Low doses of anandamides inhibit pharmacological effects of Δ9- tetrahydrocannabinol

E. Fride, J. Barg, R. Levy, D. Saya, E. Heldman, R. Mechoulam, Z. Vogel

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81 Scopus citations


It has been shown previously that the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide 20:4, n-6) induces in vivo and in vitro effects typical of a cannabinoid partial agonist. We now report that the synthetic docosahexaenylethanolamide (anandamide 22:6, n-3) shows similar activities. In addition we show that these two anandamides, under certain experimental conditions, antagonize the effects of Δ9-THC both in vivo and in vitro. Thus a significant decrease in the potency of Δ9-THC-induced inhibition of adenylate cyclase was observed in N18TG2 neuroblastoma cells that were pretreated with low concentrations of anandamides. At these low concentrations of anandamides had no effect when applied alone. In vivo, Sabra or ICR mice were subjected to a tetrad of tests, designed to detect cannabinoid-induced effects. Mice pretreated (i.p.) with 10 mg/kg of Δ9- THC received injections with anandamides. Only low doses (0.0001-0.1 mg/kg) of the anandamides, which had no effects when administered alone, partially or fully inhibited the THC-induced effects. These findings suggest that the inhibition of Δ9-THC-induced effects by low doses of anandamides may be due to partial agonistic effects of these materials. It is possible that low doses of the anandamides are capable of activating a Gs protein mediated signaling pathway, or may cause an allosteric modulation of the cannabinoid receptor.

Original languageEnglish
Pages (from-to)699-707
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1 Jan 1995
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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