Safety Profile
Known Safety Concerns
- Limited long-term safety data beyond 12 months
- May interact with endocannabinoid system medications theoretically
- Limited data in pregnancy and severe hepatic/renal impairment
Contraindications
- Limited long-term safety data beyond 12 months
- May interact with endocannabinoid system medications theoretically
Interactions
Information not yet available for this ingredient profile.
Evidence and Scientific Findings
Ingredient Overview
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide with anti-inflammatory and analgesic properties, acting on PPAR-alpha. Registered as a medical food in some European countries for chronic pain. Well-tolerated across multiple clinical trials.
Biological and Chemical Classification
- Scientific Name
- Palmitoylethanolamide (N-(2-hydroxyethyl)hexadecanamide)
Mechanism of Action
Information not yet available for this ingredient profile.
Clinical Evidence of Effectiveness
Information not yet available for this ingredient profile.
Pharmacokinetics
Information not yet available for this ingredient profile.
Recommended Dosage
Information not yet available for this ingredient profile.
SETI — Scientific Evidence Transparency Index
Executive Summary — Ingredient Assessment
- 10 studies reviewed
- 0 high-quality studies (meta-analysis or RCT)
- Main clinical benefit observed: Metabolic
- Evidence consistency: High consistency across studies (100%)
- Limited long-term safety data beyond 12 months
- May interact with endocannabinoid system medications theoretically
- Limited data in pregnancy and severe hepatic/renal impairment
The available scientific evidence for Palmitoylethanolamide (PEA) indicates notable safety signals that warrant caution. Use should be considered carefully and monitored, particularly in sensitive populations or alongside other medications.
Total SETI Score
High risk| Evidence quality | 10/40 |
| Evidence consistency | 20/20 |
| Safety signals | 0/20 |
| Study recency | 10/10 |
| Evidence transparency | 10/10 |
Evidence Summary
- 10 studies reviewed
- 0 high-quality studies (meta-analysis or systematic review)
- 0 studies identified benefits or no safety concern (GREEN)
- 10 studies reported limited or advisory safety evidence (YELLOW)
Evidence Policy
Only peer-reviewed scientific literature indexed in PubMed or comparable databases is included in this evaluation. Commercial websites, blogs, and marketing materials are excluded. All references include direct traceable links to source documents.
Last updated: 25 მარ 2026, 23:24
Evidence Distribution
-
Observational / other LOW evidence YELLOWLevagen+ (palmitoylethanolamide) alleviates joint pain and reduces the impact of joint pain in canines and felines: a double-blind, placebo-controlled, randomized clinical trial. ↗Briskey D et al.. Levagen+ (palmitoylethanolamide) alleviates joint pain and reduces the impact of joint pain in canines and felines: a double-blind, placebo-controlled, randomized clinical trial.. Front Vet Sci. 2026. PMID:41767672.PMID 41767672 ↗Journal Front Vet SciYear 2026Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41767672/
-
Observational / other LOW evidence YELLOWPhospholipid-Based Delivery System Optimizes the Solubility and Systemic Exposure of Palmitoylethanolamide and Supports Clinical Benefits in Chronic Neuropathic Low Back Pain. ↗Khan A et al.. Phospholipid-Based Delivery System Optimizes the Solubility and Systemic Exposure of Palmitoylethanolamide and Supports Clinical Benefits in Chronic Neuropathic Low Back Pain.. Biomedicines. 2026. PMID:41751279.PMID 41751279 ↗Journal BiomedicinesYear 2026Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41751279/
-
Observational / other LOW evidence YELLOWInvestigating Properties of Palmitoylethanolamide in Physiology and Disease: Far Beyond an Anti-Inflammatory Shield. ↗Veredice C et al.. Investigating Properties of Palmitoylethanolamide in Physiology and Disease: Far Beyond an Anti-Inflammatory Shield.. Diseases. 2026. PMID:41745090.PMID 41745090 ↗Journal DiseasesYear 2026Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41745090/
-
Observational / other LOW evidence YELLOWA novel fasting mimetic (Mimio) creates fasting-like benefits to hunger control, oxidative stress, and cardiometabolic health in humans. ↗Grant AD et al.. A novel fasting mimetic (Mimio) creates fasting-like benefits to hunger control, oxidative stress, and cardiometabolic health in humans.. Sci Rep. 2026. PMID:41720867.PMID 41720867 ↗Journal Sci RepYear 2026Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41720867/
-
Observational / other LOW evidence YELLOWProbiotics and palmitoylethanolamide (PEA) for osteoarthritic pain: individual effects in a multiple baseline design study. ↗Taye I et al.. Probiotics and palmitoylethanolamide (PEA) for osteoarthritic pain: individual effects in a multiple baseline design study.. BMC Complement Med Ther. 2026. PMID:41709243.PMID 41709243 ↗Journal BMC Complement Med TherYear 2026Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41709243/
-
Observational / other LOW evidence YELLOWPalmitoylethanolamide (PEA) regulates cell cycle progression and promotes an anti-inflammatory transcriptomic signature in C2C12 skeletal muscle cells. ↗Cole PL et al.. Palmitoylethanolamide (PEA) regulates cell cycle progression and promotes an anti-inflammatory transcriptomic signature in C2C12 skeletal muscle cells.. Physiol Rep. 2026. PMID:41693292.PMID 41693292 ↗Journal Physiol RepYear 2026Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41693292/
