cis-9,10-Octadecenoamide
Oleoylamide
Oleic Acid Amide
Oleylamide
ODA
Cerebrodiene

---
canonical_name: Oleamide
alternate_names: cis-9,10-Octadecenoamide, Oleoylamide, Oleic Acid Amide, Oleylamide, ODA, Cerebrodiene
canonical_topic: Oleamide for Health & Longevity
short_topic_lc: oleamide
creation_date: 2026-0624-1316
creator_ai_fullname: Opus 4.8
---

# Oleamide for Health & Longevity

Evidence Review created on 06/24/2026 using [AI4L](https://github.com/forever-healthy/AI4L) / Opus 4.8

**Also known as:** cis-9,10-Octadecenoamide, Oleoylamide, Oleic Acid Amide, Oleylamide, ODA, Cerebrodiene

## Motivation

Oleamide (oleic acid amide) is a fat-derived signaling molecule the body makes on its own. It was first pulled from the spinal fluid of sleep-deprived cats, where it builds up the longer an animal goes without sleep — and when given to rested animals, it makes them fall asleep faster. Because it is the simple amide of oleic acid, the main fat in olive oil, it is sold as a low-cost powder or capsule marketed for relaxation and sleep.

Interest comes from how it works. Oleamide is broken down by the same enzyme that clears anandamide, one of the body's own cannabis-like messengers, so it may indirectly raise anandamide and nudge the same calming receptors involved in mood and sleep. Nearly all of this evidence comes from cells and rodents; one small human trial exists, and the molecule breaks down quickly when taken by mouth.

This review examines what is known about oleamide as a supplement: how it is thought to act, the effects reported in laboratory and animal work, and the practical and safety questions a health- and longevity-focused reader would weigh.

**[Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol) - [Conclusion](#conclusion)**

## Recommended Reading

This section lists high-level overviews and foundational sources that introduce oleamide's biology, sleep role, and pharmacology for a non-specialist reader.

* [Oleamide: an endogenous sleep-inducing lipid and prototypical member of a new class of biological signaling molecules](https://pubmed.ncbi.nlm.nih.gov/10197045/) - Boger et al., 1998

  The foundational review by the Scripps group that discovered oleamide; it narrates the discovery story, the link to sleep deprivation, and the enzyme that controls it, making it the single best entry point to the molecule's biology.

* [The hypnotic actions of the fatty acid amide, oleamide](https://pubmed.ncbi.nlm.nih.gov/11682271/) - Mendelson & Basile, 2001

  A focused narrative review of oleamide's sleep-promoting actions, covering its effects on serotonin and GABA (the brain's main calming chemical messenger) currents and the role of the cannabis-like pathway, written accessibly enough to orient a non-specialist to why the molecule is studied for sleep.

* [Oleamide: a member of the endocannabinoid family?](https://pubmed.ncbi.nlm.nih.gov/14691053/) - Fowler, 2004

  A short expert commentary weighing whether oleamide should be classed alongside anandamide as a true cannabis-like messenger; valuable for understanding the unresolved debate over its direct versus indirect mechanism.

* [Oleamide: a fatty acid amide signaling molecule in the cardiovascular system?](https://pubmed.ncbi.nlm.nih.gov/17445087/) - Hiley & Hoi, 2007

  A broad narrative review extending oleamide beyond sleep to its blood-vessel-relaxing and signaling roles, useful for seeing the full range of receptor systems the molecule touches.

* [Unique allosteric regulation of 5-hydroxytryptamine receptor-mediated signal transduction by oleamide](https://pubmed.ncbi.nlm.nih.gov/9391162/) - Thomas et al., 1997

  The key primary study showing oleamide acts at a separate "side door" site on serotonin receptors to amplify their signaling, the mechanistic finding most often cited to explain its mood and sleep effects.

Note: None of the five priority experts (Rhonda Patrick, Peter Attia, Andrew Huberman, Chris Kresser, Life Extension) has published content addressing oleamide by name, so no expert-sourced item could be included; the five sources above are drawn from the foundational scientific literature instead.

## Grokipedia

* [Oleamide](https://grokipedia.com/page/Oleamide) - Grokipedia

  Grokipedia hosts a dedicated, fact-checked article on oleamide covering its chemistry, discovery, sleep biology, receptor pharmacology, and industrial uses, providing a structured single-page overview of the molecule.

## Examine

* [Oleamide](https://examine.com/supplements/oleamide/) - Examine

  Examine maintains a dedicated supplement page describing oleamide as a derivative of oleic acid associated with sleep, summarizing the animal-level evidence and its overlap with the cannabis-like receptor system in an evidence-graded format.

## ConsumerLab

No dedicated ConsumerLab article or product-test report for oleamide was found.

## Systematic Reviews

No systematic reviews or meta-analyses for Oleamide were found on PubMed as of 2026-06-24.

## Mechanism of Action

Oleamide is the primary amide of oleic acid (cis-9,10-octadecenoamide), a lipid the nervous system can build on its own. Its biology is best understood through several overlapping, and partly competing, pathways.

* **Enzyme-blocking (indirect cannabis-like) pathway.** Oleamide is broken down by fatty acid amide hydrolase (FAAH, the enzyme that clears fat-derived signaling amides). Because FAAH also destroys anandamide — one of the body's own cannabis-like messengers — oleamide can act as a competing substrate, slowing anandamide breakdown and raising its levels. This "entourage" or substrate-competition effect is the most widely accepted explanation for oleamide's calming and sleep-promoting actions, since the CB1 (the main brain receptor for cannabis) receptor blocker rimonabant (SR141716) cancels its sleep effect in rodents.

* **Direct receptor actions.** Separately, oleamide has been reported to act directly at the CB1 cannabinoid receptor (the main brain target of cannabis), at the TRPV1 channel (a heat- and pain-sensing channel), and as a positive allosteric modulator — a "side-door" amplifier — of serotonin receptors (5-HT2A, 5-HT2C, 5-HT7) and GABA-A receptors (the brain's main calming receptor). It also enhances glycine receptor currents and blocks gap junctions (direct cell-to-cell channels).

* **Competing interpretations.** Whether oleamide is a true cannabis-like messenger in its own right or merely an indirect amplifier of anandamide remains unsettled. One camp argues its effects are explained entirely by FAAH inhibition raising anandamide; another points to its direct allosteric serotonin and GABA actions, which occur independently of the cannabinoid system. Both interpretations are supported by in vitro data, and the field has not resolved the question.

The explanation matters because it shapes what oleamide might do and how reliably an oral dose could reproduce it.

Key pharmacological properties (largely from animal and in vitro work; human pharmacokinetic data are essentially absent):

* **Half-life:** Very short. Oleamide is rapidly hydrolyzed by FAAH, and oral bioavailability in humans is unquantified; rodent effects are typically shown with injected dosing.
* **Selectivity:** Low — it touches cannabinoid, serotonergic, GABAergic, glycinergic, TRPV1, and gap-junction systems rather than acting on a single target.
* **Tissue distribution:** Detected in plasma and cerebrospinal fluid; the synthetic and degradative machinery (PAM, an amide-forming enzyme, for synthesis; FAAH for breakdown) is concentrated in the central nervous system.
* **Metabolism:** Primary degradation by FAAH to oleic acid and ammonia; biosynthesis is thought to proceed via oleoylglycine converted by peptidylglycine α-amidating monooxygenase (PAM).

## Historical Context & Evolution

Oleamide's story begins not with a drug-development program but with a basic-science hunt for a "sleep factor." In the mid-1990s, Benjamin Cravatt, Dale Boger, and colleagues at the Scripps Research Institute isolated a lipid that accumulated in the cerebrospinal fluid of cats deprived of sleep and, when injected into rested rats, induced normal sleep. They identified it as oleamide and proposed it as the prototype of a new class of fatty-acid signaling molecules.

The original intended "use" was therefore as a natural sleep-regulating substance, not a supplement. Interest in health optimization followed from two threads: the discovery that FAAH degrades both oleamide and anandamide tied oleamide to the then-emerging cannabis-like signaling system, and the appeal of a cheap, naturally occurring molecule that might promote sleep without the dependence profile of conventional sedatives.

The actual early findings — sleep induction, accumulation during sleep deprivation, serotonin and GABA modulation — have held up as reproducible laboratory observations. What has shifted is the interpretation of mechanism rather than a wholesale reversal. Early enthusiasm framed oleamide as a possible new endocannabinoid; later work (e.g., Fowler, 2004) questioned whether it acts directly or only by raising anandamide, and that debate is genuinely unresolved rather than settled. No drug or approved sleep aid emerged from this line of work, and the molecule migrated into the nootropic supplement market on the strength of preclinical data. The current standing is best described as a biologically real signaling lipid whose human relevance as an oral supplement remains unproven.

