HU-444, a novel, potent anti-inflammatory, nonpsychotropic cannabinoid

Christeene G. Haj, Percy F. Sumariwalla, Lumír Hanuš, Natalya M. Kogan, Zhana Yektin, Raphael Mechoulam, Mark Feldmann, Ruth Gallily

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas. In contrast to Δ9-tetrahydrocannabinol (Δ9-THC), it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of tumor necrosis factor (TNF)-α, a proinflammatory cytokine, and was found to be an oral antiarthritic therapeutic in murine collagen-induced arthritis in vivo. However, in acidic media, it can cyclize to the psychoactive Δ9-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ9-THC-like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-α production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ9-THC-like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.

Original languageEnglish
Pages (from-to)66-75
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1 Oct 2015
Externally publishedYes


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