-
Observational / other LOW evidence YELLOWEfficacy, safety, and tolerability of palmitoylethanolamide in the management of diabetic neuropathic pain: a systematic review and meta-analysis. ↗Prado MB Jr et al.. Efficacy, safety, and tolerability of palmitoylethanolamide in the management of diabetic neuropathic pain: a systematic review and meta-analysis.. J Diabetes Metab Disord. 2026. PMID:41664677.PMID 41664677 ↗Journal J Diabetes Metab DisordYear 2026Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41664677/
-
Observational / other LOW evidence YELLOWN-Acylethanolamine Acid Amidase Inhibition Reduces SARS-CoV-2 Infection in Human Precision Cut-Lung Slices and Downregulates NF-KBB Signalling. ↗La Rocca V et al.. N-Acylethanolamine Acid Amidase Inhibition Reduces SARS-CoV-2 Infection in Human Precision Cut-Lung Slices and Downregulates NF-KBB Signalling.. J Med Virol. 2026. PMID:41578924.PMID 41578924 ↗Journal J Med VirolYear 2026Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41578924/
-
Observational / other LOW evidence YELLOWPalmitoylethanolamide ameliorates postoperative cognitive dysfunction via microglial PPARu03b1-mediated anti-inflammatory and neuroprotective mechanisms. ↗Zhang X et al.. Palmitoylethanolamide ameliorates postoperative cognitive dysfunction via microglial PPARu03b1-mediated anti-inflammatory and neuroprotective mechanisms.. Exp Neurol. 2026. PMID:41577115.PMID 41577115 ↗Journal Exp NeurolYear 2026Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41577115/
-
Observational / other LOW evidence YELLOWDistinct serum endocannabinoid profiles in treatment-nau00efve Han Chinese children with ADHD: a case-control pilot study. ↗Liao W et al.. Distinct serum endocannabinoid profiles in treatment-nau00efve Han Chinese children with ADHD: a case-control pilot study.. Front Neurol. 2025. PMID:41603005.PMID 41603005 ↗Journal Front NeurolYear 2025Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41603005/
Score Transparency
0 of 10 approved references (score saturates at 10). More peer-reviewed studies = stronger evidence base.
Method: Q = number of approved references ÷ 10 (capped at 1.0)
Limited — mostly case reports or animal studies
Method: L = mean study-level weight across approved references. Level 1 (meta-analysis / systematic review) = 1.0; Level 2 (RCT) = 0.8; Level 3 (cohort/case-control) = 0.6; Level 4 (case report) = 0.4; Level 5 (animal / in-vitro) = 0.2.
Mixed or neutral — roughly equal benefit and risk signals
Method: D = (sum of risk-scored references − sum of benefit-scored references) ÷ total evidence score, then scaled from [−1, 1] to [0, 1]. 0.0 = pure benefit; 0.5 = neutral; 1.0 = pure risk.
One or more monitoring-level safety signals active
Method: S = 0.5 (neutral baseline) + sum of active signal severity deltas ÷ 10. Severity deltas: Critical = +2.0, High = +1.5, Moderate = +1.0, Low = +0.5. Capped at 1.0.
Final GIRI Score for Palmitoylethanolamide (PEA). Risk level thresholds: Low 0–3.0 · Moderate 3.0–5.5 · High 5.5–7.5 · Critical 7.5–10.
Full methodology & data sources
The GIRI Score is computed entirely from structured data — no editorial scoring or subjective weighting is applied at any step.
- References: Only approved references are counted. Each reference is assigned an evidence level (L1–L5) and a direction (risk / neutral / benefit) by the reference manager or AI classifier.
- Safety Signals: Sourced from regulatory agencies (FDA, EMA, Health Canada, TGA, and others) and pharmacovigilance databases. Only active signals count toward the score.
- Formula version: GIRI Score v3.7.0 — Q × L × D × S × 10.
- Limitations: The score reflects published evidence and recorded signals as of the last update date. It is not a clinical risk assessment and should not replace advice from a qualified healthcare professional.
Risk Level Classification
Based on available regulatory signals and scientific evidence, this ingredient presents a low safety concern under normal conditions of use.
0–3.0
3.0–5.5
5.5–7.5
7.5–10
The score pin shows exactly where this ingredient falls on the fixed risk scale.
What drove the Low classification for Palmitoylethanolamide (PEA)
A score of 2.0 places this ingredient in the Low band. Thresholds: Low 0–3.0 · Moderate 3.0–5.5 · High 5.5–7.5 · Critical 7.5–10.
0 approved references.
Limited — mostly case reports or animal studies (Level 4–5).
Neutral or mixed — benefit and risk signals roughly balanced.
No active signals — S component is at neutral baseline (0.5), contributing no extra risk weight.
No major regulatory restrictions or advisories recorded across monitored jurisdictions (FDA, EMA, Health Canada, TGA, and others).
How are the Low / Moderate / High / Critical thresholds defined?
The four risk levels are fixed score bands. A score is assigned to exactly one level based on where it falls:
| Level | Score | Meaning |
|---|---|---|
| LOW | 0.0 – 2.9 | Sparse or predominantly beneficial evidence. No active safety alerts. |
| MODERATE | 3.0 – 5.4 | Mixed signals — some risk alongside benefit. Caution at high doses or in sensitive groups. |
| HIGH | 5.5 – 7.4 | Multiple studies or regulatory alerts documenting adverse effects. Professional oversight recommended. |
| CRITICAL | 7.5 – 10 | Regulatory restrictions in one or more major jurisdictions. Serious documented harm. Avoid without specialist supervision. |
Thresholds are fixed constants (GIRI_Score_Utils::LEVEL_THRESHOLDS). They do not change per ingredient and are never subject to editorial adjustment.