Agmatine Sulfate

Agmatine is an amino acid that offers cognitive boosting benefits. It has excellent effects on reducing neuropathic pain, and drug addiction (repetitive) habits. Its neuroprotectant and can reduce tolerance to medications like benzodiazepines, morphine, and painkillers. Furthermore it synergizes with SSRI's & cannabis.

Overview

What is Agmatine Sulfate?

Agmatine is a form of amino acid that derives from L-Arginine. It has been shown to inhibit receptors for the neurotransmitter acetylcholine, which plays a major role in memory and reasoning.

Agmatine supplement also regulates levels of Nitric Oxide by the affecting nitric oxide synthase enzyme. It controls cellular energy levels by influencing polyamine metabolism and function.

In some studies, it has been shown to enhance the effects of both morphine and fentanyl to increase pain killing, reduce tolerance, and lower addiction, as well as working synergistically with marijuana.

It is also found naturally in every day foods, including beer, wine, coffee, and other fermented foods.

Because it is capable of targeting multiple receptors, agmatine may benefit a spectrum of complex diseases, including diabetes, Alzheimer’s disease, opioid addiction, mood disorders, and even cancer. Furthermore, agmatine may enhance cognitive function, stress resiliency, mood, and8 athletic performance. The highest levels of agmatine are found in the gut, where it is produced by the microbes living there. It is also found in dietary form, mainly in fermented foods, and in supplemental form like agmatine sulfate. Agmatine is also produced in small amounts within the body by the mitochondria in the liver.

Benefits and Effects

What Are Agmatine Sulfate Benefits?

1. Reduces Pain Sensitivity
2. Reduces Symptoms of Anxiety & Depression
3. Neuroprotection & Longevity
4. Improves Weight Loss & Prevents Weight Gain
5. Supports Muscle Growth
6. Helps Erectile Dysfunction & Infertility
7. Help with Alzheimer's Disease
8. Helps Alcohol & Morphine Withdrawal

Supporting research:

Reduces Pain Sensitivity

In research studies, Agmatine shows to be an effective way for pain relief. Especially in the case of thermal hyperalgesia, a condition where the body is sensitive to changes in temperatures. The body becomes hypersensitive to heat or cold.
Agmatine improves those pain sensations, which is a result of its pro-circulations effect.
In studies looking at pain reduction in neuropathic conditions or inflammatory pain, agmatine was not found to produce a statistically significant effect. However, anecdotal, first-hand reports show that it actually did work for neuropathic conditions. So in this specific situation, it seems to be subjective to each individual.

Reduces Symptoms of Anxiety and Depression

Agmatine exhibits antidepressant effects and promotes mood improvement as well as anxiety reduction and relief. It helps the brain and body manage and overcome stress by reducing anxiety and promoting a sense of well-being.

By increasing NRF2, agmatine prevents depressive behavior by protecting brain cells from high levels of stress hormone cortisol. [R]

Agmatine increases adenylate cyclase in the prefrontal cortex, and decreases levels of adenylate cyclase which associate with depression. [R, R].

Furthermore, it blocks the NMDA receptor, prevents calcium overloading, as well as reverses the decrease of monoamines such as norepinephrine, epinephrine, and dopamine. Depression often associated with a reduction of monoamines in the brain [R, R]

Studies and Research

A small pilot study on three patients suffering depression, Agmatine supplement caused a complete disappearance of depression symptoms in all patients. It most likely did so through NMDA receptor-blocking and not through serotonin pathways. [R]
Agmatine also reduced anxiety in rats when they were put in swimming and maze navigation tests. [R]

Neuroprotection and Longevity

Agmatine acts as an anti-oxidant and is continuously under more research for its anti-aging and longevity potential. It has been found to exhibit neuroprotective effects against oxidative damage and injuries to the Central Nervous System (CNS). It is also believed to limit the activity of glutamate receptors and thus, the over-excitation of neurons within the brain.
Additionally, by inhibiting iNOS and nNOS and increasing eNOS, Agmatine protects against brain damage from stroke. Increasing eNOS protects the brain by dilating the blood vessels to increase blood flow. This prevents damage during times of lack of oxygen from reduced blood flow to the brain (also known as ischemic stroke).
Agmatine decreases iNOS and nNOS, two enzymes that contribute to brain damage from stroke. [R]

