Agmatine as a Low Toxicity Neuromodulator and Neuroprotector
Agmatine is derived naturally in the body from L-arginine, but it can also be taken in supplement form to treat an array of neurological and mental health issues.Arginine is typically produced in the small intestines and kidneys. Reduced function in either of these organs can result in a deficiency of arginine as can physiological stress due to injury, infection, or severe burns.
Agmatine is an arginine-derived substance that acts as a neuromodulator and neuroprotector in the body. Agmatine is found naturally in the human body, but it can also be taken orally as a supplement. The enzyme arginine decarboxylase in the human body produces this polyamine which modulates several receptors in the human brain.
Agmatine is an aminoguanidine compound that’s found in bacteria, plants, invertebrate animals, and mammals. It is an endogenous polyamine that is derived from L-arginine. It is produced in the body via the enzyme arginine decarboxylase. For this reason, agmatine is sometimes referred to as decarboxylated arginine.
Agmatine is an intermediary in the production of polyamines in the body, a pathway that is also related to the production of important neurotransmitters including glutamate and GABA. As such, agmatine has an impact on the glutamatergic system in the brain and body. It is widely distributed throughout, but the highest concentration is found in the stomach, followed by the aorta, and then the small intestine. The smallest levels are found in the spleen, adrenal glands, skeletal muscle, and brain. Large quantities of agmatine can also be found in the blood.
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In the brain, agmatine is found in higher quantities in the neurons of the rostral brainstem and forebrain. Indeed, this substance is found in the cytoplasm of neurons in areas such as the neocortex; a critical region in the adaptive response to stress. Agmatinergic cell groups project into the cortex from the thalamus, the hypothalamus, and the diffuse projection systems.Natural Brain Anti-inflammatory
Agmatinase, an enzyme associated with agmatine, is found throughout the brain. It is found in the highest quantities in the hypothalamus, the medulla oblongata, and the hippocampus. The lowest amount of agmatinase was found in the striatum and the cerebral cortex. Like arginine decarboxylase, agmatinase is found primarily in the mitochondria of cells. Both arginine decarboxylase and agmatinase have been found in astrocytes.Many scientists today are studying agmatine because of its extremely low toxicity and its ability to reduce symptoms of dementia, brain injury, stroke, learning and memory problems, mental health issues such as PTSD, depression, and anxiety, and more. Agmatine is able to reduce brain inflammation naturally and improve neuron growth and creation following injury to the brain, infection, or mental health issues that alter the synaptic connections in the brain.
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Agmatine as a Neuromodulator and Neuroprotector
Agmatine is a neuromodulator that promotes balance in the GABA / glutamate system. Agmatine is recognized as a neuromodulator for the following reasons:- The concentration of agmatine in the brain is comparable to that of the neurotransmitters.
- Agmatine is taken up by presynaptic axon terminals. It is stored in synaptic vesicles and it is released upon membrane depolarization.
- Agmatinase activates agmatine, converting it into putrescine.
- Agmatine has been co-localized with other neurotransmitters, especially glutamate in the nerve cells and synapses.
- Agmatine activates certain post-synaptic membrane receptors, especially the nicotinic receptors, the alpha2-adrenergic receptors, serotonin 5HT2A and 5HT3 receptors as well as the imidazoline I1 and I2 receptors.
- Agmatine inhibits cell membrane calcium channels, all brain isoforms of nitric oxide synthase, and NMDA receptors.
Studies indicate that agmatine provides neuroprotection and neuromodulation in the event of any of the following:
- Stroke / brain ischemia
- Hypoxia (lack of oxygen) to the brain
- Spinal cord injury
- Traumatic Brain Injury (TBI)
- Drug Addiction
- Brain damage due to morphine
- Brain damage due to scopolamine
- MPTP-mediated toxicity
- Glutamate neurotoxicity
- Epilepsy / Seizures
- Dementia
- Parkinson’s disease
- Alzheimer’s disease
- NMDA-induced neurotoxicity
- Glucocorticoid neurotoxicity
- Depression
- Anxiety
- Psychosis
- Schizophrenia
- Rotenone-mediated neurotoxicity
- Neuropathy / Neuropathic Pain
- Beta-amyloid plaque build-up (which can occur due to certain types of dementia)
- Brain damage due to streptozotocin
- Brain damage due to bacterial lipopolysaccharide
Some forms of agmatine have also been studied in regard to its ability to prevent herpes infection and also treat herpes infection naturally. This fact might be obscured by anecdotal reports that agmatine can cause a herpes outbreak. Herpes outbreaks don’t occur in everyone who takes agmatine and in fact, agmatine may, over the course of time, be able to get rid of the herpes virus naturally. However, taking lysine at a dose equivalent to the agmatine dose may help prevent outbreaks.
