in sheep.

http://onlinelibrary.wil....1002/jsfa.3158/abstract
Sheep foraging behavior in response to interactions among alkaloids, tannins and saponins.

https://www.ncbi.nlm.nih.../pmc/articles/PMC3653934
Identification of Adiponectin Receptor Agonist Utilizing a Fluorescence Polarization Based High Throughput Assay.

https://www.ncbi.nlm.nih.gov/pubmed/19131120
Gramine-induced growth inhibition, oxidative damage and antioxidant responses in freshwater cyanobacterium Microcystis aeruginosa.

Here's a few more references, hopefully relevant and useful:

http://www.ncbi.nlm.nih.gov/pubmed/22647218

Heterocycle-functional gramine analogues: solvent- and catalyst-free synthesis and their inhibition activities against cell proliferation.
Ke S, Shi L, Cao X, Yang Q, Liang Y, Yang Z.
Eur J Med Chem. 2012 Aug; 54:248-54
doi: 10.1016/j.ejmech.2012.05.003

Abstract
A series of novel gramine analogues were designed and synthesized via a convenient three-component reaction, and which were evaluated for their inhibition activities against cell proliferation. Their structures were confirmed by satisfactory spectra analyses mainly including (1)H NMR, and ESI-MS analyses. The preliminary assays indicated that some of the newly synthesized compounds displayed significantly good inhibition activities against human lung cancer (NCI-H460), hepatocellular liver carcinoma (HepG2), gastric cancer (SGC-7901 and BGC-823) cell lines compared with the control 5-Fluorouracil (5-FU), which might be developed as novel lead scaffold for potential anticancer agents.


http://www.ncbi.nlm.nih.gov/pubmed/10528147

Structure-activity relationship of gramine derivatives in Ca(2+) release from sarcoplasmic reticulum.
Nakahata N, Harada Y, Tsuji M, Kon-ya K, Shizuri Y, Ohizumi Y.
Eur J Pharmacol. 1999 Oct 8;382(2):129-32.
doi: 10.1016/S0014-2999(99)00591-9

Abstract
5,6-Dibromo-1,2-dimethylgramine evoked Ca(2+) release from skeletal muscle sarcoplasmic reticulum through ryanodine receptors in a concentration-dependent manner with an EC(50) of 22.2 microM. Since the EC(50) of caffeine was 0.885 mM, 5,6-dibromo-1,2-dimethylgramine was 40 times more sensitive than caffeine. Among 14 gramine derivatives having different substituents at N-1, C-2, C-5 or C-6 of the indole skeleton, we found that five derivatives were effective. Study of the structure-activity relationship for Ca(2+) release indicated that 1-methylation and/or both 5- and 6-bromination are important for Ca(2+) release. Thus, gramine derivatives are useful tools for the investigation of Ca(2+) release from sarcoplasmic reticulum.


http://www.ncbi.nlm.nih.gov/pubmed/15095157

Gramine: a vasorelaxing alkaloid acting on 5-HT(2A) receptors.
Froldi G, Silvestrin B, Dorigo P, Caparrotta L.
Planta Med. 2004 Apr;70(4):373-5.
doi: 10.1055/s-2004-818953

Abstract
The vascular effects of gramine on resistance vessels were evaluated, in particular as regards the 5-hydroxytryptamine (5-HT) system. We compared the action of gramine with that of ketanserin, a 5-HT (2A) antagonist; both compounds induced concentration-dependent relaxation in precontracted arterial rings. Also, the 5-HT concentration-effect curve shifted to the right in the presence of gramine, like ketanserin. These results suggest that gramine is a vasorelaxing agent acting mainly by antagonism at 5-HT (2A) receptors.

