PEA for Fibromyalgia and MCAS Relief

Living with fibromyalgia often means dealing with widespread pain, fatigue, and a host of other symptoms that can make everyday life difficult. While prescription medications like duloxetine, pregabalin, and gabapentin are commonly used, many people continue to experience persistent pain.

One supplement gaining attention for fibromyalgia is palmitoylethanolamide (PEA). Research suggests that PEA may help reduce pain and inflammation, offering a natural, well-tolerated option to complement standard treatments.

In this article, we’ll explore what PEA is, how it works, what the clinical trials show, and how it may fit into a comprehensive fibromyalgia treatment plan. We’ll also look at its role in related conditions, such as mast cell activation syndrome (MCAS).

What Is PEA?

Palmitoylethanolamide (PEA) is a naturally occurring fatty acid amide made by the body in response to stress, inflammation, or pain. It belongs to a group of compounds known as endocannabinoid-like molecules, which help regulate inflammation and nerve signaling.

Unlike CBD, PEA doesn’t act directly on cannabinoid receptors. Instead, it works through other cellular pathways, especially by activating PPAR-α receptors and calming overactive mast cells (Landolfo et al., 2022).

PEA levels tend to decrease in states of chronic inflammation, which are common in conditions like fibromyalgia, ME/CFS, and long-haul COVID. Supplementing with PEA may help restore balance and reduce hypersensitivity to pain signals.

How PEA Works for Pain Relief

Fibromyalgia pain is thought to stem from central sensitization, where the nervous system becomes overly reactive to pain signals. PEA may help calm this overactivity through several mechanisms:

• Reducing mast cell activation, which plays a role in inflammation and nerve irritation

• Activating PPAR-α receptors, which regulate pain and immune responses

• Balancing the endocannabinoid system without psychoactive effects

• Supporting healthy nerve function

By addressing both inflammation and nerve hypersensitivity, PEA targets two key drivers of fibromyalgia pain.

PEA for Mast Cell Activation Syndrome (MCAS)

Many people with fibromyalgia, ME/CFS, and long-haul COVID also struggle with mast cell activation syndrome (MCAS). Mast cells are immune cells that release histamine and other chemicals, driving symptoms like:

• Pain and hypersensitivity

• Flushing, hives, or rashes

• Digestive issues like bloating and nausea

• Fatigue and brain fog

• Orthostatic intolerance

PEA is especially interesting for MCAS because it directly calms mast cells, reducing their activation and inflammatory output (Landolfo et al., 2022).

While research on PEA for MCAS specifically is still emerging, its mast cell-stabilizing effects make it a promising low-risk addition to MCAS protocols. Products combining PEA and luteolin or quercetin may be particularly effective since these have strong antihistamine and antioxidant properties.

What the Research Says About PEA and Fibromyalgia

Several clinical studies have explored PEA’s role in fibromyalgia:

• A randomized-controlled trial found that combining ultra-micronized PEA with acetyl-L-carnitine, duloxetine, and pregabalin significantly reduced pain and fatigue compared to medication alone (Salaffi et al., 2023).

• A large observational study showed that PEA supplementation led to meaningful improvements in pain and quality of life with excellent safety and tolerability (Del Giorno et al., 2015).

• Reviews confirm PEA’s ability to modulate inflammation and nerve signaling, supporting its use for neuroinflammatory conditions like fibromyalgia (Landolfo et al., 2022).

These findings suggest PEA is most effective when used as an adjunct to standard treatments, not as a standalone therapy.

Why Formulation Matters for PEA

PEA is naturally a lipid-based compound with low solubility and poor bioavailability. Standard PEA powders may not dissolve well in the gut, limiting absorption and effectiveness (Landolfo et al., 2022).

To overcome this, researchers developed micronized (m-PEA) and ultra-micronized (um-PEA) forms. These have much smaller particle sizes, which:

• Improve dissolution and absorption

• Provide better bioavailability and more consistent blood levels

• Deliver stronger clinical effects for pain and inflammation

Patented PEA Formulations: Normast and EquiPEA®

Like with all supplements, formulation quality is critical when choosing a PEA supplement. Poorly absorbed powders may deliver little benefit and result in wasted money. Researchers have focused on improving PEA’s bioavailability and clinical effectiveness with patented formulations proven to work.

