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Agmatine Sulphate – For Lower Opiate Tolerance – Research Summary

Posted by Anonymous on October 22, 2014  /   Posted in Khemcorp Originals, Reverse Tolerance

Disclaimer: All thoughts and advice expressed are the personal opinions and gatherings of the author and do not constitute medical advice. If you are seeking medical advice please consult a doctor.

What is Agmatine Sulphate?

Screen Shot 2014-10-17 at 1.59.56 pm Agmatine

Agmatine also known as (4-aminobutyl)guanidine is an aminoguanidine that was discovered in 1910 by the Nobel laureate Albrecht Kossel. Agmatine is a perculiar chemical that is a derivative of the much more popular and well know L-arginine (often used in sports supplements).  It is an endogenous amine that is synthesized following the decarboxylation of Arginine. Discovered in 1910 by Albrecht Kossel, it was however mostly not researched until the mid 1990s, where the evidence of its endogenous properties became better known. It occurs naturally in the body, stored in neurons. It is bother a neurotransmitter and neuromodulator, having a wide variety of effects via multiple mechanisms. In action it is more complex than Proglumide. Much research has shown that Agmatine has direct uses in the treatment of drug addiction, hence drug tolerance, especially in the attenuation in terms of pain neurological pathways.  Agmatine like Proglumide has weak analgesic effects of it’s own, but nothing special to take note of. Despite the fact that Agmatine is highly promising as a drug for a variety of treatment, it is not promoted widely due to the fact that it is a health supplement that can’t really be patented, hence like Proglumide the lack of interest due to the lack of profits for major pharmaceutical companies. A caveat of Agmatine is in the way that the research is spans a large array of research but due to the lack of funding for such research, the scale is usually small or restricted.

That said 10 years of research have successfully replicated research results again and again in support of lower opiate tolerance in the usage of Agmatine Sulphate.

What’s mechanism behind it in regards to tolerance and opiate attenuation?

In terms of broad it effects, Agmatine inhibited NDMA, imidazoline nicotinic acetylcholine receptors in different varying strengths, it effects goes beyond this. What Agmatine uniquely does is it also inhibits nitric oxide synthase enzymes, thus altering the levels of nitric oxide in the body, this has a variety of positive effects. Opioids are widely used in pain relief, but their clinical use is highly limited by the quick development of tolerance on repeated or prolonged use.

Agmatine is a Biphasic Opioid Modulator meaning that it both potentiates opiates and reduces tolerance and dependency of opiate receptor acting chemicals such as morphine without interacting directly with the opiate receptor. This is because it is generally discovered that multiple mechanisms is at play when it comes to tolerance development, some chemicals have the ability to affect other neurotransmitter pathways unrelated to their own.

Recently it has been revealed that some agents which are not able to interact with opioid receptors play an important role in regulating the pharmacological actions of opioidsEspecially, some of them show biphasic modulation on opioid functions, which enhance opioid analgesia (positive action), but inhibit tolerance to and substance dependence on opioids (negative actions)The mechanisms associated with their biphasic modulation on opioid function as mentioned above might be related to their inhibitory actions on NMDA receptor system at different levelsThese agents at least include imidazoline receptor agonist agmatine, N-methyl-D-aspartate (NMDA) receptor antagonists, NOS inhibitors, and voltage-dependent calciumchannel blockersWe would like to call these agents which do not interact with opioid receptors, but do have biphasic modulation on opioid functions as biphasic opioid function modulator (BOFM)… …In nearly past 10 years, more and more accumulated results reported by our laboratory and others point out that agmatine has obvious actions on opioid functions, which is a very good example for BOFM.

SU Rui-Bin, LI Jin1, QIN Bo-Yi Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China

