Agmatine: Neuropathic pain and mood

Key takeaways:
~Agmatine is a compound created in the body that acts within neurons.
~ Studies show that it may be helpful for neuropathic pain, depression, and brain function.
~ Clinical trials in humans are few, though, which is something to consider when looking at the benefits of a supplement.

What is Agmatine?

Agmatine is produced in the body from the essential amino acid L-arginine. It is found in plants, bacteria, and animals. In humans, agmatine is produced throughout the body, acting as a neurotransmitter and neuromodulator.

The amino acid L-arginine is converted to agmatine, an amine, using the enzyme agmatine decarboxylase.

In the brain, agmatine has neuroprotective effects by protecting against excitotoxicity. Some research points to it blocking the NMDA receptors and also inhibiting nitric oxide production in the brain. Protecting the brain against excess excitation may be beneficial in dementia, depression, and schizophrenia.[ref]

Research Studies and Benefits of Agmatine:

Agmatine as a supplement is being used for treating neuropathic pain, such as peripheral neuropathy or small fiber neuropathy. It has been studied for the relief of sciatica (radiating lower back pain).

It also has research for depression, and some use it as a nootropic for focus and cognitive function.

Animal studies also show that it may help with addiction, such as decreasing alcohol withdrawal symptoms.[ref] It also has anti-anxiety properties in animals.[ref]

Let’s dive into what the research shows for agmatine:

Mechanism of Action for Depression:

Animal studies show that agmatine may act similarly to ketamine, which is a known rapid-onset antidepressant.

There are a couple of ways that agmatine may be working here:

• In animal trials, agmatine has been shown to produce fast antidepressant-like effects by stimulating the mTORC1 signaling pathway. This pathway is also implicated in the antidepressant-like effects of ketamine.
• Recent evidence suggests agmatine may act as an antidepressant by modulating the NLRP3 inflammasome and impacting the gut microbiota. For some people, depression is caused by elevated inflammatory cytokines, so it makes sense that stopping inflammation via NLRP3 would have antidepressant effects. [ref]

In humans, a pilot study in patients with major depressive disorder showed that agmatine caused total remission in all of them. The trial participants used 2-3mg/day of agmatine.[ref]

Related article: Depression and Inflammation

In adult major depressive disorder patients, researchers found that agmatine levels were higher than in an age- and sex-matched control group.[ref]

One more mechanism of action for agmatine in depression may be its acting on imidazoline receptors. Agmatine activates the imidazoline 2 receptor, which causes the release of beta-endorphins.[ref][ref]

A recent animal study investigated how statins produce an antidepressant effect in mice. The researchers found that agmatine augmented the antidepressant effect, possibly through interaction with the imidazoline receptors.[ref]

Lithium interaction: An animal study showed that agmatine enhances the antidepressant effects of lithium.[ref] While just an animal study, this is something to keep in mind if taking lithium orotate, perhaps resulting in needing a lower dose.

Related article: Lithium orotate and mood

Agmatine for Small Fiber Neuropathy:

Small fiber neuropathy is a painful condition affecting the somatic nerve fibers, which are pain and temperature sensitive, as well as small autonomic nerve fibers that regulate heart rate and sweating.

A clinical trial of small fiber neuropathy patients found that agmatine sulfate after two months decreased pain scores by an average of 46%. The participants took 2.67g/day, divided into two or three doses.[ref]

Important to note in the small fiber neuropathy trial is that the beneficial effects took 4 to 6 weeks. The decrease in pain scores ranged from 17% – 97%, indicating that agmatine may be more effective for some people than for others.

Relate article: Small Fiber Neuropathy Genes

Several animal studies also show that agmatine may help with persistent neuropathic pain. Agmatine reduced TNF-alpha and IL-1B in mice with partial sciatic nerve ligation. It also has been studied for its effect on diabetic neuropathy pain in animals.[ref][ref][ref]

Lower back pain (sciatica) reduced by agmatine:

Sciatica is radiating pain from a pinched nerve in the lower back, often caused by herniated lumbar discs.

