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Research tools

AM404

An inhibitor of anandamide transport, a TRPV1 agonist, and an active metabolite of paracetamol.

Unscheduled
Level of detail

Harm-reduction warning

No characterised human dose: animal / in vitro data only. Effect profile, safety margin and acute toxicity are not documented in human clinical practice. Extremely potent compound: severe effects, seizures and deaths reported in the literature.

C₂₆H₃₇NO₂

CAS 183718-77-6

Family
ECS pharmacological toolTransport inhibitor
Molar mass
395.60 g/mol

Updated on

In plain terms

AM404 is a laboratory molecule, absent from cannabis as from any other plant. It has the particularity of also being formed in the brain after paracetamol is taken, from a breakdown product of that medicine. Researchers use it to slow the elimination of anandamide, a cannabinoid made by the body, but it is neither a supplement nor a product intended to be consumed.

Receptors and activity

Target network

TRPV1Agonistno measured value
  • Activates
  • Blocks or inhibits

The lower the cited value, the closer the target sits to AM404: one ring per factor of 100. A target with no measured value stays on the edge.

Where these targets live

Where each target has been found in humans, according to the cited studies. The map shows the target, not an effect of AM404.

Brain, side view
Body, front view
Blood

TRPV1TRPV1 found in 7 regions of the body

  1. Sensory gangliapresentExpressed in dorsal root ganglia1
  2. Spinal cordpresentNerve fibres in the spinal dorsal horn2
  3. CortexpresentParietal cortex neurons (layers 3 and 5)3
  4. SkinpresentWidely distributed in the skin4
  5. Blood vesselspresentPresent on dermal blood vessels4
  6. BonepresentPresent on osteoclasts5
  7. LiverpresentRNA enriched in the liver6

Map sources

  1. Cortright DN et al. The tissue distribution and functional characterization of human VR1. Biochem Biophys Res Commun, 2001 (new tab)
  2. Facer P et al. Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy. BMC Neurol, 2007 (new tab)
  3. Mezey E et al. Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc Natl Acad Sci U S A, 2000 (new tab)
  4. Ständer S et al. Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp Dermatol, 2004 (new tab)
  5. Rossi F et al. The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption. Bone, 2009 (new tab)
  6. Human Protein Atlas. TRPV1 tissue expression (RNA consensus) (new tab)

Cited values

  1. TRPV1Agonistno measured value cited
  2. Transport membranaire de l'anandamideInhibitorno measured value cited
  3. COX-1 and COX-2Inhibitorno measured value cited
Bar length follows the measured value (Ki, Kd, EC50 or IC50), on one scale shared by every entry, from 100 µM to 0.1 nM. A target with no cited value has no bar.

Pharmacology

AM404 was described as an inhibitor of anandamide accumulation in neurons and astrocytes: it does not itself activate cannabinoid receptors, but it enhances responses to anandamide in vitro and in vivo (Beltramo et al., Science 1997, PMID 9262477). Its pharmacology later proved broader: it activates the TRPV1 channel (Högestätt et al. 2005; Stueber et al. 2018, activation from 1 µM) and inhibits purified COX-1 and COX-2. Its renown rests mainly on its second identity: in 2005, the conjugation of p-aminophenol to arachidonic acid by FAAH was demonstrated in the mouse brain and spinal cord, making AM404 a bioactive metabolite of paracetamol (Högestätt et al., J Biol Chem 2005, PMID 15987694), a candidate to explain the central action of this analgesic (review by Mallet et al. 2023). In rats given paracetamol at 20 mg/kg, AM404 reaches 150 pg/g in the brain (Muramatsu et al. 2016). In humans it was detected in the cerebrospinal fluid after paracetamol; no direct administration of AM404 to humans was found in the sources consulted. An abuse signal deserves mention: the compound was self-administered intravenously by squirrel monkeys and reinstated drug seeking, effects reduced by a CB1 antagonist (Schindler et al. 2016, PMID 26803499).

Key sources.

History

Source
AM404 is found neither in cannabis nor in any other plant. It is a synthetic molecule, the amide of arachidonic acid and 4-aminophenol. It also forms in the nervous system after paracetamol is taken: paracetamol, deacetylated to p-aminophenol in the liver, is conjugated to arachidonic acid in the brain and spinal cord by FAAH (Högestätt et al. 2005); in humans, AM404 was detected in the cerebrospinal fluid after a single 1 g dose of paracetamol, in 17 of the 26 patients studied (Sharma et al. 2017, reported by the review of Mallet et al. 2023).

Origin

Research tool

No plant pathway: AM404 does not come from cannabis. Its only documented natural formation is metabolic, in mammals. After paracetamol is ingested, deacetylation releases p-aminophenol, which is conjugated to arachidonic acid in the brain and spinal cord by fatty acid amide hydrolase (FAAH). This conjugation is absent in mice lacking FAAH, which identifies this enzyme as responsible for the reaction (Högestätt et al. 2005).

Classification

Family, origin and source verification

Family

ECS pharmacological tool › Transport inhibitor

Verification

Classification, sources and binding values checked on 20 October 2026; text read against its sources and Wikipedia.

Wikipedia (English)

AM404 (new tab)

Article paired by the molecule's structure (InChIKey), revision read on 19 October 2026. Read as a second opinion, never cited as a source.

References

  1. Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science. 1997;277(5329):1094-7. (new tab)PMID 9262477
  2. Högestätt ED, Jönsson BAG, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM. Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem. 2005;280(36):31405-12. (new tab)PMID 15987694
  3. Mallet C, Desmeules J, Pegahi R, Eschalier A. An updated review on the metabolite (AM404)-mediated central mechanism of action of paracetamol (acetaminophen): experimental evidence and potential clinical impact. J Pain Res. 2023;16:1081-1094. (new tab)PMID 37016715
  4. Schindler CW, Scherma M, Redhi GH, Vadivel SK, Makriyannis A, Goldberg SR, Justinova Z. Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys. Psychopharmacology (Berl). 2016;233(10):1867-77. (new tab)PMID 26803499
  5. Muramatsu S, Shiraishi S, Miyano K, et al. Metabolism of AM404 from acetaminophen at human therapeutic dosages in the rat brain. Anesth Pain Med. 2016;6(1):e32873. (new tab)PMID 27110534
  6. Stueber T, Meyer S, Jangra A, Hage A, Eberhardt M, Leffler A. Activation of the capsaicin-receptor TRPV1 by the acetaminophen metabolite N-arachidonoylaminophenol (AM404). Life Sci. 2018;194:67-74. (new tab)PMID 29273526
  7. PubChem, compound record CID 6604822 (AM404), National Library of Medicine. (new tab)
  8. ChEMBL, record CHEMBL39878 (AM404), European Bioinformatics Institute. (new tab)

Identifiers

Names

IUPAC name
(5Z,8Z,11Z,14Z)-N-(4-hydroxyphenyl)icosa-5,8,11,14-tetraenamide
Other names
N-arachidonoylphenolamine · N-(4-hydroxyphenyl)arachidonylamide

Identifiers

Formula
C₂₆H₃₇NO₂
CAS
183718-77-6
PubChem CID
6604822(new tab)
InChIKey
IJBZOOZRAXHERC-DOFZRALJSA-N
SMILES
CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NC1=CC=C(C=C1)O

Machine-readable entry (JSON)

LLM ingestion format: a structured superset of the entry (identifiers, binding, versioned legal status). Full corpus.