## Expected Benefits

A dedicated search of PubMed, examine.com, and general web sources was performed for oleamide's full benefit profile. Nearly all evidence is preclinical (cell and rodent); a single small human randomized controlled trial (RCT, a study that randomly assigns participants to treatment or placebo) of a low oral dose exists, which still caps the achievable evidence grade at Low.

### Low 🟩

#### Cognitive Function and Memory Support

This is the only benefit with direct human evidence. In a small randomized, double-blind, placebo-controlled trial in healthy older Japanese adults aware of cognitive decline ([Sasaki et al., 2024](https://pubmed.ncbi.nlm.nih.gov/38600994/)), a low oral dose (60 μg/day for 12 weeks) significantly improved a composite cognitive screen and short-term/working memory (immediate and delayed free recall) versus placebo, alongside a positive change in serum brain-derived neurotrophic factor (BDNF, a protein that supports nerve-cell growth and survival). The proposed mechanism overlaps with oleamide's serotonin and cannabis-like signaling actions, though the trial was small (≈20 per arm), industry-sponsored, and used a microgram dose far below the milligram amounts in marketed sleep products, so the grade is held at Low.

**Magnitude:** In the one human RCT, the oleamide group showed a statistically significant improvement on a memory-screen composite and on immediate and delayed free recall versus placebo over 12 weeks; effect sizes were not reported in a form comparable across studies.

#### Sleep Induction and Improved Sleep Quality

This is oleamide's defining and best-supported effect, but only in animals. It accumulates in cerebrospinal fluid during sleep deprivation and, when administered to rodents, shortens the time to fall asleep and increases total and REM (rapid-eye-movement, the dreaming phase of) sleep. The proposed mechanism combines indirect raising of anandamide via FAAH competition with direct calming actions at GABA-A and serotonin receptors; the cannabinoid blocker rimonabant abolishes the effect, supporting cannabis-system involvement. The evidence basis is multiple independent rodent studies and in vitro receptor work, supported by a single small human RCT in older adults ([Sasaki et al., 2024](https://pubmed.ncbi.nlm.nih.gov/38600994/)) in which a low oral dose (60 μg/day for 12 weeks) produced within-group improvement in subjective sleep quality and sleep latency but no significant difference versus placebo; the grade is held at Low.

**Magnitude:** In rodents, injected oleamide reduces sleep latency and increases sleep time; one report showed it could lower sleep latency synergistically with a sub-threshold dose of the sedative triazolam. In the one human RCT, the oleamide group improved on subjective sleep quality and sleep latency within-group, but the between-group difference versus placebo was not significant.

#### Anxiety Reduction and Mood Modulation

Oleamide produces calming, anxiety-reducing behavior in rodent models and modulates serotonin signaling, the system targeted by common mood medications. It acts as a positive allosteric modulator (a side-door amplifier) of 5-HT2A, 5-HT2C, and 5-HT7 serotonin receptors and indirectly engages the cannabis-like system, both plausibly relevant to mood. The evidence basis is animal behavioral studies and in vitro receptor pharmacology; no human mood data exist, so the grade is Low.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Vasodilation and Cardiovascular Signaling

In isolated rat arteries, oleamide relaxes blood vessels through nitric-oxide and endothelial mechanisms and engages a not-yet-identified G-protein-coupled receptor, raising the possibility of blood-pressure-related effects. The basis is in vitro vascular pharmacology only; no in vivo cardiovascular outcomes or human data exist, and a physiological role has not been demonstrated, so this is purely mechanistic and speculative.

#### Neuroprotection and Anticonvulsant Potential ⚠ Conflicted

Oleamide shows anticonvulsant activity in rodent and brain-slice seizure models and modulates inhibitory GABA and glycine currents, prompting speculation about broader neuroprotective or memory-related roles. The basis is isolated preclinical models with conflicting memory findings and no controlled studies in disease; the evidence is mechanistic and anecdotal only, warranting a Speculative grade.

## Benefit-Modifying Factors

* **FAAH genetic variation:** Because oleamide's leading mechanism depends on competing with anandamide for the FAAH enzyme, common variants that reduce FAAH activity (e.g., the C385A polymorphism in the FAAH gene, which lowers enzyme function and raises baseline anandamide) could blunt or alter any added effect of oleamide. This is mechanistically plausible but untested for oleamide specifically.

* **Baseline endocannabinoid and sleep status:** Individuals with already-low sleep pressure or high baseline anandamide tone may respond differently than the sleep-deprived state in which oleamide naturally rises; the molecule's animal effects are most evident against a backdrop of sleep deprivation.

* **Sex-based differences:** The cannabis-like and serotonin systems oleamide engages show known sex differences in animals (driven partly by sex-hormone effects on endocannabinoid tone), but no oleamide-specific sex-difference data exist in humans.

* **Pre-existing conditions:** Conditions affecting serotonin signaling (e.g., mood disorders, or use of serotonergic medication) or cannabinoid tone could in principle modify oleamide's effects, though this is unstudied.

* **Age:** Endocannabinoid tone and sleep architecture change with age, and older adults at the upper end of the target range may have altered FAAH activity and sleep responses; no age-stratified human data are available for oleamide.

## Potential Risks & Side Effects

A dedicated search of drug-reference and toxicology sources, examine.com, PubMed, and general web sources was performed. Because the only human trial is a single small study of a microgram oral dose ([Sasaki et al., 2024](https://pubmed.ncbi.nlm.nih.gov/38600994/), which reported no adverse events related to the test product) and there is no regulatory safety dossier, the side-effect profile is largely inferred from mechanism and animal work; all grades are capped accordingly.

### Low 🟥

#### Sedation and Next-Day Grogginess

As a sleep-inducing molecule, oleamide's most predictable effect is drowsiness, and a long-acting or poorly-timed dose could plausibly carry over into next-day sedation, much like other sleep aids. The mechanism is the same GABA, serotonin, and cannabis-system modulation that drives its intended effect. The evidence basis is the consistent sedative effect in animal studies plus mechanistic reasoning; human data are absent, so the grade is Low.

**Magnitude:** In rodents the sedative effect is dose-dependent and large enough that oleamide lowers sleep latency even at a sub-threshold triazolam dose; in the single human trial of a 60 μg/day oral dose, no sedation-related adverse events were reported, suggesting any human next-day sedation at marketed (milligram) doses is unquantified but plausibly mild-to-moderate by comparison to conventional hypnotics.

### Speculative 🟨

#### Unknown Long-Term and Whole-Body Safety

Oleamide acts on many systems — cannabinoid, serotonin, GABA, TRPV1, blood vessels, and gap junctions — and the absence of any human safety data means long-term or off-target effects cannot be excluded. Gap-junction inhibition, for example, has roles in heart and tissue development that are poorly characterized after supplementation. The basis is the breadth of its in vitro targets combined with a complete lack of human toxicology, making this a speculative but genuine concern.

#### Serotonergic Interaction Risk

Because oleamide amplifies several serotonin receptors, a theoretical concern is additive serotonergic effects if combined with serotonin-raising medications, which in the extreme could contribute to excess serotonin activity. This is mechanistic speculation only; there are no reports of such events with oleamide, and the basis is its receptor pharmacology rather than any clinical observation.

#### Cardiovascular and Blood-Pressure Effects

Oleamide relaxes blood vessels in isolated-tissue experiments, raising a speculative possibility of blood-pressure lowering or interaction with blood-pressure medication. No in vivo cardiovascular safety data exist; the concern rests entirely on in vitro vascular findings.

## Risk-Modifying Factors

* **FAAH genetic variation:** Reduced-function FAAH variants (e.g., the C385A polymorphism that lowers FAAH activity) raise baseline anandamide and could in theory amplify both the sedative effect and any cannabis-system-related side effects of oleamide; untested for oleamide specifically.

* **Baseline blood pressure:** Given the in vitro vessel-relaxing actions, individuals with already-low blood pressure or on antihypertensive therapy might be more susceptible to any blood-pressure-lowering effect, though this is unproven in humans.

* **Sex-based differences:** Sex differences in endocannabinoid and serotonin signaling could modify side-effect susceptibility, but no oleamide-specific human data exist.

* **Pre-existing conditions and concurrent medication:** People taking serotonergic or sedative medications, or with disorders of mood or sleep, represent a plausibly higher-risk group for additive central-nervous-system effects, based on mechanism rather than evidence.

* **Age:** Older adults at the upper end of the target range may be more sensitive to sedation and to drug interactions owing to slower metabolism and altered sleep, though oleamide-specific data are lacking.

## Key Interactions & Contraindications

All interactions below are theoretical, derived from oleamide's mechanism; none are documented in human studies.

* **Sedatives and hypnotics (benzodiazepines such as triazolam and diazepam; "Z-drugs" such as zolpidem; barbiturates):** Additive sedation. Severity: caution. Clinical consequence: excessive drowsiness, impaired coordination. Animal work explicitly showed oleamide synergizes with a sub-threshold dose of triazolam, making this the best-supported interaction. Mitigating action: avoid combining; if sleep aids are already in use, do not layer oleamide on top.