NDMA Pathway of Tolerance Attentuation

Research shows Agmatine is an promising and effective adjunt to treating opiate tolerance, there are however multiple reasons of why Agmatine potentiates as well as reduces tolerance to opiates and opioids. Its likely in my view that a few of the mechanisms create this effect, some more than others. The NDMA pathway is of specific interest since this glutaminergic pathway regulates neuroplasticity in the neuronal network, and is one of the key reasons tolerance develops (link to broad opiate tolerance article) In chronic studies, agmatine at a low dose (0.1 mg/kg) which does not affect morphine analgesia acutely prevents tolerance following chronic morphine dosing for 10 days. A higher agmatine dose (10 mg/kg) has a similar effect. Agmatine also blocks tolerance to the δ-opioid receptor ligand [d-Pen2,d-Pen5]enkephalin given intrathecally, but not to the κ3-opioid receptor agonist naloxone benzoylhydrazone. Despite its inactivity on κ1-opioid analgesia in the acute model, agmatine prevents κ1-opioid receptor-mediated tolerance. These studies demonstrate the dramatic interactions between agmatine and opioid analgesia and tolerance. Agmatine is also a neurotransmitter which is released by the neuronal system in the body to promote neuroplasticity, in other words other ways a way for the nervous system to return to homeostasis, which may explain its comprehensive action in reducing tolerance (citation needed).

Agmatine has been detected biochemically and immunohistochemically in the central nervous system. Consequently, it is conceivable that agmatine operates in an anti-glutamatergic manner in vivo; the role of endogenous agmatine in the central nervous system remains minimally defined. The current study used an immunoneutralization strategy to evaluate the effect of sequestration of endogenous agmatine in acute opioid analgesic tolerance in mice. First, intrathecal pretreatment with an anti-AG IgG (but not normal IgG) reversed an established pharmacological effect of intrathecal agmatine: antagonism of NMDA-evoked behavior. This result justified the use of anti-AG IgG to sequester endogenous agmatine in vivo. Second, intrathecal pretreatment with the anti-AG IgG sensitized mice to induction of acute spinal tolerance of two micro-opioid receptor-selective agonists, [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin and endomorphin-2. A lower dose of either agonist that, under normal conditions, produces moderate or no tolerance was tolerance-inducing after intrathecal pretreatment of anti-AG IgG (but not normal IgG). The effect of the anti-AG IgG lasted for at least 24 h in both NMDA-evoked behavior and the acute opioid tolerance. These results suggest that endogenous spinal agmatine may moderate glutamate-dependent neuroplasticity.

Sensitization Immunoneutralization of Agmatine Sensitizes Mice to Micro-Opioid Receptor Tolerance, 2009, Wade CL, Eskridge LL, H Nguyen OX, Kitto KF, Stone LS, Wilcox G, Fairbanks CA

Nitric Oxide Pathway of Tolerance Attenuation

Agmatine Sulphate’s nitric oxide actions seems to aid with withdrawal symptoms particularly, reducing opiate/opoid dependence, this is very interesting as if we can endure withdrawal better then we can have off days to allow our tolerance to lower. At the very least the suffering of withdrawal that occurs will be less.

Inhibitors of NOS modulate withdrawal from opioids and ethanol, diminishing many signs of withdrawal. In addition, NOS inhibitors suppress signs of withdrawal from nicotine. These data suggest that NO may be involved in the expression of withdrawal signs, and they leave open the possibility that NO may mediate the development of many of these signs. Although preliminary, data to date suggest that glutamate neurotransmission may be related to these beneficial effects of NOS inhibitors on signs of withdrawal. Emerging data further suggest that NO may have a general role in the dependence potential of various classes of drugs of abuse. Thus, modulation of NO systems may be a potential therapeutic target for treatment of substance abuse. Constitutively formed nitric oxide modulates the actions of morphine and related analgesics by either enhancing or reducing antinociception. Tolerance to and dependence on morphine or its withdrawal syndrome are likely prevented by nitric oxide synthase inhibition. Information concerning modulation of morphine actions by nitric oxide is undoubtedly useful in establishing new strategies for efficient antinociceptive treatment and for minimizing noxious and unintended reactions.

Imidazoline Pathway of Tolerance Attenuation

Considered widely as an endogenous ligand for the imidozoline receptors, it is another mechanism which has a ton if research showing it aids in a novel method of modulating opioid function. The brain actually has storage of Agmatine that is released for neuromodulation itself. Because of the wide variety of neuromodulation that agmatine, it is considered a neurotransmitter of sorts.

Pretreatment of mice with both of agmatine and morphine made morphine loss the ability to induce tolerance. Withdrawal jumps and loss in body weight induced by naloxone in morphine-dependent mice were prevented by agmatine (2.5-10 in a dose-dependent manner. ED50 of naloxone (21.4, 18.4-24 required to precipitate withdrawal jumps in mice pretreated with both agmatine and morphine was 8 times higher than that with morphine alone (2.5, 2.1-2.8 These effects of agmatine were blocked by idazoxan.