A placebo-controlled clinical trial found that agmatine sulfate reduced pain (somewhat) and increased quality of life scores significantly compared to placebo.[ref]

The trial tested different doses, ranging from 1.3mg to 3.5 mg/day for 10 days. A follow-up study used 2.67g/day for 14 days. No treatment-related adverse events.

Of note here is the short duration of the clinical trial. The small fiber neuropathy trial (above) results mentioned that more benefits were seen after 4-6 weeks.

Related article: Genes related to back pain

Anti-seizure properties:

Animal studies show that agmatine decreases seizures and blocks neuronal damage. Importantly, agmatine decreased inflammatory molecules such as TLR4, MYD88, NF-kB, and NLRP3 in the brain.[ref]

Mitochondrial and endothelial dysfunction:

A cell study showed a unique property of agmatine. The study used palmitate, a fatty acid, to induce endothelial dysfunction. The endothelium is the lining of the blood vessels, and endothelial dysfunction is linked to heart disease and possibly long Covid.[ref] The study found that agmatine diminished mitochondrial dysfunction in endothelial cells. This was shown through increased ATP and decreased mitochondrial ROS production.[ref]

Other studies elucidate how agmatine is transported into the mitochondria and protects against apoptosis.[ref][ref][ref]

An animal study found that agmatine reduced macrophage content in atherosclerotic plaque and prevented fatty liver in mice fed a high-fat diet.[ref]

Related article: Long Spike

Addiction:

Animal studies show that agmatine reduces addiction-like behavior. A 2023 study showed that agmatine reduced alcohol drinking in alcoholic mice. It did not reduce sugar-water drinking, though.[ref]

Agmatine also helps in animal studies with opioid addiction through a combination of action on the imidazoline (I1, I2) receptors and the α₂-adrenergic receptors.[ref]

Note for clarity: I’ve included this section to point out the mechanism of action rather than to suggest that someone with an addiction should just use agmatine. There are much more thoroughly researched options for addiction that your doctor can help you with.

Related article: Alcohol Use Disorder and Genetics

Risks and Side Effects:

Please talk with your doctor if you have questions about whether a supplement is right for you. Talk to your doctor or pharmacist about interactions with medications.

In a clinical trial using up to 3.5g/day agmatine sulfate in adults with back pain, three of the participant (out of 51) reported mild-to-moderate diarrhea and mild nausea. [ref]

A case report examined the long-term use of agmatine. The two people in the report took 2.67g/day of agmatine, split between morning and evening doses, for five years. The individuals had clinical lab tests and periodic physical exams, with no adverse effects.[ref] While nice to see a long-term study, do keep in mind that it was only two people.

Of note, people on forums such as Reddit mention that anger or irritability is a side effect for some people.

Agmatine Supplements: Doses, Absorption, and Types

Agmatine often is found as a supplement in a salt form, called agmatine sulfate. It is readily absorbed in the gastrointestinal tract and rapidly distributed through the body. Agmatine does cross the blood-brain barrier.[ref]

Agmatine supplements have a half-life of about 2 hours, and excess agmatine is excreted by the kidneys.[ref]

The clinical trials mentioned above used between 1 and 3 g/day of agmatine.

Importantly, most of the trials used a lower dose to start with and increased it over a few weeks.

Also important to note is that the trials split the doses in two, morning and night.

Food sources of agmatine:

While agmatine is found in tiny amounts in many foods, alfalfa microgreens contain ~5g/kg.[ref]

Conclusion:

Agmatine is not all that well known as a supplement, but research studies do show a lot of potential.

I would love to see larger clinical trials on agmatine for neuropathy and pain, especially studies that look into the genetic connections for who would be more likely to benefit.  The current options for small fiber neuropathy are limited, and a natural option for sciatic pain would benefit many.

Agmatine, being a naturally occurring molecule, cannot be patented and therefore lacks the potential to generate billions for pharmaceutical companies. Realistically, there is little motivation for conducting extensive clinical trials on a large scale.