* **Serotonergic drugs (SSRIs, or selective serotonin reuptake inhibitors, such as sertraline; SNRIs, or serotonin-norepinephrine reuptake inhibitors, such as venlafaxine; triptans; MAO, or monoamine oxidase, inhibitors — all antidepressant or migraine drugs that raise serotonin):** Theoretical additive serotonin activity because oleamide amplifies serotonin receptors. Severity: caution. Clinical consequence: in the extreme, features of serotonin excess (agitation, rapid heart rate, tremor). Mitigating action: avoid combination pending data; seek clinical advice.

* **Alcohol and other central nervous system depressants:** Additive sedation. Severity: caution. Clinical consequence: pronounced drowsiness and impairment. Mitigating action: avoid concurrent use.

* **Cannabis and cannabinoid products (THC, CBD, FAAH inhibitors):** Because oleamide engages and competes within the cannabis-like (FAAH/anandamide) system, combined use could unpredictably raise endocannabinoid tone. Severity: caution. Clinical consequence: enhanced sedation or psychoactive effect. Mitigating action: separate use; monitor response.

* **Antihypertensive medications:** Theoretical additive blood-pressure lowering, given in vitro vasodilation. Severity: monitor. Clinical consequence: low blood pressure, dizziness. Mitigating action: monitor blood pressure if combined.

* **Other supplements with additive effects:** Sleep- and calm-promoting supplements — melatonin, valerian, magnesium, glycine, kava, GABA, and L-theanine (an amino acid from tea) — could add to oleamide's sedative effect and should be approached with the same caution as sedative drugs.

* **Populations who should avoid oleamide:** Pregnant or breastfeeding individuals (no safety data; gap-junction effects relevant to development); people with low blood pressure; those on serotonergic or sedative medication; anyone operating vehicles or machinery after dosing. Because there is no human safety evidence at all, oleamide is best avoided by anyone who is not prepared to accept fully unquantified risk.

## Risk Mitigation Strategies

* **Lowest-effective single evening dose:** Because the main predictable effect is sedation, keep any trial to a single low dose taken at night rather than divided daytime dosing, mitigating next-day grogginess and daytime impairment.

* **Avoid stacking with other depressants:** Do not combine oleamide with alcohol, sedative or hypnotic medication, or multiple calming supplements (melatonin, valerian, kava), directly mitigating the additive-sedation risk that animal data flag as oleamide's clearest interaction.

* **Screen concurrent serotonergic medication:** Before any use, confirm there is no overlap with SSRIs, SNRIs, triptans, or MAO inhibitors, mitigating the theoretical serotonin-excess interaction created by oleamide's serotonin-receptor amplification.

* **No driving or machinery after dosing:** Because onset and duration in humans are unknown, avoid operating vehicles or hazardous equipment for the rest of the evening after a dose, mitigating injury risk from unexpected sedation.

* **Blood-pressure awareness:** Individuals on antihypertensives or with low baseline blood pressure should check blood pressure when trialing oleamide, mitigating the theoretical additive blood-pressure-lowering effect suggested by in vitro vasodilation.

* **Avoid in untested populations:** Withhold use entirely in pregnancy, breastfeeding, and in those with significant cardiovascular or psychiatric conditions, mitigating the wholly unquantified long-term and whole-body safety risk.

## Therapeutic Protocol

No validated human protocol exists for oleamide; the following reflects how the molecule is marketed and the practical reasoning applied to such an unstudied compound, not established clinical practice.

* **Standard marketed use:** Supplement vendors (e.g., nootropic retailers) position oleamide as an evening relaxation and sleep aid, typically in powder or capsule form at doses on the order of low hundreds of milligrams. No leading clinical practitioner or named clinic has popularized a defined oleamide protocol, reflecting its lack of human evidence.

* **Competing approaches:** Two practical philosophies coexist without one being the default — taking oleamide directly as a sleep aid, versus the alternative strategy in the research literature of inhibiting FAAH to raise the body's own oleamide and anandamide rather than supplementing the molecule itself. Neither is clinically validated.

* **Best time of day:** Given its sedative profile, any use is oriented to the evening, shortly before intended sleep.

* **Half-life consideration:** Because oleamide is rapidly broken down by FAAH and oral absorption in humans is unquantified, the practical expectation is a short window of action; this is why animal studies rely on injection and why oral human efficacy is uncertain.

* **Single versus split dosing:** A single evening dose is the only rational approach for a sleep-targeted, short-acting, sedating compound; split daytime dosing would invite daytime sedation without a clear rationale.

* **Genetic considerations:** FAAH variants (e.g., the reduced-function C385A polymorphism affecting how quickly fat-derived signaling amides are cleared) could in principle influence response, but no pharmacogenetic guidance exists for oleamide.

* **Sex-based differences:** No human dosing differences by sex have been established; sex differences in endocannabinoid tone are documented in animals only.

* **Age considerations:** Older adults at the upper end of the target range may need to assume greater sensitivity to sedation; no age-specific dosing exists.

* **Baseline biomarkers:** No biomarker is validated to guide oleamide dosing; sleep quality and subjective response are the only practical gauges.

* **Pre-existing conditions:** Those with cardiovascular, psychiatric, or sleep disorders should regard any protocol as experimental and approach it only with clinical oversight.

## Discontinuation & Cycling

* **Lifelong versus short-term:** There is no basis to consider oleamide a lifelong intervention; its plausible use is short-term and situational (occasional sleep support), reflecting the absence of long-term human data.

* **Withdrawal effects:** No withdrawal syndrome has been documented in humans. Mechanistically, because it works partly through the cannabis-like system, abrupt cessation after sustained use is not expected to cause significant withdrawal, but this is unstudied.

* **Tapering:** No tapering protocol is established or thought necessary given its short action and lack of dependence data; this remains theoretical.

* **Cycling:** Whether cycling preserves any effect is unknown. If tolerance to the sedative effect develops (as can occur with sleep aids generally), intermittent rather than nightly use would be the conservative approach, but no oleamide-specific tolerance data exist.

* **Practical stance:** Given the evidence vacuum, intermittent, as-needed use is more defensible than continuous daily use, purely as a precaution.

## Sourcing and Quality

* **Source and form:** Oleamide is sold as a synthetic powder or capsule, most visibly through nootropic-focused online retailers (e.g., Nootropics Depot). It is also an industrial chemical (a "slip agent" in plastics manufacturing), so supplement-grade material must be distinguished from industrial-grade.

* **Purity and third-party testing:** Because oleamide is not a mainstream regulated supplement and ConsumerLab and major testing bodies do not appear to evaluate it, buyers should look for a vendor-provided certificate of analysis (CoA) confirming identity and purity and, ideally, independent third-party testing for contaminants and correct compound identity.

* **Isomer specificity:** Biological activity is specific to the cis isomer (cis-9,10-octadecenoamide); the trans isomer lacks most of oleamide's reported actions, so identity testing that confirms the active cis form matters.

* **Reputable suppliers:** Among consumer channels, established nootropic retailers that publish CoAs are the most credible option; no compounding pharmacy or pharmaceutical-grade product exists because oleamide is not an approved drug.

* **Storage and stability:** As a lipid amide, material should be kept sealed and protected from heat and moisture to limit degradation, consistent with general handling of fatty-acid compounds.

## Practical Considerations

* **Time to effect:** Unknown in humans. In animals, injected oleamide acts within the timeframe of a single sleep session; orally in humans, onset, magnitude, and even whether an effect occurs are unestablished.

* **Common pitfalls:** Assuming rodent injection results translate to oral human benefit; confusing industrial-grade oleamide (a plastics additive) with supplement-grade material; stacking it with other sedatives or sleep supplements and over-sedating; and expecting a validated "dose" where none exists.

* **Regulatory status:** Oleamide is not an approved drug and is not specifically authorized as a dietary supplement ingredient by the FDA; it is sold in a regulatory gray area, often labeled "for research" or as a nootropic, with no FDA evaluation of its safety or efficacy as a supplement.

* **Cost and accessibility:** It is inexpensive and readily available online, which is part of its appeal; cost is not a barrier, but the lack of quality oversight is the practical limiting factor.

## Interaction with Foundational Habits

* **Sleep:** Direct and potentiating. Oleamide's primary reported action is sleep induction via GABA, serotonin, and cannabis-system modulation, so its main interaction with sleep is intended enhancement; the practical caution is timing it only at night to avoid daytime sedation, and not layering it onto existing sleep medications.

* **Nutrition:** Indirect. Oleamide is the amide of oleic acid, the dominant fat in olive oil, and is a normal dietary-fat-derived signaling lipid; while there is no evidence that diet meaningfully changes supplemental oleamide's effect, a diet adequate in monounsaturated fat supports normal endogenous fatty-acid-amide signaling. As a fat-soluble compound, taking it with some dietary fat may aid absorption, though this is unconfirmed.