Study on Effects of Agmatine Sulfate on Nerve Injury

• OBJECTIVE: Evaluate the effect of agmatine sulphate on facial nerve regeneration after facial nerve injury using electron and light microscopy.
• METHODS: The study was performed on 30 male Wistar albino rats split into: a control group, a sham-treated group, a study control group, an anastomosis group, and an anastomosis plus agmatine sulphate treatment group. The mandibular branch of the facial nerve was dissected, and a piece was removed for histological and electron microscopic examination.
• RESULTS: Regeneration was better in the anastomosis group than in the study control group. However, the best regeneration findings were seen in the agmatine sulphate treatment group. There was a significant difference between the agmatine group and the others in terms of median axon numbers (p < 0.004) and diameters (p < 0.004).
• CONCLUSION: Agmatine sulphate treatment with anastomosis in traumatic facial paralysis may enhance nerve regeneration.

 PMID: 28122652

Improves Weight Loss and Prevents Weight Gain

Individuals who struggle to gain weight can benefit from Agmatine supplements. In some studies, subjects increased food consumption rates by 44% to 54% in 24 hours.
Moreover, in the following studies, Agmatine shows an increase in fat burning, a decrease in fat composition, and an increase in muscle mass [R], which also contributes to the next benefit of Agmatine:

Supports Muscle Growth

Agmatine stimulates the production of luteinizing hormone (LH). Increasing these hormone levels lead to an increase in testosterone levels.
By increasing testosterone levels, Agmatine contributes to an optimal hormonal environment for muscle growth, enhances athletic performance, and fastens recovery. [R]
Agmatine also increases insulin sensitivity and the uptake of glucose into the muscle. Increasing insulin sensitivity results in more effective shuttling of amino acids as well as glucose into the tissues for growth and repair. [R] [R]

Helps Erectile Dysfunction (ED) and Infertility

Studies show that L-arginine is involved in the process of cell replication, in addition to enhancing blood circulation, so it can help improve both sperm production and motility.

Men dealing with cardiovascular issues due to low levels of NO in the blood are more prone to experience erectile dysfunction and fertility problems because an erection requires a relaxation of smooth muscles, which Nitric Oxide triggers.

Although it doesn't apply to every person, a significant rate of male infertility cases (92%) is treatable with L-arginine supplements in combination with dilators, antioxidants and/or anti-inflammatories. [R]

Research suggests that high-stress levels lower L-arginine levels in the sperm production pathway. Therefore, men with chronic stress specifically can benefit from Agmatine supplement.

According to Dr. Axe, a combination of L-arginine, L-glutamate and yohimbine hydrochloride is a common way of treating erectile dysfunction. And it works better than L-arginine alone. [R]

“In fact,” he says, “many of the most frequently prescribed medications for ED work similarly to L-arginine: by increasing nitric oxide production.”

Furthermore, there’s research suggesting treatment with N-Acetyl Cysteine (NAC) and L-arginine together can help balance hormones naturally and restore normal sexual function in women with polycystic ovary syndrome and estrogen imbalances.

Other studies suggest that L-arginine with herbs such as chasteberry, green tea extract, and antioxidant supplements improve pregnancy rates in women struggling to conceive. [R]

Helps Alzheimer's Disease

Insulin resistance could cause an increase of plaque and neurofibrillary tangles in the brain, which are the signs of Alzheimer’s disease. Agmatine prevents cognitive decline by rescuing insulin signaling and avoiding potential accumulation of those tangles. [R]

Helps Alcohol & Morphine Withdrawal

Agmatine reduces and to an extent, prevents, symptoms of alcohol withdrawal such as “wet dog shakes,” anxiety, flashes, and shakings. [R] [R]

Mechanism of Action

How Does Agmatine Sulfate Work?

