Agmatine is a compound naturally produced within the body that plays a key role in a range of bodily processes. However, agmatine interacts with a number of supplements and drugs. Read on to learn more about the purported benefits and side effects of agmatine.
What Is Agmatine?
Agmatine is a compound naturally formed from the amino acid L-arginine. It is a neurotransmitter found predominantly in neurons. Because it is capable of targeting multiple receptors, researchers are investigating it in the context of a spectrum of complex diseases.
Furthermore, some research suggests that agmatine may play a role in cognitive function, stress resiliency, mood, and athletic performance [1, 2].
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 forms like agmatine sulfate. Agmatine is also produced in small amounts by mitochondria in the liver [3].
Mechanisms of Action
Agmatine is a natural component of the inner workings of many cells, and as such, it has complex interactions with cellular function. Researchers have been working to untangle agmatine’s mechanisms and effects by studying human and animal cells as well as bacteria.
Agmatine appears to block the production of NOS (nitric oxide synthase): There are 3 main enzymes that produce nitric oxide (NO); iNOS, nNOS, and eNOS:
- iNOS (inducible) produces large quantities of NO as a function of the immune system to kill harmful bacteria. If left unchecked, iNOS can cause inflammation.
- nNOS (neuronal) is a signaling molecule that facilitates communication in the brain across neurons. If left unchecked, nNOS can inhibit the growth and repair of neurons.
- eNOS (endothelial) signals vasodilation in the lining of blood vessels for increased blood flow. Increased blood flow lowers blood pressure and increases the import of oxygen and nutrients and export of cellular waste products.
Thus, some researchers believe agmatine may regulate nitric oxide levels by inhibiting iNOS and nNOS and increasing eNOS [4, 5].
In other cell studies, agmatine has been found to:
- Block NMDA receptor: Agmatine binds to 2 sites of the NMDA (N-methyl-D-aspartate) receptor and prevents glutamate from binding to them. This may prevent neuron death from overexcitation due to the neurotransmitter glutamate [6].
- Activate alpha-2 adrenergic (α2A) receptors: Agmatine is strongly attracted to the alpha-2 adrenergic receptors. Low-dose agmatine amplifies α2A receptor activation while higher concentrations block it. Some effects of agmatine can be abolished with α2A receptor blockers, such as yohimbine and rauwolscine [7, 8, 9, 10].
- Block nicotinic acetylcholine receptors: Agmatine binds to nicotinic acetylcholine receptors and prevents acetylcholine from binding to it [11].
- Activate imidazoline receptors: Agmatine is a strong imidazoline receptor activator. Activation of imidazoline receptors can cause an increase in beta-endorphins (opioid receptor activators that decrease pain and regulate behavior in response to pain, stress, or fear) from the adrenal glands [8, 12, 13].
- Activate mechanistic target of the rapamycin (mTOR) pathway: mTOR is a protein that regulates cell growth and survival, as well as protein synthesis. Agmatine activates this pathway, which may produce antidepressant effects [14].
- Activate nuclear factor E2-related factor 2 (Nrf2): Agmatine activates the Nrf2 pathway, which increases the production of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation [15, 16].
These cell studies can give us some insight into how agmatine works and interacts with cellular function, but they cannot tell us whether or how agmatine might affect health outcomes. For that, we need clinical trials – which are sorely lacking for this compound.
Potential Benefits of Agmatine
Agmatine supplements have not been approved by the FDA for medical use and lack solid clinical research. Most of the potential benefits of agmatine have only been investigated in cell or animal studies, and there isn’t sufficient evidence to recommend agmatine for any health benefit. In all cases, a better studied alternative is available.
Regulations set manufacturing standards for supplements but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing with agmatine.
Insufficient Evidence For
The following purported benefits are only supported by limited, low-quality clinical studies. There is insufficient evidence to support the use of agmatine for any of the below-listed uses. Remember to speak with a doctor before taking agmatine, and never use it in place of something your doctor recommends or prescribes.
1) Pain
Researchers are currently exploring the potential role of agmatine in pain management, but human research is lacking.
In 2 studies of 61 participants with a herniated lumbar disk, agmatine supplementation for 10 days reduced pain and improved quality of life [17].
Agmatine reduced hypersensitivity to pain and reduced the size of spinal cord injury in rats [18, 19].
Furthermore, agmatine reduced neuropathic pain by preventing nitric oxide synthase activation and blocking NMDA receptors in rats [20].
2) Mental Health
Researchers are currently investigating the effect of agmatine supplementation on mental health. Based on animal studies alone, agmatine could have some potential in managing anxiety, depression, or stress, but human studies will be required, and there are plenty of better-studied strategies available.
Anxiety and Depression
By increasing NRF2, agmatine prevented depressive behavior in rats by protecting brain cells from high levels of the stress hormone cortisol [16].