* **Exercise:** Indirect/none established. Exercise transiently raises the body's own cannabis-like signaling (part of the "runner's high"), which overlaps mechanistically with oleamide's pathway, but there is no evidence that oleamide blunts or enhances exercise adaptations, and no timing guidance exists. Given its sedative profile, evening use away from training is the practical default.

* **Stress management:** Direct/potentiating in principle. By amplifying serotonin signaling and the cannabis-like system, oleamide could in theory support relaxation and stress resilience, complementing practices such as meditation; however, this is mechanistic speculation with no human stress or cortisol data, so it should not be relied upon as a stress intervention.

## Monitoring Protocol & Defining Success

Because oleamide has no validated human use, formal laboratory monitoring is limited; tracking is primarily through subjective and safety-oriented measures. Baseline assessment before any trial centers on cardiovascular and central-nervous-system safety rather than an oleamide-specific biomarker, and ongoing follow-up is mainly self-monitoring of sleep and side effects.

Baseline testing is sensible before starting, focused on screening for the populations and interactions of concern (blood pressure, concurrent medications) rather than measuring oleamide itself, for which no clinical assay is offered. Ongoing monitoring has no fixed laboratory cadence; a reasonable approach is a baseline check, then reassessment of subjective sleep and any side effects after the first 1–2 weeks of use, with blood-pressure checks as needed for those on antihypertensives.

| Biomarker | Optimal Functional Range | Why Measure It? | Context/Notes |
| --------- | ------------------------ | --------------- | ------------- |
| Blood pressure | ~110–125 / 70–80 mmHg | Screens for low blood pressure given oleamide's in vitro vessel-relaxing action | Measure seated after 5 min rest; conventional "normal" is <120/80, but functional practitioners flag values that are low-normal in those prone to dizziness; recheck if combined with antihypertensives |
| Resting heart rate | 50–70 bpm | Baseline for detecting any serotonergic over-activation (rapid heart rate) when combined with serotonergic drugs | Best measured in the morning before rising; trend matters more than a single value |
| Comprehensive metabolic panel (a standard blood panel of liver, kidney, and electrolyte markers) | Within standard reference ranges | General safety baseline given the complete absence of human toxicology data | Requires an 8–12 hour fast; pairs well with a baseline lipid panel |
| Subjective sleep latency | <20 min to fall asleep | Tracks the intended primary effect | Best logged nightly via a sleep diary or wearable; compare against a pre-supplement baseline week |

Qualitative markers are the most practical gauge of success or trouble:

* Sleep quality and time to fall asleep (the primary intended benefit)
* Next-day alertness versus grogginess (key side-effect signal)
* Daytime mood and anxiety levels
* Daytime dizziness or lightheadedness (possible blood-pressure effect)
* Overall energy and cognitive clarity

## Emerging Research

* **Minimal human-trial footprint:** A search of ClinicalTrials.gov returned no interventional or observational studies of oleamide as an intervention as of June 2026; the only completed human trial is a single small Japanese RCT registered outside ClinicalTrials.gov ([Sasaki et al., 2024](https://pubmed.ncbi.nlm.nih.gov/38600994/)) testing a microgram oral dose for cognition and sleep, leaving the molecule almost entirely preclinical and this near-absence of human data its most notable research feature.

* **FAAH-inhibition strategy:** Much forward-looking work targets the enzyme rather than the molecule — raising endogenous oleamide and anandamide by blocking FAAH. The cautionary backdrop is the 2016 Bial BIA 10-2474 trial, a FAAH-inhibitor study that caused severe neurological harm, which tempers enthusiasm for manipulating this pathway and is reviewed by [McKinney & Cravatt, 2005](https://pubmed.ncbi.nlm.nih.gov/15952893/) on FAAH structure and function.

* **Mechanistic resolution (could strengthen the case):** Studies clarifying whether oleamide acts directly at CB1 or only indirectly via anandamide — building on [Fowler, 2004](https://pubmed.ncbi.nlm.nih.gov/14691053/) — could firm up the rationale for supplementation if a robust, reproducible direct action is confirmed.

* **Oral pharmacokinetics (could weaken the case):** The critical untested question is whether oral oleamide survives digestion and FAAH breakdown to reach the brain at active levels; a negative human pharmacokinetic result would substantially undercut its value as a supplement. No published human pharmacokinetic study exists, and [Boger et al., 1998](https://pubmed.ncbi.nlm.nih.gov/10197045/) underscores how rapidly FAAH clears it.

* **Cardiovascular signaling (direction uncertain):** Whether oleamide's in vitro vasodilation translates to any in vivo effect — explored mechanistically by [Hiley & Hoi, 2007](https://pubmed.ncbi.nlm.nih.gov/17445087/) — remains an open area that could reveal either a benefit (blood-pressure support) or a risk (interaction with antihypertensives).

## Conclusion

Oleamide is a fat-derived signaling molecule the body makes itself, first found building up in the spinal fluid of sleep-deprived animals and able to bring on sleep when given to them. It is sold cheaply as a relaxation and sleep supplement, and its appeal rests on an interesting mechanism: it is cleared by the same enzyme that clears one of the body's own cannabis-like messengers, so it may indirectly raise that messenger while also gently amplifying calming brain receptors involved in sleep and mood.

The central feature of the evidence is its imbalance. Almost everything known comes from cells and rodents, while only a single small human study of a very low oral dose exists, and the human safety record is sparse. The clearest signals — falling asleep faster and calming effects — are reproducible in animals but lightly explored in people, and the molecule's mechanism is described in the literature as still debated rather than resolved.

For a health- and longevity-minded reader, oleamide is best understood as a biologically real but unproven option whose main predictable effect is drowsiness and whose long-term safety record is sparse. The overall picture is one of science that is rich at the laboratory level and thin at the human level, and that contrast is the defining characteristic of the current evidence.

**[Top](#top) - [Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol)**


---
canonical_name: Oleoylethanolamide
alternate_names: OEA, N-Oleoylethanolamine, cis-9-Octadecenoylethanolamide, N-(2-Hydroxyethyl)oleamide
canonical_topic: Oleoylethanolamide for Health & Longevity
short_topic_lc: oleoylethanolamide
creation_date: 2026-0709-0125
creator_ai_fullname: Opus 4.8
---

# Oleoylethanolamide for Health & Longevity

Evidence Review created on 07/09/2026 using [AI4L](https://github.com/forever-healthy/AI4L) / Opus 4.8

**Also known as:** OEA, N-Oleoylethanolamine, cis-9-Octadecenoylethanolamide, N-(2-Hydroxyethyl)oleamide

## Motivation

Oleoylethanolamide (OEA) is a fat-derived signaling molecule that the body makes in the small intestine after a meal. It is built from oleic acid, the same monounsaturated fat that is abundant in olive oil. Its best-known job is to act as a natural "I am full" signal: it slows eating, lengthens the gap between meals, and nudges the body toward burning stored fat for energy. Because a synthetic version is sold as a dietary supplement, it has drawn interest from people looking for a gentler way to curb appetite and support a healthy weight.

Interest in taking OEA as a supplement grew out of the observation that its levels rise and fall with feeding and that giving it to animals reliably reduces how much they eat. Human trials, mostly in people with excess weight, prediabetes, or fatty liver, have since tested whether an oral dose can reproduce these effects and improve markers of blood sugar, blood fats, and inflammation.

This review examines what the current evidence shows about oleoylethanolamide as a supplement, weighing its effects on appetite, body weight, and metabolic health against its known risks, the quality of the underlying studies, and the many questions that remain unanswered.

**[Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol) - [Conclusion](#conclusion)**

## Recommended Reading

This section lists high-quality overview resources that discuss oleoylethanolamide and its core biology in depth.

* [Gastrointestinal regulation of food intake: general aspects and focus on anandamide and oleoylethanolamide](https://pubmed.ncbi.nlm.nih.gov/18426498/) - Capasso & Izzo, 2008

This narrative review is an accessible entry point to why OEA acts as a gut-derived "satiety signal" while its cousin anandamide acts as a "hunger signal," and how PPAR-α (peroxisome proliferator-activated receptor alpha, a cellular fuel-sensing switch that controls fat burning) links eating behavior to fat metabolism.

* [Oleoylethanolamide: a novel potential pharmacological alternative to cannabinoid antagonists for the control of appetite](https://pubmed.ncbi.nlm.nih.gov/24800213/) - Romano et al., 2014

This paper directly compares OEA against the withdrawn weight-loss drug rimonabant and argues that OEA reduces food intake by promoting genuine satiety, without the aversive, mood-related effects that come from blocking the CB1 (cannabinoid receptor type 1) directly.

* [Oleoylethanolamide facilitates PPARα and TFEB signaling and attenuates Aβ pathology in a mouse model of Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/37580742/) - Comerota et al., 2023

A standout for the longevity audience: it summarizes evidence that OEA extends lifespan in worms and then shows in mice that a stable OEA analog clears amyloid-beta (Aβ, the sticky protein that builds up in Alzheimer's disease) and improves memory, connecting OEA to cellular clean-up pathways relevant to aging.