Additionally, agmatine has demonstrated anti-convulsive / anti-seizure effects as well as pain-relieving effects. Below are the neuroprotective effects of agmatine that have been studied to date:
- Prevents seizures
- Pain relief
- Neuropathy relief
- Reduces inflammation
- Prevents cell death
- Antioxidant
- Inhibits gliosis
- Inhibits edema
- Promotes nerve cell growth
- Prevents herpes virus infection
- Helps release trauma and can be used as a natural cure for complex PTSD and regular PTSD
Several independent research groups have investigated the neuroprotective properties of agmatine. Neuroprotection can occur in a variety of diseases or disorders using agmatine. This nutritional supplement reduces edema and inflammation in the brain as well as neurotoxicity.
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Agmatine Dosage
When administered orally, agmatine is absorbed through the gastrointestinal tract and then it is distributed throughout the body. It is able to cross the blood-brain barrier. The agmatine half-life is about 2 hours. Excess agmatine that is not used is excreted by the kidneys.Agmatine is considered to be a low toxicity compound that can be administered in doses from 250 mg to 2.6 to 3.5 grams per day in adults. It has not been studied for its effects during pregnancy or breastfeeding. It does not cause side effects. Note, however, that in low doses, agmatine can suppress unpleasant fear-based memories, but in higher doses it provides access to these memories. This can be an important consideration because some people with a traumatic past may experience anger or irritability when first beginning therapy with agmatine at higher doses. Most studies start by giving patients low doses and slowly increasing the dose over the course of a few weeks. Scientists typically provided study participants with divided doses (morning and night).
The child dose for agmatine would depend on the child's weight and should be administered at 1.6 to 6.4 mg per kg of the child's weight. Start with a low dose initial and raise the dose slowly over the course of a few weeks. Divide the total dose in half and give it to the child twice daily in the morning and at night.
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Resources:
• Rafi, H. et al. (2021). Inhibition of NMDA receptors by agmatine is followed by GABA/glutamate balance in benzodiazepine withdrawal syndrome. Retrieved September 30, 2023 from https://bjbas.springeropen.com/articles/10.1186/s43088-021-00125-8
• Rawls, S. M. et al. (2008). Agmatine: identification and inhibition of methamphetamine, kappa opioid, and cannabinoid withdrawal in planarians. Retrieved September 30, 2023 from https://pubmed.ncbi.nlm.nih.gov/18792993/
• Benjamin, E. et al. (2022). Physiology, NMDA Receptor. Retrieved September 30, 2023 from https://www.ncbi.nlm.nih.gov/books/NBK519495/
• Freitas, A. E. et al. (2016). Agmatine, a potential novel therapeutic strategy for depression. Retrieved September 30, 2023 from https://pubmed.ncbi.nlm.nih.gov/27836390/
• Aricioglu, F. (2016). PS252. Effect of agmatine on behavioral changes over time in post-traumatic stress disorder. Retrieved September 30, 2023 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5616847/
• Gilad, G. M. and Gilad, V. H. (2014). Long-term (5 years), high daily dosage of dietary agmatine – evidence of safety: a case report. Retrieved September 30, 2023 from https://pubmed.ncbi.nlm.nih.gov/25247837/
• Moretti, M. et al. (2014). Role of agmatine in neurodegenerative diseases and epilepsy. Retrieved September 30, 2023 from https://pubmed.ncbi.nlm.nih.gov/24896210/
• Donalisio, M. et al. (2016). The AGMA1 poly(amidoamine) inhibits the infectivity of herpes simplex virus in cell lines, in human cervicovaginal histocultures, and in vaginally infected mice. Retrieved September 30, 2023 from https://pubmed.ncbi.nlm.nih.gov/26854390/
