Allosteric Modulation of the CB1 Receptor by a Juniper Berry Seasoning Extract: Deoxypodophyllotoxin as the Major Active Constituent.

Juniper (Juniperus communis L.) berries are widely used as a culinary spice and flavoring ingredient. While their volatile profile is well characterized, much less is known about the composition and biological activity of their nonvolatile constituents. Here, we show that a commercial carbonic extract prepared from juniper berry seasoning displays positive allosteric modulator (PAM)-like activity at the cannabinoid type-1 receptor (CB1R). Bioactivity-guided fractionation identified deoxypodophyllotoxin as a principal contributor to this effect. In the presence of a CB1R orthosteric agonist, this cyclolignan enhanced cAMP- and ERK-dependent signaling and β-arrestin recruitment, supporting a modulatory interaction with CB1R. Oral administration of the seasoning extract and related cyclolignans altered murine nociceptive responses without impairing motor coordination. These findings identify deoxypodophyllotoxin as a food-derived CB1R modulator and suggest that nonvolatile constituents of juniper berries may contribute to sensory responses associated with food consumption.