* [Atheroprotective effect of oleoylethanolamide (OEA) targeting oxidized LDL](https://pubmed.ncbi.nlm.nih.gov/24465540/) - Fan et al., 2014

This experimental study explores a cardiovascular angle beyond weight, reporting that OEA reduced artery plaque formation in animals by limiting damage to LDL (low-density lipoprotein, the cholesterol-carrying particle that drives plaque) and calming vessel-wall inflammation.

* [Fatty acid amide hydrolase (FAAH) and the endocannabinoid system in obesity: mechanistic insights and pharmacological opportunities beyond incretin-based therapies](https://pubmed.ncbi.nlm.nih.gov/42144898/) - Serra et al., 2026

This recent review places OEA within the wider fat-signaling system and explains how blocking FAAH (fatty acid amide hydrolase, the enzyme that breaks OEA down) could prolong OEA's action and complement newer weight-loss drugs.

Note: No in-depth, OEA-specific article, podcast, or video was found from the priority experts (Rhonda Patrick, Peter Attia, Andrew Huberman, Chris Kresser, or Life Extension). OEA is a niche compound covered mainly in the academic literature, so the list draws on qualifying narrative reviews and primary research instead.

## Grokipedia

* [Oleoylethanolamide](https://grokipedia.com/page/Oleoylethanolamide)

The Grokipedia article gives a broad, referenced overview of OEA's chemistry, its role as a satiety signal, and its metabolic effects, serving as a useful orientation before diving into the primary literature.

## Examine

* [Oleoylethanolamide benefits, dosage, and side effects](https://examine.com/supplements/oleoylethanolamide/)

Examine's independent, research-graded page summarizes the human and animal evidence for OEA on appetite and body weight and flags where the supporting studies are strong versus preliminary.

## ConsumerLab

No dedicated ConsumerLab article or product review exists for oleoylethanolamide as of July 2026. OEA is mentioned only inside ConsumerLab's coverage of the related compound PEA (palmitoylethanolamide), where a combined product was discussed, but no standalone OEA testing or review is available.

## Systematic Reviews

This section summarizes the systematic reviews and meta-analyses that pool the human and preclinical evidence on oleoylethanolamide.

* [Oleoylethanolamide supplementation on cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials](https://pubmed.ncbi.nlm.nih.gov/40469682/) - Bahari et al., 2025

Pooling 10 randomized controlled trials (RCTs, studies in which participants are randomly assigned to treatment or placebo), this meta-analysis found that OEA significantly reduced body weight, body mass index, waist circumference, fat mass, triglycerides, fasting glucose, insulin, and the inflammatory markers CRP (C-reactive protein) and TNF-α (tumor necrosis factor-alpha), while cholesterol and HbA1c (a measure of average blood sugar over three months) were unchanged.

* [The effect of oleoylethanolamide supplementation on cardiometabolic factors: a systematic review and meta-analysis](https://pubmed.ncbi.nlm.nih.gov/40661161/) - Eslahi et al., 2025

Drawing on 13 studies, this meta-analysis quantified the average benefits, reporting reductions in fasting blood sugar, insulin, waist circumference, triglycerides, and inflammatory markers alongside a rise in total antioxidant capacity, and it usefully reports effects as weighted mean differences (the average real-world change in each measure).

* [A systematic review of the effects of oleoylethanolamide, a high-affinity endogenous ligand of PPAR-α, on the management and prevention of obesity](https://pubmed.ncbi.nlm.nih.gov/31868943/) - Tutunchi et al., 2020

This review focuses specifically on obesity, cataloguing how OEA curbs food intake and promotes fat burning through PPAR-α and the fat-transport protein CD36, and it is the best single source for the proposed appetite and energy-balance mechanisms.

* [The effects of oleoylethanolamide, an endogenous PPAR-α agonist, on risk factors for NAFLD: a systematic review](https://pubmed.ncbi.nlm.nih.gov/31111657/) - Tutunchi et al., 2019

Centered on NAFLD (non-alcoholic fatty liver disease, a build-up of fat in the liver not caused by alcohol), this review gathers evidence that OEA improves liver-related lipid metabolism, inflammation, and oxidative stress, and is the key reference for OEA's liver effects.

* [Efficacy of selected dietary supplements and pharmacological agents on metabolic and oxidative stress outcomes in metabolic dysfunction-associated fatty liver disease (MAFLD): a Bayesian network meta-analysis](https://pubmed.ncbi.nlm.nih.gov/41695987/) - Yang et al., 2025

This network meta-analysis ranks OEA against many other supplements and drugs for fatty liver disease, providing helpful comparative context on where OEA sits relative to alternatives, though OEA is only one of several agents evaluated.

## Mechanism of Action

Oleoylethanolamide is an N-acylethanolamine (NAE, a family of fat-based signaling molecules chemically related to the body's own cannabis-like compounds). It is manufactured on demand in the cells lining the small intestine from dietary oleic acid, and its production rises after a fatty meal and falls during fasting.

Its primary and best-characterized action is as a high-affinity agonist (activator) of PPAR-α, a nuclear receptor that acts as a master switch for burning fat. Activating PPAR-α turns up genes that drive lipolysis (the breakdown of stored fat) and beta-oxidation (the process cells use to convert fatty acids into energy), and it improves the liver's handling of fats. Because these are the same downstream effects targeted by fibrate cholesterol drugs, OEA is often described as a natural PPAR-α agonist.

OEA controls appetite largely from the gut. Rather than entering the brain in bulk, it activates local sensory nerve endings — chiefly fibers of the vagus nerve, the main information cable between the gut and the brain — which relay a satiety message to feeding-control centers in the brainstem and hypothalamus. This triggers downstream release of signals such as oxytocin and brain histamine that reinforce fullness and delay the next meal. OEA also engages other receptors, including TRPV1 (a sensory ion channel involved in nerve signaling), GPR119 (a gut receptor that boosts release of the fullness-and-insulin hormone GLP-1, glucagon-like peptide-1), and CD36 (a fat-sensing transporter).

Importantly, OEA does NOT bind directly to the classic cannabinoid receptors CB1 or CB2, which distinguishes it from anandamide and explains why it lacks the mood and reward side effects of cannabinoid-blocking drugs. OEA is broken down by two enzymes, FAAH and NAAA (N-acylethanolamine acid amidase), which gives it a short duration of action and makes these enzymes drug-development targets.

A competing view tempers the appetite story: some researchers argue that part of OEA's food-intake reduction in animals reflects mild malaise or reduced movement rather than "clean" satiety, and that very high injected doses behave differently from modest oral doses. Both interpretations appear in the literature, and human oral trials — which show reduced hunger without reported distress — are used to argue against the malaise explanation.

As a lipid supplement, OEA is not a conventional drug, but its relevant pharmacological properties are: a short half-life due to rapid enzymatic breakdown by FAAH and NAAA; high selectivity for PPAR-α among its targets; concentration in gut and liver tissue where it is produced and acts; and metabolism by lipid-amide hydrolysis rather than by the liver's cytochrome P450 (CYP) enzyme system, meaning classic CYP-based drug interactions are unlikely.

## Historical Context & Evolution

Oleoylethanolamide was first identified as a naturally occurring lipid decades ago, but its role in physiology only became clear in the early 2000s when researchers discovered that its levels in the gut track feeding and that administering it to rodents produced dose-dependent satiety and weight loss. This positioned OEA not as an external drug but as part of the body's own system for matching food intake to energy needs.

Interest in OEA for health optimization grew from two converging threads. First, the search for anti-obesity therapies that work through the endocannabinoid-like system gained urgency after the CB1-blocking drug rimonabant was withdrawn for causing depression and anxiety; OEA offered a way to influence the same appetite circuitry without touching cannabinoid receptors. Second, the recognition of OEA as a potent natural PPAR-α agonist connected it to the well-established metabolic benefits of that pathway, prompting trials in obesity, prediabetes, and fatty liver.

The scientific picture has continued to evolve rather than settle. Early enthusiasm from animal work has been partly borne out by small human trials showing modest metabolic benefits, but the debate over whether OEA's appetite effect is "true satiety" or partly non-specific remains open, and newer directions — lifespan extension in worms, brain clean-up pathways relevant to Alzheimer's disease, and enzyme-inhibition strategies to prolong OEA's action — suggest the compound's full profile is still being mapped. What changed most recently is the accumulation of human meta-analyses, which have moved OEA from a purely mechanistic curiosity toward a compound with measurable, if modest, clinical signals.

## Expected Benefits

Benefits below are framed for a proactive, health-optimizing adult and graded by the strength of the underlying evidence. Most human data come from short (8-12 week) trials in people with excess weight, prediabetes, or fatty liver, which shapes how confidently each benefit applies.