Agmatine prevented tolerance to and substance dependence on morphine in mice by activation of imidazoline receptors. Zhongguo Yao Li Xue Bao. 1999 Mar;20(3):232-8. Agmatine is an endogenous amine that is synthesized following the decarboxylation of L-arginine by arginine decarboxylase. Agmatine exists in mammalian brain and has been proposed as a neurotransmitter and/or neurotransmodulator. Agmatine binds to several targets and is considered as an endogenous ligand for imidazoline receptors. This review, mainly based on our research work in the past decade, focused on the modulations by agmatine action on imidazoline receptors to opioid analgesia, tolerance and dependence, and its possible neurochemical mechanisms. We went on to propose that agmatine and imidazoline receptors constitute a novel system of modulating opioid functions. Cellular and

Molecular Neurobiology August 2008, Volume 28, Issue 5, pp 629-641 Date: 25 Jul 2007 Agmatine and Imidazoline Receptors: Their Role in Opioid Analgesia, Tolerance and Dependence.

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 agmatine amphetamine experience

What’s the Dosage and How Should it Be Taken?

The standard dosage of Agmatine Sulphate for NO effects are 250mg, however for opiate tolerance reduction – effective dosages range from 500mg to 2000mg, this is referenced both anecdotaly and in research:

a single human study used 1,300-2,670mg of agmatine, daily for the treatment of neuropathic pain. The estimated human dose for improving cognition is 1.6-6.4mg/kg of agmatine, taken orally. This is based off of the 10-40mg/kg dosage range for rats, and is equivalent to 217-435mg for a 150lb person. Supplementation should not exceed 6.4mg/kg of bodyweight.

Studies on agmatine use a daily dosing protocol.

Agmatine is not absorbed well when taken with dietary protein, because it uses the same transporters as Arginine. Further research is needed to determine if oral agmatine supplementation provides the same benefits as were observed in animal studies.

Agmatine –

“The most fascinating aspect of agmatine, an endogenous molecule, is its ability to potentiate the analgesic effect of morphine and at the same time to reduce the morphine dependence and withdrawal. The findings from this and previous reports suggest that increasing endogenous agmatine could offer novel therapeutic advantage in morphine analgesia and dependence. For example, combining agmatine with morphine during pain management, while reducing the effective dose of morphine, will also prevent the development of dependence to morphine.”

I’m not sure about whether you have to have a constant level in your system. I’ve been taking it (500mg) before dosing, but I dose a couple of time daily so for me that covers it either way.


Very much feels like a low-level opiate sensation. As OmegaMan speculates, I’m also guessing this is why it seems to potentiate – it’s genuinely acting on your opiate receptors itself. This would also explain why it’s been studied to relieve WDs to some extent, because it’s mimicking the mechanisms of their normal DoC……but IMO is *very* well worth checking out for help with WD symptoms.


What’s the upper ceiling?

Dosages beyond 2000mg is not recommended, whilst there should be little threat of severe illness due to rate limiting mechanisms in the body. Beyond 2000mg the increase of nitric oxide can cause some side effects like increased heart rate, which would be dangerous for people with underlying heart conditions. Naseau and headache is also reported at higher dosages of Agmatine Sulphate, probably via the nitric oxide pathway, which may promote too much vascularity, as well as the plenthora of effects nitric oxide has on the body and brain.

I would not worry too much about Agmatine and blood pressure. Although NOS inhibitors usually should increase blood pressure, agmatine does not last long in serum (10 minutes or less) and taking one dose at a separate time from your arginine or citrulline supplementation should not interfere with the benefits thereof.

Also, this thing is synergistic with everything illicit or pharmaceutical it seems (Bupropion, alcohol, marijuana, opioidergic drugs). Perhaps the most interesting thing to come from agmatine in the future is the drug-drug interactions.

Some oral pharmacokinetic studies in humans are sorely needed to help harmonize the in vitro studies to supplementation of agmatine.

Kurtis Frank,


Potential interactions and risks to watch out

There are no official drug interactions, since Agmatine is technically a supplement, however since it acts a large amount of mechanisms, one should take caution. Especially regarding underlying heart conditions. Its action on Nitric Oxide, means its probably contrained with other drugs/supplements that boosts vascularity, heart pressure and heart rate. By itself this mechanism alone is unlikely to product any undesirable side effects, however mixing Agmatine with other things that affect similiar systems is unadvisable.