Agmatine increased adenylate cyclase in the prefrontal cortex of rats. Decreased levels of adenylate cyclase are associated with depression [21, 22].
In a small pilot study of 3 depressed patients, agmatine supplementation caused a complete disappearance in depressive symptoms in all patients, likely through NMDA receptor-blocking and not through serotonin pathways [23].
Agmatine also reduced anxiety in rats during swimming tests and navigating mazes [24].
Stress
Agmatine significantly reduced high body temperature from prolonged heat stress and fever in mice caused by bacterial toxins called lipopolysaccharides (LPS). Agmatine also increased the survival rate of mice exposed to LPS [25].
Animal & Cell Research (Lacking Evidence)
No clinical evidence supports the use of agmatine] for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.
3) Muscle Growth
Agmatine stimulated the production of luteinizing hormone (LH) in rats. Increased levels of LH increase testosterone levels. By increasing testosterone levels, agmatine contributed to an optimal hormonal environment for muscle growth and enhanced athletic performance [26].
Agmatine increased insulin sensitivity and uptake of glucose into the muscles of mice. Increased insulin sensitivity results in more effective shuttling of glucose and amino acids into muscles for growth and repair [27, 28].
Agmatine also increased appetite in rats. An increased appetite can lead to increased caloric consumption, which is necessary for increasing muscle mass [29, 9].
This potential benefit has only been studied in animals. Human trials will be required to determine whether agmatine could be useful for this purpose.
4) Brain Health & Neurological Disorders
Stroke
By inhibiting iNOS and nNOS and increasing eNOS, agmatine protected against brain damage from stroke in rats. Increasing eNOS protects the brain by dilating the blood vessels to increase blood flow. This prevents damage during times of lack of oxygen from a reduction in blood flow to the brain (ischemic stroke). Additionally, agmatine decreased iNOS and nNOS, 2 enzymes that contribute to brain damage from stroke [5].
Alzheimer’s Disease
Insulin resistance can lead to the accumulation of plaque and neurofibrillary tangles in the brain, which are the hallmarks of Alzheimer’s disease. Agmatine prevented cognitive decline by rescuing insulin signaling and preventing the accumulation of plaques and neurofibrillary tangles in the brains of rats [27, 30].
Nerve Repair
Agmatine increased nerve regeneration in rats with facial nerve injuries. This may be due to agmatine’s inhibition of nNOS, which can inhibit the growth and repair of neurons [19].
Seizures
Glutamate and the NMDA receptor have been implicated in the initiation and spread of seizure activity. Agmatine prevents seizures in mice and rats by blocking NMDA receptors [31, 32].
These benefits have only been studied in animals so far. Human trials will be required to determine agmatine’s safety and effectiveness for this purpose.
5) Spatial Memory
Researchers are investigating agmatine’s potential role in memory formation (especially via BDNF and adenylate cyclase), but again, human trials are lacking [33, 21].
Agmatine is increased during spatial learning tasks and is stored in high levels in the hippocampus (a region of the brain associated with memory). Its role as a neurotransmitter is associated with memory formation [34, 35, 36].
Agmatine improved spatial memory consolidation, or the initial recording and storing of memory, but had no effect on the retrieval of memories in rats [37].
6) Weight Management
Agmatine reduced weight gain in rats [38].
Agmatine increased fat burning, decreased fat composition, and increased muscle mass in rats [38].
Once again, only animal studies are available. There are better options available for weight loss and weight management, and the best strategies are always a healthy diet and exercise.
7) Insulin Sensitivity and Blood Sugar
Agmatine improved insulin sensitivity in insulin-resistant rats by reducing mTOR and glucose transporter 2 (GLUT2) production in rats [27, 38, 39].
Agmatine reduced blood sugar levels in rats by increasing β-endorphin production by the adrenal glands. β-endorphins cause the uptake of glucose from the blood into skeletal muscle tissue [40, 12, 28].
Clinical trials will be required to repeat these results in humans.
8) Hardening of the Arteries
Agmatine reduced plaques (atherosclerotic lesions) that lead to hardening of the arteries by 40% and increased good (HDL) cholesterol levels in mice, but this effect has not been studied in humans [41].
9) Inflammation
Agmatine reduced inflammation by suppressing the expression of iNOS after inflammatory stimulation in rats [25].
In rats, agmatine prevented decreased blood pressure and kidney function associated with septic shock due to its anti-inflammatory effects [25].
Human trials have not yet been conducted to investigate this potential benefit. Talk to your doctor about other strategies to reduce inflammation.
10) Alcohol and Morphine Withdrawal
Agmatine prevented symptoms of alcohol withdrawal such as “wet dog shakes,” anxiety, and tremors in rats. These effects have not been studied in humans undergoing withdrawal [42, 43].