Normast

One of the best-known patented formulations is Normast, developed in Italy. Normast uses ultra-micronized PEA (um-PEA), which dramatically reduces particle size for better solubility and absorption.

Normast has been tested in multiple clinical trials, including studies in fibromyalgia, neuropathic pain, and other neuroinflammatory conditions. Because it is manufactured to pharmaceutical-grade standards, Normast provides a reliable and consistent form of PEA (Varrassi et al., 2025).

Some versions of Normast also combine PEA with luteolin, a flavonoid with strong antioxidant and mast cell–stabilizing effects. This combination, called co-ultra-micronized PEA-luteolin (PEA-Lut), has shown synergistic benefits for calming neuroinflammation and improving pain signaling.

EquiPEA®: A Next-Generation Formulation

A newer patented formulation, EquiPEA®, combines PEA with Equisetum arvense (horsetail extract). This innovation aims to enhance absorption and bioavailability further, not only by reducing particle size but also by improving how PEA crosses the intestinal barrier (Varrassi et al., 2025).

Early research suggests that EquiPEA® may:

• Increase PEA uptake compared to standard ultra-micronized PEA

• Provide stronger anti-inflammatory and analgesic effects in neuropathic pain models

While more research is needed, EquiPEA® represents a promising step forward in the evolution of PEA supplements. It highlights the importance of formulation science when selecting a product, especially for individuals with complex conditions like fibromyalgia and MCAS.

How to Take PEA for Fibromyalgia or MCAS

Most clinical studies use 300–600 mg of PEA twice daily, though dosing may vary based on the specific product.

Tips for taking PEA:

• Start at a lower dose to check tolerance, especially if you are sensitive to supplements.

• Always take with food.

• Take consistently for at least 4–8 weeks, as benefits may take time to appear.

• Use PEA alongside—not in place of—your prescribed medications.

• Choose products that are third-party tested to ensure purity and potency. (The FullScript store shows you which products have been third-party tested.)

As with any supplement, it’s best to discuss PEA with your healthcare provider, particularly if you take other medications. Side effects of PEA are rare but may include occasional digestive upset.

PEA as a Supportive Option for Fibromyalgia & MCAS

Fibromyalgia is a complex condition that often requires a multifaceted approach. Medications, physical therapy, lifestyle strategies, and supplements can all play a role. MCAS is often difficult to manage, and few medications are effective in management.

PEA offers a natural, well-tolerated option for supporting pain relief and stabilizing mast cells. While it’s not curative, research shows it may help improve daily functioning and quality of life, especially when combined with other standard treatments.

Key Takeaways

• PEA is a natural compound that calms inflammation, stabilizes mast cells, and reduces nerve hypersensitivity.

• Clinical studies show PEA can improve fibromyalgia pain and fatigue, especially when combined with standard medications.

• Look for micronized or ultra-micronized formulations for the best absorption.

• PEA may also benefit people with MCAS, particularly in combination with luteolin or quercetin.

• It is considered safe and well-tolerated, with minimal side effects.

Have you tried it? Let us know in the comments.

References

Landolfo E, Cutuli D, Petrosini L, Caltagirone C. Effects of Palmitoylethanolamide on Neurodegenerative Diseases: A Review from Rodents to Humans. Biomolecules. 2022;12(5):667. Published 2022 May 5. doi:10.3390/biom12050667

Del Giorno R, Skaper S, Paladini A, Varrassi G, Coaccioli S. Palmitoylethanolamide in Fibromyalgia: Results from Prospective and Retrospective Observational Studies. Pain Ther. 2015;4(2):169-178. doi:10.1007/s40122-015-0038-6

Salaffi F, Farah S, Sarzi-Puttini P, Di Carlo M. Palmitoylethanolamide and acetyl-L-carnitine act synergistically with duloxetine and pregabalin in fibromyalgia: results of a randomised controlled study. Clin Exp Rheumatol. 2023;41(6):1323-1331. doi:10.55563/clinexprheumatol/pmdzcq

Varrassi G, Rekatsina M, Leoni MLG, et al. A Decades-Long Journey of Palmitoylethanolamide (PEA) for Chronic Neuropathic Pain Management: A Comprehensive Narrative Review. Pain Ther. 2025;14(1):81-101. doi:10.1007/s40122-024-00685-4