There are many people taking opioids such as codeine, fentanyl, hydrocodone / Norco / Vicodin, and oxycodone / OxyCotin for various types of chronic pain around the world and especially in the U.S. Even though these medications were never intended to used long-term, many people have become addicted to them due to their tolerance and withdrawal effects.

In this article, I am not arguing that people should stop taking opioids. However, what if there was a simple supplement that they could take along with the opioids that would not only increase the potency of the opioids, but also reduce the tolerance and withdrawal effects so that they could get off of them more easily when they want / need to?

Agmatine is a supplement that has been shown to do this. I’ll go over the research in this article examining the evidence, and I’ll give specific instructions on how to take agmatine.

Disclaimer: Nothing in this article is intended as medical advice. Do not stop taking medications without your doctor’s approval. This website is for informational purposes only.

What is Agmatine?

Agmatine is a naturally occurring polyamine formed in our body by breaking down the amino acid arginine. Agmatine behaves very differently than arginine in the body, and it influences multiple molecular targets such as nitric oxide, NMDA receptors, and imidazoline receptors. It has been subject to heavy research and has found to be beneficial, with both animal and human studies, for depression, anxiety, neuropathic pain, cognitive decline and learning impairment, dependence on drugs, and metabolic diseases (diabetes and obesity). (1)

In this article, I’m going to focus on the ability of agmatine to help improve the effectiveness of opiate-based medication as well as help to reduce the tolerance, addiction, and withdrawal effects of the drugs.

Considering the prevalence of opioid addiction now, much of the time beginning with a real need for the medication, knowing strategies that can help reduce the addictiveness, the tolerance, and the withdrawal effects can be very beneficial to many people around the world. If you know someone who may benefit from this article, please share it with them!

How Agmatine Affects Opioid Tolerance and Withdrawal

Agmatine has been extensively studied in its ability to reduce the tolerance and addictive effects of opioids. It has been shown to reduce the adaptations that come from chronic morphine use in the brain, including the increased glutamate release (which is damaging the neurons in high amounts) (2, 3), the decreased neurogenesis in the hippocampus (4), and the disrupted dopamine pattern via tyrosine hydroxylase (5).

What this means is that agmatine has the potential to inhibit the brain and nervous system adaptations that come from prolonged opioid use.(6) These adaptations are what cause the tolerance effects as well as many side effects. These effects on the brain also are responsible for the sometimes terrible withdrawal symptoms when trying to stop the medication.

Withdrawal behaviors after stopping morphine (M) in rats with or without agmatine (Agm)(5)

Be Careful with Adding Agmatine to an Opioid

While agmatine can help the person from becoming addicted to and getting a withdrawal from opioids, it also increases the effect of opioids. (7, 8)

You can see from the graph below that agmatine can have quite a potentiating effect on pain-reduction from morphine in mice. Also, the more agmatine they were given, the stronger the effect.

Agmatine potentiates morphine analgesia (pain-reduction) (9)

This is important to keep in mind, otherwise you might end up getting a much stronger effect than you anticipated.

Because of this, in addition to getting the okay from your primary care physician, you should cut the dose of the opioid by about half the first few times you take it with agmatine until you know how it affects you.

How to Take Agmatine

Agmatine has been shown to be very safe with minimal side effects. The most common side effect is diarrhea with a large dose.

Agmatine can be taken daily, and this will likely be more effective to wean off of opioids than only taking it with the opioid. A usual dose schedule is something around 500 mg three times a day. If you want to take a larger dose 15-20 min before taking your opioid, you can do that too.

The total dose varies, but the usual dose is 700 mg to 2,000 mg a day in split servings. Taking it with food can help to reduce the chance of diarrhea.

Agmatine can also have beneficial effects on depression and anxiety (which I will be covering in a future article), so you might want to monitor for mood changes.

Below is what I would recommend as a good combination of price and purity. The first one is a pill, and the second one is in powder form that is cheaper for what you get. Agmatine does have a slightly bitter taste, so keep that in mind if choosing powder.

Note: By using these links to make any purchase, you will be supporting the future of this website at NO extra cost to you, as I am an Amazon affiliate. Thank you for your support!

Please post any comments or questions below!

  1. Akasaka, N., & Fujiwara, S. (2019). The therapeutic and nutraceutical potential of agmatine, and its enhanced production using Aspergillus oryzae. Amino Acids.
  2. Wang XF, Zhao TY, Su RB, Wu N, Li J. Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats. Neurosci Bull. 2016;32(6):523–530. doi:10.1007/s12264-016-0031-z
  3. Wang, X.-F., Wu, N., Su, R.-B., Lu, X.-Q., Liu, Y., & Li, J. (2011). Agmatine modulates neuroadaptations of glutamate transmission in the nucleus accumbens of repeated morphine-treated rats. European Journal of Pharmacology, 650(1), 200–205.
  4. Liu, Y., Lu, G.-Y., Chen, W.-Q., Li, Y.-F., Wu, N., & Li, J. (2018). Agmatine inhibits chronic morphine exposure-induced impairment of hippocampal neural progenitor proliferation in adult rats. European Journal of Pharmacology, 818, 50–56.
  5. Aricioglu F, Means A, Regunathan S. Effect of agmatine on the development of morphine dependence in rats: potential role of cAMP system. Eur J Pharmacol. 2004;504(3):191–197. doi:10.1016/j.ejphar.2004.10.011
  6. Regunathan, S. (2006). Agmatine: Biological role and therapeutic potentials in morphine analgesia and dependence. The AAPS Journal, 8(3), E479–E484.
  7. Bhalla, S., Ali, I., Lee, H., Andurkar, S. V., & Gulati, A. (2013). Potentiation of oxycodone antinociception in mice by agmatine and BMS182874 via an imidazoline I2 receptor-mediated mechanism. Pharmacology Biochemistry and Behavior, 103(3), 550–560.
  8. Yesilyurt, O. (2001). Agmatine Potentiates the Analgesic Effect of Morphine by an α2-Adrenoceptor-Mediated Mechanism in Mice. Neuropsychopharmacology, 25(1), 98–103.
  9. Yesilyurt, O. (2001). Agmatine Potentiates the Analgesic Effect of Morphine by an α2-Adrenoceptor-Mediated Mechanism in Mice. Neuropsychopharmacology, 25(1), 98–103.


Doug · February 25, 2022 at 5:37 pm

I have been taking hydrocodone 5-325 3x day for a few years now. I have severe back and foot pain from injuries,surgeries and arthritis. I read that agmatine could really help the strength of the hydrocodone. I purchased the 1,000 mg you have posted from Amazon. I have no idea how much to take with each hydro. Any help would be greatly appreciated.

    Khoi · March 23, 2022 at 10:29 am

    Take one gram or two capsules at first and that’ll increase the hydro effects by a factor of 2.
    I take 4 grams with all my kratom n opioid doses and it can be twice as strong as if I didn’t take agamatine. Or you can do that and cut your opioid dose in half to reduce tolerance but still have a great effect

    Warning though. When I take agamatine to much I get crazy diarrhea….the type that burns your bootyhole. Lol

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