Table 1. Evidence of CB1R functional selectivity.

Ligand	Functional selectivity	Experimental approach	Reference
Endocannabinoids
2-AG	No bias towards cAMP inhibition over pERK 1/2	Alphascreen cAMP and SureFire assay with CB1R-expressing CHO cells	[60]
	Increases CB1R surface expression through Gβγ signaling	cAMP accumulation assay in CB1R-expressing CHO cells.	[58]
Anandamide	Biased towards Gi over Go	CB1R urea-extracted from sf9 membranes and reconstituted with varying Ga and Gβγ subunits.	[56]
	Biased towards Gi over Gs and doesnot signal through Gq	cAMP accumulation assay in CB1R-expressing CHO cells.	[58]
	Biased towards cAMP inhibition over pERK 1/2	Alphascreen cAMP and SureFire assay with CB1R-expressing CHO cells	[60]
Eicosanoids
Methanandamide	Inverse agonist at Gi1 and Gi2; Agonist at Gi3	CB1R-G protein complex were CHAPS-extracted from N18TG2 cell membrane and quantified by coimmunoprecipitation	[57]
	Biased towards cAMP inhibition over pERK 1/2	Alphascreen cAMP and SureFire assay with CB1R-expressing CHO cells	[60]
Classical Cannabinoids
THC	Biased towards cAMP inhibition over pERK 1/2	Alphascreen cAMP and SureFire assay with CB1R-expressing CHO cells	[60]
	Induces expression of Tyrosine Hydrooxylase	mRNA and Protein analysis in mouse neuroblastoma cells N1E-115	[61]
	Induced receptor internalization through β-arrestin recruitment	CREB phosphorylation in mouse striatal medium spiny projection neurons (STHdhQ7/Q7)	[59]
Desacetyl-Levonantradol	Agonist at Gi1 and Gi2; Inverse agonist at Gi3	CB1R-G protein complex were CHAPS-extracted from N18TG2 cell membrane and quantified by coimmunoprecipitation	[57]
HU210	Non-selective between Gi, Go and Gs pathways	cAMP accumulation assay in CB1R-expressing CHO cells.	[58]
	Biased towards cAMP inhibition over pERK 1/2	Alphascreen cAMP and SureFire assay with CB1R-expressing CHO cells	[60]
		Decreases Tyrosine Hydroxylase expression unlike CP55940	Tyrosine hydroxylase expression in N1E-115 Neuroblastoma cells	[61]
Non-classical Cannabinoids
CP55940	Activates Gs pathway	CREB phosphorylation in mouse striatal medium spiny projection neurons (STHdhQ7/Q7)	[59]
	Biased towards Gi over Gs and does not signal through Go and Gq	cAMP accumulation assay in CB1R-expressing CHO cells.	[58]
	Induced receptor internalization through β-arrestin recruitment	CREB phosphorylation in mouse striatal medium spiny projection neurons (STHdhQ7/Q7)	[59]
Aminoalkylindole
WIN55212	Activates Gq pathway	Intracellular calcium accumulation in CB1R-expressing HEK293 cells and cultured hippocampal neurons.	[47]
	Non-selective between Gi1, 2 and 3 subtypes	CB1R-G protein complex were CHAPS-extracted from N18TG2 cell membrane and quantified by coimmunoprecipitation	[57]