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, 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, 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 form like agmatine sulfate. Agmatine is also produced in small amounts within the body by the mitochondria in the liver .
Mechanisms of Action
Blocks 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.
- Blocks NMDA receptor: Agmatine binds to 2 sites of the NMDA (N-methyl-D-aspartate) receptor and prevents glutamate from binding to them. This prevents neuron death from overexcitation due to the neurotransmitter glutamate .
- 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].
- Blocks nicotinic acetylcholine receptors: Agmatine binds to nicotinic acetylcholine receptors and prevents acetylcholine from binding to it .
- Activates 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].
- Activates 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 .
- Activates 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].
Health Benefits of Agmatine
1) Agmatine Reduces Pain
Furthermore, agmatine reduced neuropathic pain by preventing nitric oxide synthase activation and blocking NMDA receptors in rats .
In 2 studies (dose-escalation study and DB-PCT) of 61 participants with a herniated lumbar disk, agmatine supplementation for 10 days reduced pain and improved quality of life .
2) Agmatine May Help with Depression and Anxiety
Additionally, blocking the NMDA receptor prevents calcium overloading and reverses the decrease of monoamines (such as norepinephrine, epinephrine, and dopamine) in rats. Depression may be associated with a decrease of monoamines in the brain [23, 24].
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 .
Agmatine also reduced anxiety in rats during swimming tests and navigating mazes .
3) Agmatine May Promote 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 .
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 [28, 29].
4) Agmatine May Protect the Brain from Damage Due to 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 reduced blood flow to the brain (ischemic stroke). Additionally, agmatine decreased iNOS and nNOS, 2 enzymes that contribute to brain damage from stroke .
5) Agmatine May Improve Recording of Spatial Memory
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 [31, 32, 33].
Agmatine improved spatial memory consolidation, or the initial recording and storing of a memory, but had no effect on the retrieval of memories in rats .
Agmatine increased adenylate cyclase activity in the prefrontal cortex of rats, a molecule associated with memory formation .
6) Agmatine May Suppress Tumor Growth
Agmatine also prevented the growth of intestinal tumor cells in a lab study by decreasing polyamine production .
7) Agmatine May Improve Weight Loss and Prevent Weight Gain
Agmatine reduced weight gain in rats .
Agmatine increased fat burning, decreased fat composition, and increased muscle mass in rats .
8) Agmatine May Improve Insulin Sensitivity and Reduce Blood Sugar
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 [42, 12, 29].
9) Agmatine May Help with 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 [28, 43].
10) Agmatine May Protect Against Hardening of the Arteries
11) Agmatine May Increase 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 .
12) Agmatine Protects Against Seizures
13) Agmatine May Protect Against 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 .
14) Agmatine May Reduce Inflammation
Agmatine reduced inflammation by suppressing the expression of iNOS after inflammatory stimulation in rats .
In rats, agmatine prevented decreased blood pressure and kidney function associated with septic shock due to its anti-inflammatory effects .
15) Agmatine May Help with Alcohol and Morphine Withdrawal
Ways to Increase Agmatine Levels
2) Cold Thermogenesis (Cold Exposure)
Agmatine levels increased in all regions of the 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 .
3) Agmatine Sulfate Supplementation
Agmatine is widely available as an oral supplement in powder form known as agmatine sulfate, which is effective at increasing agmatine levels in the body.
Drug and Supplement Interactions
1) Arginine May Reduce the Effectiveness of Agmatine
Arginine increases nNOS and eNOS. Agmatine and arginine both work to increase eNOS (relaxing blood vessels and increasing blood flow); however, the combined effects are not yet clear. Many user reports 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 inhibits its beneficial neurological effects such as nerve regeneration and prevention of opioid tolerance [52, 53, 54].
2) Citrulline May Reduce the Effectiveness of Agmatine
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, it is likely to expect increased blood vessel relaxation and blood flow, while inhibiting the beneficial effects of reduced nNOS in the brain similar to arginine supplementation [52, 53, 54].
3) Yohimbine Blocks Some of the Effects of Agmatine
Agmatine activates the α2A receptor and yohimbine blocks it. This negates the beneficial effects of agmatine associated with α2A receptor activation, including reduced pain and increased appetite [9, 55].
4) Alcohol Taken with Agmatine Increases Ulcer Risk
Agmatine should not be taken together with alcohol, due to an increased risk of developing ulcers .
Agmatine in Combination with Other Compounds/Drugs
1) Agmatine Enhances the Antidepressant Effects of Lithium
Agmatine and lithium interact synergistically with NMDA receptors to produce enhanced antidepressant effects. Agmatine enhanced the antidepressant effect of lithium in mice .
2) Agmatine Enhances the Pain-Relieving Effects of 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 [58, 59].
3) Agmatine Enhances the Pain-Relieving Effects of 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) .
Supplementing With Agmatine
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)
- To improve cognitive function: 200 to 500 mg of agmatine (daily)
- Fo vasodilation and enhanced recovery: 500 to 1,000 mg of agmatine (30 minutes pre-workout)
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 .
Limitations and Caveats
There have been few human studies on the effects of agmatine supplementation. Most research has been conducted in rodents, so caution should be used in applying this research to use in humans.
Users report several benefits of agmatine sulfate, including improved athletic performance, mood, sleep, and pain management. However, some users have also noted a potential side effect of mild headaches.
When taken before sleep, many users report improved sleep quality.
Many users also report that agmatine increases sensitivity to cannabis.