Pepcan-12 (RVD-hemopressin; RVDPVNFKLLSH) is the major peptide of a family of endogenous peptide endocannabinoids (pepcans) shown to act as negative allosteric modulators (NAM) of cannabinoid CB1 receptors. Noradrenergic neurons have been identified to be a specific site of pepcan production. However， it remains unknown whether pepcans occur in the periphery and interact with peripheral CB2 cannabinoid receptors. Here， it is shown that pepcan-12 acts as a potent (K value ~50?nM) hCB2 receptor positive allosteric modulator (PAM). It significantly potentiated the effects of CB2 receptor agonists， including the endocannabinoid 2-arachidonoyl glycerol (2-AG)， for [35S]GTPγS binding and cAMP inhibition (5-10 fold). In mice， the putative precursor pepcan-23 (SALSDLHAHKLRVDPVNFKLLSH) was identified with pepcan-12 in brain， liver and kidney. Pepcan-12 was increased upon endotoxemia and ischemia reperfusion damage where CB2 receptors play a protective role. The adrenals are a major endocrine site of production/secretion of constitutive pepcan-12， as shown by its marked loss after adrenalectomy. However， upon I/R damage pepcan-12 was strongly increased in the liver (from ~100 pmol/g to ~500 pmol/g) independent of adrenals. The wide occurrence of this endogenous hormone-like CB2 receptor PAM， with unforeseen opposite allosteric effects on cannabinoid receptors， suggests its potential role in peripheral pathophysiological processes.