Agmatine has several mechanisms. It can inhibit N-methyl-D-aspartate (NMDA) and nicotinic acetylcholine receptors, as well as activate imidazoline receptors. Agmatine can also inhibit nitric oxide synthase enzymes, which allows it to regulate elevated levels of nitric oxide. Agmatine can inhibit calcium channels and specific serotonin receptors as well. Further research is needed to determine the full extent of agmatine mechanisms. [R]

Agmatine was found to exert modulatory actions directly and indirectly at multiple key molecular targets underlying cellular control mechanisms of cardinal importance in health and disease. It is considered capable of exerting its modulatory actions simultaneously at multiple targets. The following outline indicates the categories of control mechanisms and identifies their molecular targets:

Neurotransmitter receptors and receptor ionophores. Nicotinic, imidazoline I1 and I2, α2-adrenergic, glutamate NMDAr, and serotonin 5-HT2A and 5HT-3 receptors. Ion channels. Including: ATP-sensitive K+ channels, voltage-gated Ca2+ channels, and acid-sensing ion channels (ASICs).

Membrane transporters. Agmatine specific-selective uptake sites, organic cation transporters (mostly OCT2 subtype), extraneuronal monoamine transporters (ENT), polyamine transporters, and mitochondrial agmatine specific-selective transport system. Nitric oxide (NO) synthesis modulation. Both differential inhibition and activation of NO synthase (NOS) isoforms is reported.

Polyamine metabolism. Agmatine is a precursor for polyamine synthesis, competitive inhibitor of polyamine transport, inducer of spermidine/spermine acetyltransferase (SSAT), and inducer of antizyme. Protein ADP-ribosylation. Inhibition of protein arginine ADP-ribosylation. Matrix metalloproteinases (MMPs). Indirect down-regulation of the enzymes MMP 2 and 9. Advanced glycation end product (AGE) formation. Direct blockade of AGEs formation. NADPH oxidase. Activation of the enzyme leading to H2O2 production. – Wikipedia

Dosage

How to Take Agmatine Sulfate?

There is currently no standard dosage for agmatine sulfate because there haven’t been enough human studies for determination. These numbers are rough estimates to give an idea of typical, experimental dosing:

For treatment of neuropathic pain

1,000 to 2,500 mg of agmatine (daily)

For improving cognitive function

200 to 500 mg of agmatine (daily)

For vasodilation and enhanced recovery

500 to 1000 mg of agmatine (30 minutes pre-workout)

Note: Agmatine is not absorbed well when taken with dietary protein, because it uses the same transporters as arginine

Quoting Examine; “there are no standard dosages for agmatine because of the lack of human evidence for its effects. However, 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 217-435 mg 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.”

“The generally accepted daily dosage range for Agmatine Sulfate is between 250 mg and 2.5 grams. Avoid taking higher than necessary dosages to reduce the risk of side effects.”

Side Effects

What Are Agmatine Sulfate Side Effects?

According to studies conducted so far, it appears that Agmatine Sulfate is safe even in relatively high doses. While there have been few studies conducted thus far, they have not shown any side effects to be associated with this supplement.
If you follow the recommended Agmatine sulfate dosage protocol and do not have any pre-existing contraindications for use, the risk of serious adverse effects is very low. Minor side effects included nausea, diarrhea, and vomiting in a small percentage of participants, which cleared up after a few days of discontinuing use. [R]

User Experience

Reddit

“Not only does it have varied anti-addiction properties to Opioids, amphetamines, caffeine, nicotine & alcohol, but it also seems to make other drugs, and medicines more potent in their effects. It also shares the properties of Ketamine's antidepressant effects, via the mTOR AMPA pathway. A small study found a robust antidepressant effect; all patients reported remission of depression. Considering that, shutting down Serotonin production via parachlorophenylalanine, did not reverse the antidepressant effects, shows how punchy this substance is. It's also a painkiller. I'd recommend this be added to everyone's stack, provided they aren't too fond of Alcohol, as I noticed it definitely seems to blunt the good feelings of certain drugs.” [Ref]

Frequently Asked Questions

Further Readings

1. Agmatine – Wikipedia
2. Agmatine – Scientific Review – Examine
3. Nootropics FAQs