Agmatine does not go well with: L-Arginine, L-Citrulline, Yohimbine, Rauwolscine, Any Nitric Oxide enhancer, Creatine, D-Aspartic Acid,. It is highly advisble to take these other supplements seperately. There isn’t any reason to mix and match anyways since Agamtine Sulphate by itself has many benefits.

It would be common sense to derive from the above that taking high doses of multiple supplements and drugs that affect the heart could yield dangerous effects. People above the age of 40 should beware of underlying heart conditions and check up with a doctor before mixing multiple heart medications, these include beta blockers, alpha blockers, nitrates and PDE4 inhibitors like Viagra.

Bonus Information

Mixing multiple drugs/supplements that affect the heart with an underlying conditions can cause death.

You should not for example mix cocaine with alchohol, or cocaine with beta blockers, or nitrites with Viagra. Such mixing of heart attentuation medication/recreational drugs can cause sudden fall in blood pressure, cardiac arrest and death. Beta blockers, Alpha Blockers, Clot Busters and Nitrites ALL have COMPLICATED effects on the heart, without consultation of medical advice it is extremely unadvisable to mix and match heart drugs yourself.

Research References

Modulation of opioid analgesia by agmatine • Yuri Kolesnikova, b, • Subash Jainb, • Gavril W. Pasternak, a, c, d, e, Corresponding author. Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. Tel.: 212 639-7046; fax: 212 794-4332 • a The Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA • b Department of Anesthesiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA • c Department of Neurology, Cornell U. Medical College, New York, NY 10021, USA • d Department of Neuroscience, Cornell U. Medical College, New York, NY 10021, USA • e Department of Pharmacology, Cornell U. Medical College, New York, NY 10021, USA Received 5 October 1995, Accepted 10 October 1995, Available online 1 March 1999 Nitric oxide and substance dependence • I. Tayfun Uzbaya, , , • Michael W. Oglesbyb • a Gülhane Military Medical Academy, Department of Medical Pharmacology, Psychopharmacology Research Unit, Etlik 06018, Ankara, Turkey • b University of North Texas Health Science Center, Department of Pharmacology and Neuroscience, 3500 Camp Bowie Blvd., TX 76107-2699, USA Received 23 May 2000, Revised 24 October 2000, Accepted 25 October 2000, Available online 2 February 2001 Modulation of Opioid Actions by Nitric Oxide Signaling Toda, Noboru M.D., Ph.D.*; Kishioka, Shiroh M.D., Ph.D.†; Hatano, Yoshio M.D., Ph.D.‡; Toda, Hiroshi M.D., Ph.D.§ Section Editor(s): Warner, David S. M.D.; Warner, Mark A. M.D., Editors Cellular and Molecular Neurobiology August 2008, Volume 28, Issue 5, pp 629-641 Date: 25 Jul 2007 Agmatine and Imidazoline Receptors: Their Role in Opioid Analgesia, Tolerance and Dependence • Ning Wu, • Rui-Bin Su, • Jin Li Zhongguo Yao Li Xue Bao. 1999 Mar;20(3):232-8. Effects of agmatine on tolerance to and substance dependence on morphine in mice. Li J1, Li X, Pei G, Qin BY. Effects of agmatine on tolerance to and substance dependence on morphine in mice. Li J1, Li X, Pei G, Qin BY. Agmatine itself was a weak analgesic which enhanced analgesic action of morphine and inhibited tolerance to and dependence on opioid. The main mechanisms of agmatine were related to inhibition of the adaptation of opioid receptor signal transduction induced by chronic treatment of opioid. Su RB et al / Acta Pharmacol Sin 2003 Jul; 24 (7): 631-636 A biphasic opioid function modulator: agmatine SU Rui-Bin, LI Jin1, QIN Bo-Yi Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China Agmatine inhibited tolerance to and dependence on morphine in guinea pig ileum in vitro. (PMID:10437148) • Abstract • Citations • BioEntities • Related Articles • External Links Li J, Li X, Pei G, Qin BY Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, China. Zhongguo yao li xue bao = Acta Pharmacologica Sinica [1998, 19(6):564-568] Type: Journal Article, In Vitro Abstract Highlight