Golden Thinker ® – Encyclopedia of Substances – Palmitoylethanolamide

What is Palmitoylethanolamide?

Palmitoylethanolamide, usually shortened to PEA, is an endogenous fatty acid amide which is naturally produced in the body. Fatty acid amides are a family of molecules which have key role in regulating a number of biological functions. Small amounts of PEA can also be found in some foods, including egg yolk, peanuts, soybeans and alfalfa.

In particular, PEA can bind to endocannabinoid receptors and the peroxisome proliferator-activated receptor alpha (PPAR-α). PEA is not considered a classical cannabinoid since it cannot bind to the endocannabinoid receptors CB1 and CB2. However, it’s thought that the molecule can modulate the binding of other cannabinoids to these receptors through the ‘entourage’ effect.

Since it’s discovery in the 1950’s, PEA has been subjected to a reasonable amount of research. Neuroscientists have become particularly curious about this molecule due to its apparently beneficial effects in treating neuropathic pain.

PEA has now been shown to have robust anti-inflammatory effects. The molecule also appears to support immune system function. More recently, PEA and endocannabinoids have been shown to be directly involved in some forms of neuronal communication.

PEA supplements have become widely used for the treatment of a variety of conditions. This includes neuropathic pain, chronic pain, multiple sclerosis and fibromyalgia. More research is required to fully understanding the mechanisms underpinning these beneficial effects. However, there are a number of studies which suggest PEA could provide some powerful benefits to brain function and health.

Brain Benefits and Mode of Action
Pain Relief

A wealth amount of research now supports the benefits of PEA in the treatment of complex pain. This research now encompasses over 6 clinical trials, along with biochemical and animal studies. While most of this research has focussed on ‘pain’ in general, there is some indication that PEA can produce specific benefits to neuropathic pain.

Neuropathic pain is difficult to treat and arises from damage to nerve cells or nervous system malfunction. This type of pain is often chronic and severe, without any physical stimulus inducing the sensation.

A total of 12 human studies have shown that PEA supplementation reduced neuropathic pain intensity over the course of 3-8 weeks. None of the researchers conducting these studies found any adverse effects of PEA supplementation. In fact, it appears that the longer the period of supplementation, the stronger the pain reducing effects of PEA were.

A study looking at pain caused by the sciatic nerve have echoed these findings. In this study, researchers found that sciatic nerve pain was reduced by up to 50% after just 3 weeks of PEA supplementation. More generalised studies of pain have also shown that the supplement can be so effective in treating lower back pain, that many participants are able to cease taking painkillers before the end of the clinical trials.

The effects of PEA on pain appear to be wide ranging. The supplement can reduce pain in a diverse range of health conditions. These include:

  • Endometriosis-related pain in the pelvic region
  • Cancer pain
  • Arthritic pain
  • Pain and tenderness experienced in fibromyalgia

Mode of action: Animal studies have been able to shed some light on the underlying mechanism of PEA’s pain reducing abilities.

Numerous studies using rodent models of injury and illness have highlighted that PEA supplementation can reduce inflammation in a variety of conditions. These models include spinal cord injury, arthritis and lung-related diseases. Biochemical studies have demonstrated that PEA can directly interact with the main inflammatory immune molecules of the body, known as cytokines. PEA reduces the expression of pro-inflammatory genes and reduces the production of excess inflammatory molecules via its interaction with the PPA-α receptor. This finding has sparked interest in whether PEA may be an effective treatment for autoimmune conditions. In fact, some neuroscientists have shown that PEA may be an effective add-on supplement for the treatment of multiple sclerosis.


PEA’s potent anti-inflammatory effect may means that it confers a lot of neuroprotective benefits. Preliminary studies have shown that PEA may provide some level of neuroprotection in conditions such as neurodegenerative diseases and stroke. A small study of stroke patients showed that PEA improved overall recovery. More specifically, PEA had beneficial effects on cognition, brain health and pain.

Animal models suggest that PEA may be able to protect dopamine neurons. In a mouse model of Parkinson’s disease, PEA supplementation was shown to reduce overall neuronal damage and protect dopamine neurons. The biological hallmark of Parkinson’s disease is the loss and destruction of dopamine neurons. Neuroscientist have speculated that PEA may offer protective benefits against such neurodegenerative conditions.