But apparently much less so for chicken and pigs. I found a study that claims:



http://www.ncbi.nlm.nih.gov/pubmed/11901976

Response of animals to dietary gramine. I. Performance and selected hematological, biochemical and histological parameters in growing chicken, rats and pigs.
Pastuszewska B, Smulikowska S, Wasilewko J, Buraczewska L, Ochtabińska A, Mieczkowska A, Lechowski R, Bielecki W.
Arch Tierernahr. 2001;55(1):1-16.
doi: 10.1080/17450390109386178

Abstract
The effects of feeding varied levels of low- and high-gramine yellow lupin seeds (LG and HG, respectively), and of synthetic gramine added to the diets in amounts ranging from 0.15 to 1.2 g per kg were investigated in one experiment on growing chicken and in two experiments on growing rats. The comparison of LG and HG lupin and the effect of 0.5 g gramine per kg of LG diet were determined in a growth-balance experiment with pigs. Organ weights and histology, blood parameters and activity of liver enzymes were determined. The response to HG lupin and gramine concentration varied among the species, the rats being more affected than chicken; no adverse effects of HG lupin or gramine were found in growing pigs. The common reaction of rats and chicken to the high levels of gramine (native or synthetic) was the decrease of feed intake and body gain. The increase of the relative weight of liver or kidney, changes in hematological parameters and liver enzymes were found only in rats. The estimated NOAEL (no-observed-adverse-effect level) of gramine was about 0.3 g/kg diet for rats, 0.65 g for chicken and at least 0.5 g for growing pigs.


http://www.ncbi.nlm.nih.gov/pubmed/11901977

Response of animals to dietary gramine. II. Effects of feeding high-gramine yellow lupin seeds on reproductive performance of rats and on selected hematological and biochemical parameters in offspring.
Pastuszewska B, Ochtabińska A, Lechowski R.
Arch Tierernahr. 2001;55(1):17-24.
doi: 10.1080/17450390109386179

Abstract
Two groups of 26 male and 26 female rats at the initial age 30 +/- 2 days were fed during 31 weeks on diets containing 20 percent of yellow lupin seeds having low (LG) or high (HG) gramine content. The animals were mated twice within nutritional groups, 1 male: 1 female, and their main reproductive parameters were recorded. In both reproductive cycles body weight of females at mating, after parturition and after 21-days lactation was lower in HG than in LG group. Fertility rate and body weight of neonates were not affected by the diet while number of neonates per litter tended to be lower by 0.7 and 0.8 pups in HG than in LG group. Body weight of weaners was also substantially smaller in dams fed on HG than LG diet. Relative weight of spleen but not of liver, kidney and heart was significantly greater in HG females. Four weeks old males and females issued from the first litters born to LG and HG animals (ten males and ten females per treatment) were fed individually on respective diets during 3 weeks. Feed intake and growth rate did not differ between the treatments. In males relative weight of liver and testicles was greater, while hematocrit and red blood count were lower in HG than in LG group. In females organ weights did not differ. Activity of liver enzymes determined in males was not affected by the diet. It may be concluded that high-gramine lupin affects negatively lactational performance, probably via lower feed intake, but it does not induce apparent teratogenic effects in the progeny.

http://www.mdpi.com/1420-3049/19/7/8949/htm

Discovery of Gramine Derivatives That Inhibit the Early Stage of EV71 Replication in Vitro
Yanhong Wei, Liqiao Shi, Kaimei Wang, Manli Liu, Qingyu Yang, Ziwen Yang, and Shaoyong Ke
Molecules 2014, 19(7), 8949-8964
doi:10.3390/molecules19078949

Abstract:
Enterovirus 71 (EV71) is a notable causative agent of hand, foot, and mouth disease in children, which is associated with an increased incidence of severe neurological disease and death, yet there is no specific treatment or vaccine for EV71 infections. In this study, the antiviral activity of gramine and 21 gramine derivatives against EV71 was investigated in cell-based assays. Eighteen derivatives displayed some degree of inhibitory effects against EV71, in that they could effectively inhibit virus-induced cytopathic effects (CPEs), but the anti-EV71 activity of the lead compound gramine was not observed. Studies on the preliminary modes of action showed that these compounds functioned by targeting the early stage of the EV71 lifecycle after viral entry, rather than inactivating the virus directly, inhibiting virus adsorption or affecting viral release from the cells. Among these derivatives, one (compound 4s) containing pyridine and benzothiazole units showed the most potency against EV71. Further studies demonstrated that derivative 4s could profoundly inhibit viral RNA replication, protein synthesis, and virus-induced apoptosis in RD cells. These results indicate that derivative 4s might be a feasible therapeutic agent against EV71 infection and that these gramine derivatives may provide promising lead scaffolds for the further design and synthesis of potential antiviral agents.