### High 🟩 🟩 🟩

#### Reduced Body Weight & Fat Mass

OEA's most consistent human benefit is a modest reduction in body weight, body mass index, waist circumference, and fat mass when taken alongside a calorie-controlled diet. The proposed mechanism combines appetite suppression with increased fat burning through PPAR-α. The evidence base is a [2025 meta-analysis of 10 RCTs](https://pubmed.ncbi.nlm.nih.gov/40469682/) and a [second 2025 meta-analysis of 13 studies](https://pubmed.ncbi.nlm.nih.gov/40661161/), both finding statistically significant reductions, though effect sizes are small and trials were mostly conducted in one research setting, which is a notable limitation.

**Magnitude:** Average waist circumference reduction of roughly 2 cm and modest reductions in weight and fat mass over 8-12 weeks; not a substitute for the larger losses seen with prescription weight-loss medication.

#### Appetite Suppression & Increased Satiety

OEA reduces hunger, curbs cravings, and increases the sense of fullness, which is the mechanism behind its weight effects. Acting through gut vagal signaling and PPAR-α, it lengthens the interval between meals. A [double-blind RCT in people with obesity](https://pubmed.ncbi.nlm.nih.gov/29787831/) showed significant decreases in hunger and desire to eat and increased fullness on standardized appetite scales, consistent with a large body of animal work; the main nuance is that appetite ratings are subjective and short-term.

**Magnitude:** Significant self-reported reductions in hunger and cravings and increased fullness within 8 weeks; the effect is meaningful but gentle compared with hunger-blunting prescription drugs.

### Medium 🟩 🟩

#### Improved Glycemic Control

OEA modestly improves blood-sugar regulation, lowering fasting glucose, insulin, and insulin resistance. The likely mechanism is improved fat handling and reduced inflammation, which ease the burden on insulin signaling. Pooled human data show significant reductions in fasting glucose and insulin, and a [dedicated RCT in prediabetes](https://pubmed.ncbi.nlm.nih.gov/35659064/) reported improved glucose, insulin, insulin resistance, and HbA1c; however, one meta-analysis found no significant change in HbA1c, indicating the longer-term glucose benefit is less certain.

**Magnitude:** Fasting blood sugar reduced by roughly 6 mg/dL and fasting insulin by about 3 µIU/mL on average across trials.

#### Reduced Triglycerides

OEA lowers blood triglycerides (the main fat carried in the bloodstream), consistent with PPAR-α-driven fat clearance, while leaving total, LDL, and HDL cholesterol largely unchanged. This selective effect on triglycerides mirrors how fibrate drugs behave. The [2025 meta-analysis](https://pubmed.ncbi.nlm.nih.gov/40661161/) found a significant triglyceride reduction but no significant change in other lipids, so the benefit is real but narrow.

**Magnitude:** Average triglyceride reduction of roughly 18 mg/dL; no reliable change in LDL or HDL cholesterol.

#### Reduced Inflammatory Markers ⚠ Conflicted

OEA lowers several markers of chronic low-grade inflammation, notably CRP and TNF-α, likely via PPAR-α's anti-inflammatory actions in fat and liver tissue. The evidence is conflicted for interleukin-6 (IL-6, another inflammation signal): one [meta-analysis](https://pubmed.ncbi.nlm.nih.gov/40661161/) found a significant IL-6 reduction while [another](https://pubmed.ncbi.nlm.nih.gov/40469682/) did not, and a dedicated [NAFLD inflammation RCT](https://pubmed.ncbi.nlm.nih.gov/37089938/) reported improvements in inflammatory and oxidative markers. The overall anti-inflammatory signal is credible but the magnitude for individual markers is inconsistent.

**Magnitude:** Average TNF-α reduction of roughly 2.4 pg/mL and significant CRP reduction; IL-6 change inconsistent across studies.

#### Reduced Oxidative Stress

OEA raises total antioxidant capacity and lowers malondialdehyde (MDA, a marker of fat-molecule damage from oxidation), suggesting a shift toward better protection against cellular oxidative wear. This is thought to follow from reduced inflammation and improved lipid metabolism. Pooled analyses and the [NAFLD RCT](https://pubmed.ncbi.nlm.nih.gov/37089938/) support this, though oxidative-stress markers are indirect and their long-term clinical meaning is uncertain.

**Magnitude:** Significant rise in total antioxidant capacity and reduction in MDA over 8-12 weeks; clinical importance not yet established.

### Low 🟩

#### Improved Liver Health in Fatty Liver Disease

In people with fatty liver, OEA added to calorie restriction has improved liver enzymes, body composition, and the expression of fat-metabolism genes. The mechanism is PPAR-α-driven fat oxidation in the liver plus reduced inflammation. Evidence comes from several small [NAFLD RCTs](https://pubmed.ncbi.nlm.nih.gov/32217148/) and a [supporting systematic review](https://pubmed.ncbi.nlm.nih.gov/31111657/), but trials are small, short, and always paired with diet, so OEA's independent contribution is hard to isolate.

**Magnitude:** Improvements in liver enzymes and body-composition measures in small trials; no data on hard outcomes such as fibrosis reversal.

#### Reduced Menstrual Pain

A single RCT reported that OEA reduced period pain in young women, attributed to its anti-inflammatory and antioxidant effects lowering pain-driving signals. The [dysmenorrhea RCT](https://pubmed.ncbi.nlm.nih.gov/35293068/) found reduced pain alongside improved oxidative and inflammatory markers. As an isolated, small, single-population study, the finding is promising but not yet reproducible.

**Magnitude:** Clinically meaningful pain reduction in one trial; unreplicated.

#### Improved Mood & Reduced Fatigue

An exploratory RCT in veterans with Gulf War Illness found that OEA improved mood and reduced fatigue over 15 weeks, with participants reporting more energy and better emotional well-being. The proposed basis is OEA's anti-inflammatory and lipid-signaling effects on the brain. The [2026 exploratory trial](https://pubmed.ncbi.nlm.nih.gov/41513981/) is small and in a specific, unwell population, so generalizing to healthy adults is speculative.

**Magnitude:** Improved mood and fatigue scores in one exploratory trial; not quantified for a general population.

### Speculative 🟨

#### Neuroprotection & Longevity Signaling

OEA activates cellular clean-up and lifespan pathways that are of direct interest to longevity. In roundworms it extends lifespan through lysosome-to-nucleus signaling, and in a [mouse model of Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/37580742/) a stable OEA analog boosted the brain's immune cells to clear amyloid-beta and rescued memory. This basis is entirely preclinical, with no human longevity or cognition trials, so it is mechanistic and anecdotal only at present.

#### Atheroprotection & Cardiovascular Plaque Reduction

OEA may protect arteries beyond its effects on weight and blood fats. In [animal studies](https://pubmed.ncbi.nlm.nih.gov/24465540/) it reduced plaque formation by limiting oxidative damage to LDL particles and calming vessel-wall inflammation. No human cardiovascular-outcome data exist, so this benefit rests on animal and cell experiments only.

## Benefit-Modifying Factors

* **Genetic variation in PPAR-α:** Because OEA acts chiefly through PPAR-α, common variants in the PPARA gene (such as L162V, which alters receptor activity) may plausibly influence how strongly a person responds, though this has not been directly tested for OEA supplementation.

* **FAAH activity:** People carrying the common FAAH C385A variant (rs324420), which slows breakdown of OEA-like lipids, may have naturally higher endogenous levels and could respond differently to supplementation; this is mechanistically likely but unstudied for OEA specifically.

* **Baseline metabolic status:** Benefits are most evident in people who start with excess weight, elevated blood sugar, high triglycerides, or fatty liver. Individuals already lean and metabolically healthy have more limited room to improve and were not the population studied.

* **Sex-based differences:** Several trials were conducted in women (prediabetes, PCOS (polycystic ovary syndrome), dysmenorrhea) and others in mixed groups, but no study has directly compared OEA's effects between sexes, so any sex difference in response is currently unknown.

* **Age:** Trials enrolled adults across a broad age range but rarely older adults specifically. Since endogenous OEA signaling and PPAR-α activity may decline with age, older adults in the target audience could in theory respond differently, but direct evidence is lacking.

* **Concurrent diet:** Nearly all positive trials paired OEA with calorie restriction, and OEA's own production depends on dietary fat, so a person's baseline diet likely shapes the response.

## Potential Risks & Side Effects

Across human trials, OEA has been well tolerated with no serious adverse events reported, so its risk profile is thin and dominated by mild, theoretical, or preclinical concerns. Risks below are framed for a health-optimizing adult.

### Medium 🟥 🟥

#### Mild Gastrointestinal Effects

The most commonly plausible side effects are mild digestive symptoms — nausea, a sense of over-fullness, or stomach discomfort — consistent with OEA's action on gut motility and satiety signaling. Human trials report good overall tolerability without notable dropouts for gastrointestinal reasons, and any symptoms appear mild and transient. The main nuance is that OEA supplements are sometimes combined with other ingredients, which can confound attribution of digestive complaints.