Mode of action: PEA has been shown to increase levels of neurotrophic growth factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). This family of growth factors have well characterised roles in neuronal survival, regeneration, plasticity and protection. Hence, the increase in these molecules induce by PEA may be one of the underlying mechanisms of the supplement’s neuroprotective effects.

Mood Support

One recent study has demonstration that daily supplementation with 1.2mg of PEA over a 6-week period rapidly improved mood and symptoms of patients with depression. In combination with other depression medication, PEA helped to lower symptoms by 50% in a short period of time; these results are far more effective that classical treatments for depression. Animal models of depression have also mirrored these mood-boosting effects as a result of PEA supplementation.

Mode of action: The underlying mechanisms for these mood-boosting effects are likely two-fold. Depression is now well known to be linked with an increase in inflammatory and immune-related markers. In fact, some neuroscientists even suggest depression may be cause by immune system dysfunction and excessive inflammation. PEA’s incredible anti-inflammatory abilities may, in part, contribute to overall feelings of well being and improvements in mood.

PEA can also interact with and indirectly activate the endocannabinoid system. An increasing body of research now shows that the optimal function of the endocannabinoid system is important for immune system health, mood, memory and brain development. PEA’s activation of this system may be one of the contributing factors to improved mood.

How to Use

PEA is orally bioavailable, meaning that the supplement can be taken in either capsule or powder form. PEA appears to be safe to take for most people. Multiple clinical trials have reported no adverse effects of the supplement, even at the high doses (1,200mg/day).

Stacks well with curcumin for enhanced immune-boosting and anti-inflammatory effects. PEA also combines well with Chaga mushroom to refine cognitive function and overall brain health.

Recommended Dose: 300 – 1,200mg per day

We recommended a dose of between 300-1,200mg per day. Most clinical studies have used higher doses to treat chronic pain specifically. If you’re just looking to boost mood and improve immune system function, it’s likely that you’ll benefit for lower doses between 300-600mg per day.

Many people find it beneficial to begin at lower doses.

As with any supplement, if you have any underlying health conditions, it’s wise to consult your doctor before starting any new supplement regime. Due to a lack of clinical data, we would advise caution in taking this supplement for women who are pregnant or breast-feeding.

Classification: Protection, Mood

We’ve classified PEA as a major neuroprotectant, due to the molecule’s potent anti-inflammatory and immune system supporting properties. We’ve also classified PEA as a mood booster due to findings which suggest the supplement can improve mood and feelings of well-being in patients with depression.

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  2. Crupi, R., Impellizzeri, D., Bruschetta, G., Cordaro, M., Paterniti, I., Siracusa, R., Cuzzocrea, S., & Esposito, E. (2016). Co-Ultramicronized Palmitoylethanolamide/Luteolin Promotes Neuronal Regeneration after Spinal Cord Injury. Frontiers in pharmacology, 7, 47. https://doi.org/10.3389/fphar.2016.00047
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  4. Gabrielsson, L., Mattsson, S., & Fowler, C. J. (2016). Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. British journal of clinical pharmacology, 82(4), 932–942. https://doi.org/10.1111/bcp.13020
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  7. Keppel Hesselink, J. M., & Kopsky, D. J. (2015). Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome. Journal of pain research, 8, 729–734. https://doi.org/10.2147/JPR.S93106
  8. Orefice, N. S., Alhouayek, M., Carotenuto, A., Montella, S., Barbato, F., Comelli, A., Calignano, A., Muccioli, G. G., & Orefice, G. (2016). Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing-Remitting Multiple Sclerosis. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 13(2), 428–438. https://doi.org/10.1007/s13311-016-0420-z
  9. Maryam Ghazizadeh-Hashemi, Alireza Ghajar, Mohammad-Reza Shalbafan, Fatemeh Ghazizadeh-Hashemi, Mohsen Afarideh, Farzaneh Malekpour, Ali Ghaleiha, Mehrdad Eftekhar Ardebili, Shahin Akhondzadeh, Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial, Journal of Affective Disorders, Volume 232, 2018, Pages 127-133, ISSN 0165-0327, https://doi.org/10.1016/j.jad.2018.02.057.
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