Terms Gene Ontology(1) Diseases(1) Genes/Proteins(2) Species(2) Chemicals(4) AIM: To observe effect of agmatine (Agm) on tolerance to and substance dependence on morphine(Mor) in guinea pig ileum longitudinal muscle (GPILM). METHODS: The experiment was performed in electric field stimulation (EFS) test in vitro. RESULTS: Mor inhibited twitch contractions of GPILM induced by EFS [IC50 = 140 (107-182) nmol.L-1]. Incubation of GPILM with Mor 270 nmol.L-1 for 8 h evoked a 37-fold increase in IC50 of Mor (tolerance) and a contractile response to naloxone (Nal,substance dependence). When the preparations were coincubated with Mor + Nal and Mor + Agm,Mor lost the ability to induce tolerance and inhibited the contractile responses of the preparations to Nal by 90% and 75%, respectively. These effects of Agm could be almost completely antagonized by idazoxan. Interesting note: occur in prereceptor (alteration of neurotransmitters), receptor (change of the quantity and quality of receptor), and postreceptor (change of the signal transduction systems). Based on this hypothesis, we studied the possible mechanisms at these three levels. Arginine might not have the same direct effects of Agmatine Effect of L-arginine on morphine functions L-arginine is the substrate of endogenous agmatine, so it is possible that the concentration of endogenous agmatine might increase after administration of L-arginine and exerted the same effects on opioid function like exogenous agmatine. We found that L-arginine (0.5-50 mg/kg, sc) exhibited no analgesia and did not influence analgesia of and tolerance to morphine. The reason may be related to the different metabolism routes of L-arginine[13]. A biphasic opioid function modulator: agmatine SU Rui-Bin, LI Jin1, QIN Bo-Yi Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China • 1 Li J. Opioid function modulator. Info Chin Pharmacol Society 2002; 19: 14-5. • 2 Kolesnikov Y, Jain S, Pasternak GW. Modulation of opioid analgesia by agmatine. Eur J Pharmacol 1996; 296: 17-22. • 3 Li J, Li X, Pei G, Qin BY. Analgesic effect of agmatine and its enhancement on morphine analgesia in mice and rats. Acta Pharmacol Sin 1999; 20: 81-5. • 4 Li J, Li X, Pei G, Qin BY. Agmatine inhibited tolerance to and dependence on morphine in guinea pig ileum in vitro. Acta Pharmacol Sin 1998; 19: 564-8. • 5 Li J, Li X, Pei G, Qin BY. Effects of agmatine on tolerance to and substance dependence on morphine in mice. Acta Pharmacol Sin 1999; 20: 232-8. • 6 Lu XQ, Su RB, Liu Y, Li Jin. Determination of agmatine actions on tolerance to and dependence on morphine in CNS. P L A Acta Pharm 2003; in press. • 7 Li J, Li X, Pei G, Qin BY. Inhibition of agmatine on releasing monoamine in different brain areas of rats. PLA Acta Pharm 1999; 15: 2-7. • 8 Li J, Li X, Pei G, Qin BY. Relationship between anti-rat substance dependence of agmatine and opioid receptors. Chin J Drug Dependence1999; 8: 178-81. • 9 Li J, Li X, Pei G, Qin BY. Correlation between inhibitions of morphine withdrawal and nitric-oxide synthase by agmatine. Acta Pharmacol Sin 1999; 20: 375-90. • 10 Li J, Li X, Pei G, Qin BY. Influence of agmatine in adaptation of cAMP signal transduction system of opiate receptors. Acta Pharmacol Sin 1999; 20: 592-6. • 11 Weng XC, Gai XD, Zheng JQ, Li J. Agmatine blocked the voltage-gated calcium channel in cultured rat hippocampal neurons. Acta Pharmacol Sin 2003; 24: in press. • 12 Su RB, Li J, Li X, Qin BY. Influence of idazoxan on analgesia, tolerance, and physical dependence of morphine in mice and rats in vivo. Acta Pharmacol Sin 2000; 21: 1011-5. • 13 Su RB, Li J, Qin BY. Effects of L-arginine and anti-L-arginine decarboxylase antibody on morphine analgesia and tolerance. Chin J Drug Dependence 2003; 12: 97-101. • 14 Lu G, Su RB, Li J, Qin BY. Modulation of pain threshold and some morphine effects by -difluoromethyl-ornithine and aminoguanidine.Eur J Pharmacol 2003; in press. • 15 Su RB, Li J, Li X, Qin BY. Down-regulation of MAO-B activity and imidazoline receptors in rat brain following chronic