**Magnitude:** Uncommon and mild; typically self-limiting and not a frequent cause of discontinuation in trials.

### Low 🟥

#### Excessive Appetite Suppression in Lean Users

Because OEA's core action is to reduce hunger and food intake, individuals who are already lean or who under-eat could experience unwanted appetite loss or unintended weight reduction. This is a direct extension of its intended mechanism rather than a toxic effect. No trials have specifically studied lean or underweight users, so this is inferred from how the compound works.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Sedation & Reduced Movement at High Doses

In rodent studies, high injected doses of OEA reduced spontaneous movement and induced a quiescent, possibly malaise-like state, raising a theoretical concern about sedation or lethargy. This has not been observed with the modest oral doses used in humans, and one human trial actually reported reduced fatigue, so the concern is preclinical and dose-specific.

#### Unknown Long-Term Safety

Human trials rarely exceed 12 weeks, so nothing is known about the safety of taking OEA continuously for months or years, including effects on the liver, hormones, or metabolism over time. This is an absence-of-evidence risk rather than a documented harm.

#### Effects on Sleep and Alertness

Animal work shows OEA can influence the sleep-wake cycle through brain histamine and other pathways, raising a theoretical possibility of altered sleep or alertness in some users. No human sleep-disruption signal has been reported, making this speculative.

## Risk-Modifying Factors

* **Genetic variation in fat-amide breakdown:** Carriers of the FAAH C385A variant (rs324420), which slows degradation of OEA-like lipids, might sustain higher OEA exposure and could theoretically be more prone to appetite-related or sedation effects, though this is untested.

* **Baseline nutritional status:** Lean, underweight, or already appetite-suppressed individuals (for example those on other weight-loss agents) are at higher risk of unwanted appetite loss, whereas people with excess weight tolerate the satiety effect as a benefit.

* **Sex-based differences:** No sex-specific safety differences have been identified; women have been well represented in trials (including PCOS and dysmenorrhea studies) without distinctive adverse-event patterns, but direct comparisons are absent.

* **Pre-existing conditions:** People with eating disorders, significant gastrointestinal disease, or those who are pregnant or breastfeeding fall outside the studied populations, so risks in these groups are unknown and caution is warranted.

* **Age:** Older adults were underrepresented in trials, and altered drug metabolism and appetite regulation with age could change tolerability, but no age-specific safety data exist.

## Key Interactions & Contraindications

* **Fibrate lipid drugs (fenofibrate, gemfibrozil):** As fellow PPAR-α activators, these share OEA's mechanism, creating a theoretical additive effect on triglycerides and fat metabolism. Severity: caution/monitor; clinical consequence is largely additive benefit, but combined use is unstudied and warrants monitoring of lipids.

* **GLP-1 receptor agonists (semaglutide, liraglutide) and other appetite-suppressing drugs:** OEA's satiety effect could add to these agents, potentially causing excessive appetite loss or unintended weight reduction. Severity: caution; mitigating action is to monitor intake and weight if combined.

* **FAAH-inhibitor drugs or supplements:** Compounds that block FAAH raise endogenous OEA and related lipids, so co-use could amplify OEA exposure and its effects. Severity: caution; separate rationale and monitor for exaggerated effects.

* **Over-the-counter products:** No specific over-the-counter drug interactions are documented. OEA is metabolized by lipid-amide hydrolysis rather than the liver's CYP enzymes, so interactions with common over-the-counter analgesics or antacids are considered unlikely.

* **Supplement interactions and additive effects:** OEA is frequently paired with PEA (palmitoylethanolamide) and with berberine or green-tea extract in weight products; these combinations may be additive for metabolic or anti-inflammatory effects but are not individually validated. Other PPAR-α-influencing supplements (fish oil) could be mildly additive on triglycerides.

* **Other interventions:** OEA's benefits are consistently demonstrated alongside calorie restriction, so it interacts favorably with dietary interventions rather than adversely.

* **Populations who should avoid it:** In the absence of safety data, OEA should be avoided by those who are pregnant or breastfeeding, by people with active eating disorders (given its appetite-suppressing action), and by children and adolescents. People who are underweight (for example body mass index below 18.5) should be cautious given the risk of unwanted appetite loss.

## Risk Mitigation Strategies

* **Start low and take with food:** Beginning at a single 125 mg dose taken before a meal, rather than a full split dose, allows tolerance to be assessed and mitigates the risk of mild gastrointestinal discomfort and over-suppression of appetite.

* **Match use to a metabolic goal:** Reserving OEA for periods of intentional weight or metabolic management, and only in people with excess weight or elevated metabolic markers, mitigates the risk of unwanted appetite loss and weight reduction in lean users.

* **Monitor weight and intake:** Tracking body weight and daily food intake, especially in the first 4 weeks, guards against excessive appetite suppression; a downward trend toward underweight or inadequate intake signals the need to stop.

* **Limit duration and reassess:** Because long-term safety is unknown, using OEA in defined blocks (for example 8-12 weeks) followed by reassessment mitigates the uncertainty around chronic exposure.

* **Combine cautiously with appetite-lowering agents:** When someone already uses a GLP-1 drug or another appetite suppressant, avoiding or minimizing concurrent OEA prevents additive over-suppression of hunger.

* **Choose tested products:** Selecting third-party-tested OEA mitigates the risk of under-dosing, contamination, or undisclosed added stimulants that could cause the adverse effects OEA itself does not.

## Therapeutic Protocol

* **Standard dose:** The most common protocol used in human trials and by practitioners is 125 mg once or twice daily, giving a total of 125-250 mg per day. The twice-daily approach, taking one dose before each of the two largest meals, is used to leverage OEA's meal-related satiety effect.

* **Competing approaches:** Some formulations use a single larger daily dose or pair OEA with PEA (palmitoylethanolamide) or with an enhanced-absorption delivery system; a newer LipiSperse-formulated version aims to improve absorption. No approach has been shown superior in head-to-head trials, and the simple twice-daily 125 mg regimen has the most direct human evidence.

* **Originating researchers:** The bulk of the human dosing evidence comes from research groups at Tabriz and Qazvin University of Medical Sciences in Iran, who ran most of the obesity, prediabetes, and NAFLD trials using the 125 mg capsule.

* **Best time of day:** OEA is best taken shortly before meals (roughly 30 minutes prior) so that its satiety signal coincides with eating; there is no established benefit to bedtime dosing, and its role in the sleep-wake cycle is another reason to favor daytime, pre-meal timing.

* **Half-life:** OEA has a short duration of action because it is rapidly broken down by the enzymes FAAH and NAAA; this short half-life is the rationale for split, pre-meal dosing rather than a single dose.

* **Single versus split dosing:** Split dosing before the two main meals is generally preferred over a single dose, both to align with meal-related satiety and to work around OEA's rapid breakdown.

* **Genetic considerations:** Variants in PPARA (such as L162V) and in FAAH (rs324420) could in theory influence the ideal dose or response, but no pharmacogenetic dosing guidance exists, so protocols are not currently individualized by genotype.

* **Sex-based differences:** No sex-specific dosing has been established; women and mixed groups used the same 125 mg regimen without evidence that dose should differ by sex.

* **Age considerations:** No age-adjusted dosing has been defined; older adults in the target audience were underrepresented, so the standard adult dose is applied cautiously with attention to tolerability.

* **Baseline biomarkers:** Response is likely greatest in those with elevated fasting glucose, triglycerides, or liver fat, so baseline metabolic testing helps identify who is most likely to benefit and provides a comparison for follow-up.

* **Pre-existing conditions:** Protocols concentrate on people with excess weight, prediabetes, or fatty liver; use outside these groups is not well supported and dosing in other conditions is not established.

## Discontinuation & Cycling

* **Lifelong versus short-term:** OEA is best regarded as a short-to-medium-term aid for a specific metabolic goal rather than a lifelong supplement, because human evidence is limited to trials of 12 weeks or less and long-term data are absent.

* **Withdrawal effects:** No withdrawal syndrome has been reported; because OEA works with the body's own satiety signaling and clears quickly, stopping it is not expected to cause rebound symptoms, though appetite may return to its prior baseline.

* **Tapering:** No tapering protocol is needed or established; OEA can be stopped abruptly given its short duration of action and the lack of any documented discontinuation effects.

* **Cycling:** Using OEA in defined blocks (for example 8-12 weeks) followed by a break is a reasonable, evidence-uncertain strategy that aligns with how trials were run and limits open-ended exposure, but no data show that cycling maintains or enhances efficacy.

* **Reassessment:** Each course should end with a reassessment of weight and metabolic markers to decide whether continued use, a break, or discontinuation is warranted.

## Sourcing and Quality

* **Product form:** The active ingredient should be listed as oleoylethanolamide or N-oleoylethanolamine; buyers should confirm the labeled dose (commonly 125 mg per capsule) matches the studied regimen rather than a proprietary blend that hides the amount.