Cancer Research
Agmatine is currently under investigation as a possible anticancer compound, but the research is in its very early stages. These results only indicate that further studies should be conducted; future trials may find that agmatine is not effective at all against cancer in a living animal.
Agmatine prevented the growth of connective tissue tumors in mice [44, 45, 46].
Agmatine also prevented the growth of intestinal tumor cells in a lab study by decreasing polyamine production [47].
Again, these very early studies are not grounds to recommend agmatine in cancer; they only suggest that further research on agmatine ought to be done. If you are looking for complementary therapies to improve your odds to beat cancer, talk to your doctor about better-studied additions you can make to your existing treatment plan.
Factors that Increase Agmatine Levels
Note that agmatine levels are not measured in the human body for any medical purpose, and we don’t know if raising or lowering agmatine could be good for our health. Rather than focusing on agmatine, we recommend keeping an eye on more reliable indicators of health like inflammation, cholesterol, and other markers that your doctor may be tracking.
As always, talk to your doctor before making any significant changes to your diet, exercise, and supplement regimen.
1) Ketogenic Diet
Rats on a ketogenic diet had a significant increase in GABA and agmatine levels compared to rats on a normal diet [48].
2) Cold Thermogenesis (Cold Exposure)
Agmatine levels increased in all regions of the rat brain (except the cerebellum) after exposure to cold stress for 4 hours at 39.2°F (4°C), but not after exposure to room temperature [49].
3) Agmatine Sulfate Supplementation
Agmatine is available as an oral supplement in powder form known as agmatine sulfate, which is effective at increasing agmatine levels in the body [17].
Direct supplementation with agmatine sulfate is the only means of increasing agmatine that has been studied in humans. It is currently unclear what the long-term effects of agmatine supplementation might be on the human body; we recommend talking to your doctor about better-studied strategies for health.
Drug and Supplement Interactions
1) Arginine
Arginine increases nNOS and eNOS. It increased nitric oxide in diabetic rats. Short-term arginine supplementation might not, however, increase nitric oxide in healthy people [50, 51].
Agmatine and arginine both work to increase eNOS (relaxing blood vessels and increasing blood flow); however, the combined effects are not yet clear. Many users anecdotally report increased vasodilation effects when taken together. However, agmatine and arginine also work in opposition as agmatine decreases nNOS and arginine increases nNOS. By inhibiting agmatine’s reduction of nNOS, arginine inhibited its beneficial neurological effects such as nerve regeneration and prevention of opioid tolerance [52, 53, 54].
2) Citrulline
Little is known about the combined effects of citrulline and agmatine. However, a large proportion of citrulline is converted to arginine in the body, resulting in increased arginine levels. Therefore, citrulline may interact with agmatine in a similar manner to arginine [52, 53, 54].
3) Yohimbine
Agmatine activates the α2A receptor and yohimbine blocks it. This could negate any of the beneficial effects of agmatine associated with α2A receptor activation, including reduced pain and increased appetite [9, 55].
4) Alcohol
Agmatine should not be taken together with alcohol, due to an increased risk of developing ulcers [56].
Other Interactions
1) Lithium
Agmatine and lithium interact synergistically with NMDA receptors to produce enhanced antidepressant effects. Agmatine enhanced the antidepressant effect of lithium in mice; this effect has not been studied in humans [57].
2) Opiates (e.g. Morphine)
Agmatine enhanced the pain-relieving effect of morphine and reduced morphine dependence and withdrawal in rats and flatworms. Agmatine may allow for lower doses of addictive substances in the treatment of pain management. However, this has not been confirmed in human studies [58, 59].
3) Cannabinoid Receptor Activators
Agmatine enhanced the pain-relieving effects of cannabinoid receptor activators in decreasing sensitivity to pain from heat in rats. Although the mechanism is not clear, agmatine appears to indirectly influence cannabinoid receptor type 1 (CB1); additional studies will be required [60].
Supplementing With Agmatine
Dosage
There is currently no standard dosage for agmatine sulfate because there haven’t been enough human studies to determine one. However, studies on neuropathic pain provided between 1 g and 2.5 g of agmatine per day.
Side Effects of Agmatine
Minor side effects included nausea, diarrhea, and vomiting in a small percentage of participants, which cleared up after a few days of discontinuing use [17].
Limitations and Caveats
There have been few human studies on the effects of agmatine supplementation. Most research has been conducted in rodents, and these studies should be taken with a large grain of salt. Future clinical trials may very well refute these purported benefits in humans.
Takeaway
Agmatine is a little-studied neurotransmitter derived from arginine. It appears to play a significant role in the nervous system, especially in the nerves that run to and from the gut.
Researchers are currently investigating whether supplementing with agmatine could have health benefits. A few very early clinical studies have found promising results for pain management and mental health, but human studies are very limited, and there are better-studied alternatives for every proposed use of agmatine so far.
