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AM3506 is an investigational fatty acid amide hydrolase (FAAH) inhibitor of the sulfonyl fluoride chemical class that raises brain levels of the endocannabinoid anandamide by irreversibly blocking the enzyme that degrades it. Developed at Northeastern University's Center for Drug Discovery (Makriyannis group) and characterized largely in collaboration with the National Institutes of Health, it is a potent, selective, covalent inhibitor of both rat and human FAAH. In preclinical models it normalizes blood pressure in hypertensive rats, promotes fear extinction through the amygdala, and restores endotoxin-disturbed gastrointestinal motility, all via downstream CB1/CB2 receptor signaling. AM3506 has not entered human clinical trials and remains a research compound.
- Normalizes elevated blood pressure and cardiac contractility in hypertensive rats
- Promotes fear extinction and reduces conditioned fear via the amygdala
- Raises anandamide on-demand without direct CB1 overstimulation
- Spares liver FAAH, avoiding insulin resistance and hyperglycemia
- Restores normal gastrointestinal motility after endotoxin challenge
- Selective, equipotent covalent inhibition of rat and human FAAH
- Reactive sulfonyl fluoride warhead raises off-target/handling concerns
- Impaired working memory in rats at higher doses (CB1-mediated)
- Potential cannabis-like cognitive effects at higher exposure
Overview
AM3506 is one of the cleaner FAAH tool inhibitors in this space; it is essentially an anandamide amplifier that lets your own endocannabinoids do the work instead of flooding CB1 the way THC does. What makes it stand out is selectivity; it covalently locks up FAAH but pretty much spares the liver enzyme pool, so in the hypertension work it dropped elevated blood pressure without the insulin resistance and hyperglycemia that dogged other FAAH programs. The fear-extinction data out of the amygdala is genuinely exciting for anxiety and PTSD angles, and the gut-motility normalization is a nice bonus. Just keep it honest; this is a research-grade sulfonyl fluoride that never reached human trials, and the rat working-memory study showed it can nudge memory the way cannabis does at higher exposure. Treat it as an investigational probe, not a finished supplement.
Mechanism
AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride) is an irreversible, covalent inhibitor of fatty acid amide hydrolase (FAAH), the serine hydrolase that hydrolyzes the endocannabinoid anandamide (AEA) and related fatty acid ethanolamides such as OEA and PEA. Its reactive sulfonyl fluoride warhead forms a covalent adduct with the catalytic serine of FAAH, shutting the enzyme down; rapid-dilution assays and mass spectrometry confirmed the modification is essentially permanent rather than competitive.
Because degradation is blocked, anandamide accumulates on-demand at sites of physiological activity (for example the basolateral amygdala during extinction learning, or the brainstem in hypertension), where it activates cannabinoid CB1 receptors (and CB2 in the gut). The result is CB1-mediated reduction of sympathetic tone and blood pressure, CB1-driven long-term depression of inhibitory transmission that supports fear extinction, and CB1/CB2-mediated normalization of exaggerated gastrointestinal motility. Notably, AM3506 undergoes rapid hepatic uptake and metabolism, so it fails to durably inhibit liver FAAH; this spares the metabolic side effects ( resistance, hyperglycemia) seen with globally acting FAAH inhibitors and FAAH-knockout mice.
receptor fingerprint
FAAH (fatty acid amide hydrolase)Irreversible covalent inhibition
Anandamide (AEA)Elevates tissue levels (substrate accumulation)
CB1 receptorIndirect agonism (via elevated anandamide)
CB2 receptorIndirect agonism (via elevated fatty acid amides)
Hepatic FAAH poolMinimal durable inhibition (rapid hepatic clearance)
Safetyrisks and cautions, not medical advice
AM3506 is a preclinical research compound and has not undergone human clinical trials; its safety in people is unknown. It is a reactive sulfonyl fluoride that irreversibly modifies serine hydrolases, so off-target reactivity and handling hazards are relevant. In a rat working-memory study it was the one FAAH inhibitor among five that impaired delayed nonmatching-to-position accuracy, an effect blocked by a CB1 antagonist, indicating cannabis-like cognitive effects are possible at higher exposure. Its favorable metabolic profile (sparing liver FAAH) is demonstrated in rodents only. This is an investigational probe, not an approved or clinically validated therapeutic.
Resources
This entry is here for reference.
Research
- 2010first citedInhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension with…
- 2016most recentEffects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats
- 1.Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects
- 2.Sulfonyl fluoride inhibitors of fatty acid amide hydrolase
- 3.Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity
- 4.Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice
- 5.Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats
5 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
What is AM3506 used for?
It is a research tool that blocks FAAH to raise anandamide. In animal studies it normalizes high blood pressure, promotes fear extinction (an anxiety/PTSD angle), and restores disturbed gut motility. It is not an approved drug and has not been used in humans.
How does AM3506 work?
It irreversibly and covalently inhibits fatty acid amide hydrolase, the enzyme that breaks down the endocannabinoid anandamide. With degradation blocked, anandamide builds up where it is being produced and activates CB1 (and CB2) receptors, boosting your own endocannabinoid signaling rather than directly flooding the receptors like THC.
Is AM3506 well-researched?
It is well-characterized preclinically, with published work on its chemistry, cardiovascular effects, amygdala-driven fear extinction, gastrointestinal effects, and cognitive effects. However, all of that is in rodents and recombinant enzyme; there are no human clinical trials.
How is AM3506 different from other FAAH inhibitors like URB597?
AM3506 is a sulfonyl fluoride rather than a carbamate, and it is notable for being rapidly cleared by the liver, so it barely inhibits liver FAAH. That lets it avoid the insulin resistance and hyperglycemia seen with globally acting FAAH inhibitors while still working in the brain and cardiovascular system.
What are the main side effects of AM3506?
Because it has never been tested in humans, its side-effect profile is unknown. In rats it impaired working memory at higher doses through CB1 receptors, suggesting cannabis-like cognitive effects are possible. Its reactive chemical class also raises off-target and handling concerns.
Limitations of the evidence
- Investigational research chemical; never tested in humans
- Long-term safety and toxicology are uncharacterized
Adverse effects
- Reactive sulfonyl fluoride warhead raises off-target/handling concerns
- Impaired working memory in rats at higher doses (CB1-mediated)
- Potential cannabis-like cognitive effects at higher exposure