* **Third-party testing:** Because OEA is sold as an unregulated dietary supplement, choosing products with independent third-party testing (for identity, dose accuracy, and contaminants) is the single most important quality safeguard.

* **Absorption-enhanced formulations:** Some products use delivery systems such as LipiSperse intended to improve absorption of this fat-based molecule; these may aid bioavailability but are not required, and their added benefit over standard capsules is not firmly established.

* **Avoid undisclosed blends:** Weight-loss products sometimes combine OEA with stimulants or diuretics; selecting single-ingredient OEA or transparently labeled combinations avoids hidden actives that carry their own risks.

* **Reputable sourcing:** Purchasing from established supplement brands that publish certificates of analysis, rather than unbranded marketplace sellers, reduces the risk of underdosed or adulterated product.

## Practical Considerations

* **Time to effect:** Appetite and fullness effects can be noticed within hours to days of starting, tied to meal timing, whereas measurable changes in weight, blood sugar, triglycerides, and inflammation typically take 8-12 weeks, matching the length of the trials.

* **Common pitfalls:** The most common mistakes are expecting drug-like weight loss (the effect is modest), taking OEA without any dietary change (trials paired it with calorie restriction), dosing at the wrong time (it works best just before meals), and buying unverified products that may be underdosed.

* **Regulatory status:** OEA is sold as a dietary supplement and is not approved as a drug for any condition; it is not regulated for efficacy, and its use for weight or metabolic goals is entirely off-label in the informal sense that no health authority endorses it.

* **Cost and accessibility:** OEA is widely available online at moderate cost and is not exceptionally expensive or hard to obtain, though quality varies and enhanced-absorption formulations cost more.

## Interaction with Foundational Habits

* **Sleep:** The interaction is uncertain and potentially bidirectional. OEA influences the sleep-wake cycle through brain histamine in animal studies, so a theoretical direct effect on sleep exists; practically, taking OEA before daytime meals rather than at night avoids any risk of alertness effects near bedtime.

* **Nutrition:** The interaction is direct and central. OEA's own production and its satiety signal depend on dietary fat, and every positive human trial paired it with calorie restriction, so it works best as an adjunct to a controlled diet; there is no evidence it depletes specific nutrients, and taking it before the largest meals maximizes its fullness effect.

* **Exercise:** The interaction is indirect and complementary. OEA and exercise both activate PPAR-α and promote fat oxidation, so the two are plausibly additive for fat metabolism; no evidence suggests OEA blunts training adaptations, and no specific timing around workouts is established.

* **Stress management:** The interaction is indirect. Unlike direct cannabinoid-blocking drugs, OEA does not act on the CB1 receptor and has not been linked to anxiety or low mood; an exploratory trial even reported improved mood and reduced fatigue, suggesting a neutral-to-favorable relationship with stress and well-being rather than a harmful one.

## Monitoring Protocol & Defining Success

Before starting OEA, establishing a baseline of metabolic markers helps identify who is most likely to benefit and provides a reference point for judging response. Baseline testing should include body weight and waist circumference plus the fasting blood markers below.

Ongoing monitoring is best done by rechecking metabolic markers at roughly 8-12 weeks (the point at which trial benefits emerged), and then every 3-6 months if use continues, alongside weekly self-monitoring of weight and appetite during the first month to catch excessive appetite suppression.

| Biomarker | Optimal Functional Range | Why Measure It? | Context/Notes |
| --- | --- | --- | --- |
| Waist circumference | <94 cm (men), <80 cm (women) | Tracks central fat, OEA's most consistent target | Measure at the navel, same time of day; more responsive than scale weight |
| Fasting glucose | 75-86 mg/dL | Detects blood-sugar benefit | Conventional cutoff is <100 mg/dL; requires an 8-12 hour fast |
| Fasting insulin | 2-6 µIU/mL | Sensitive early marker of insulin resistance | Conventional labs flag only >25 µIU/mL; pair with glucose to compute HOMA-IR |
| HOMA-IR | <1.0 | Summarizes insulin resistance from glucose and insulin | Calculated value; a functional target well below the conventional ~2.5 threshold |
| HbA1c | <5.3% | Reflects average blood sugar over 3 months | Conventional prediabetes cutoff is 5.7%; slower to change, recheck at 3 months |
| Triglycerides | <80 mg/dL | OEA's clearest lipid benefit | Conventional cutoff is <150 mg/dL; requires fasting; best paired with a full lipid panel |
| hs-CRP | <0.5 mg/L | Gauges the anti-inflammatory effect | Conventional low-risk is <1.0 mg/L; avoid testing during acute illness, which falsely elevates it |
| ALT (liver enzyme) | <25 U/L (men), <20 U/L (women) | Monitors fatty-liver benefit and liver safety | Conventional upper limit (~40 U/L) is less sensitive; best paired with an ultrasound in known fatty liver |

Qualitative markers are useful alongside the labs and are often what users notice first:

* **Hunger and cravings:** Reduced hunger between meals and fewer cravings, especially for sweets.
* **Fullness and portion size:** Feeling satisfied sooner and eating smaller portions without effort.
* **Energy levels:** Stable or improved daytime energy rather than the fatigue sometimes seen with restrictive dieting.
* **Mood and well-being:** Steady or improved mood, consistent with the compound's neutral-to-favorable psychological profile.

## Emerging Research

Research framed for the health-optimizing adult is expanding OEA beyond weight management into brain, gut, and cardiometabolic health, with several registered trials underway.

* **Sleep, stress, and anxiety trial:** A recruiting Phase 2 trial is testing OEA's effect on perceived stress, anxiety, and sleep quality in a large group, extending OEA research into mental well-being. [NCT07315516](https://clinicaltrials.gov/study/NCT07315516) (planned enrollment ~240 participants).

* **Alcohol use disorder trial:** A planned Phase 2 trial will examine whether OEA lowers inflammatory signals such as IL-6 and TNF-α in young adults with alcohol use disorder, probing its anti-inflammatory action in a new population. [NCT07503782](https://clinicaltrials.gov/study/NCT07503782) (planned enrollment ~42 participants).

* **Gut microbiome and metabolic health trial:** A planned Phase 2 study will explore how OEA affects the gut microbiome and metabolic markers in healthy volunteers, building on animal findings that OEA alters gut bacteria such as *Akkermansia muciniphila* reported in an earlier [human trial](https://pubmed.ncbi.nlm.nih.gov/31132422/). [NCT07457723](https://clinicaltrials.gov/study/NCT07457723) (planned enrollment ~90 participants).

* **Absorption and GLP-1 study:** A completed Phase 4 pharmacokinetic trial compared an enhanced-absorption OEA formulation and its effect on the fullness hormone GLP-1, informing how future products might be dosed for better bioavailability. [NCT06840080](https://clinicaltrials.gov/study/NCT06840080) (40 participants).

* **Mood and fatigue direction:** A 2026 exploratory RCT reporting that OEA improved mood and reduced fatigue in veterans points toward neuropsychiatric applications that could strengthen the case for OEA if replicated in healthy adults. [Abdullah et al., 2026](https://pubmed.ncbi.nlm.nih.gov/41513981/).

* **Longevity and neurodegeneration direction:** Preclinical work connecting OEA to lifespan extension and clearance of Alzheimer's-related amyloid could redefine OEA as a longevity compound, but would require human studies to confirm and could equally fail to translate. [Comerota et al., 2023](https://pubmed.ncbi.nlm.nih.gov/37580742/).

* **Enzyme-inhibition strategy:** A 2026 review argues that blocking FAAH to prolong the body's own OEA, potentially alongside newer weight-loss drugs, is a promising but unproven direction that could either extend OEA's benefits or reveal off-target effects. [Serra et al., 2026](https://pubmed.ncbi.nlm.nih.gov/42144898/).

## Conclusion

Oleoylethanolamide is a fat-based signaling molecule the body makes in the gut after eating, where it acts as a natural fullness signal and encourages the body to burn stored fat. Taken as a supplement, it has been studied mostly in people with excess weight, high blood sugar, or fatty liver, and the pooled human evidence points to real but modest benefits: less hunger, small reductions in body weight and waist size, and improvements in blood sugar, blood fats, inflammation, and antioxidant status when it is combined with a calorie-controlled diet. Its safety record in these short studies is reassuring, with only mild and infrequent digestive complaints and no serious problems reported.

The evidence, however, is early. Most trials are small, brief, and come from a narrow set of research groups, so confidence in the size and durability of the effects is limited, and nothing is known about taking it for longer than a few months. Its most exciting possibilities — supporting the aging brain, extending lifespan, and protecting the arteries — rest entirely on animal work. For a proactive adult, oleoylethanolamide reads as a gentle, well-tolerated aid to appetite and metabolic health with a genuine but understated evidence base, rather than a proven long-term or longevity intervention. Its main value lies in supporting dietary effort, and its main limitation is how much remains unstudied.

**[Top](#top) - [Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol)**