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Reference	Research Goal	Study Design	Intervention	Participants, n (F/M)	Cannabis Application	TX Duration	Efficacy
Johnson et al. (2007)42	AjA influence on MMP production in human FLS and role of PPAR□	Ex vivo study on FLS from RA pts	AjA	Synovial fluid extracted from joints of RA, OA, or psoriatic arthritis pts	AjA acid in DMSO	60 min AjA Tx followed by stimulation with 10 ng/mL rhIL-1α rhTNFα for 18–24 hours	- AjA suppressed MMP production from FLS, independent of PPAR□ - AjA suppressed MMP3 secretion in TNFα- and IL-1α-stimulated PPAR^+/- and PPAR^-/- MEFs
Richardson et al. (2008)39	Determine if cannabinoid signaling elements are present in synovia of RA or OA pts	Ex vivo synovial fluid	Endocannabinoid levels were quantified in synovial biopsies	OA (n=32) or RA (n=13) pts undergoing knee arthroplasty and healthy volunteers	No	No	- CB1 and CB2 protein and RNA were present in synovia of OA and RA pts - Cannabinoid receptor stimulation time-dependently activated MAPK/ERK1/2, which is blocked by SR141716A (CB1 antagonist) - AEA and 2-AG found in synovia of OA and RA pts but not healthy volunteers - Fatty acid amide hydrolase active in synovia of OA and RA pts
Selvi et al. (2008)43	Anti-inflammatory properties of synthetic cannabinoids CP55,940 and WIN	Ex vivo study on FLS from pts with RA	Synthetic cannabinoids CP55,940 and WIN	Synovial fluid from 5 pts with RA and knee joint involvement (OA knee joint replacement surgery)	FLS treated with CP55,940 and WIN for 3 hours Measurement of pro-inflammatory cytokines before and after Tx	3 hours 1-hour pre-Tx with cannabinoid receptor antagonist, 1-hour pre-incubation or with 0.1 ng/mL IL-1α	- Both cannabinoids induced potent and significant reduction of IL-6 and IL-8 secretion from IL-1α-stimulated FLS - Independent from antagonistic actions
Lowin et al. (2016)44	Anti-arthritic properties of synthetic cannabinoid WIN	Ex vivo study of RASF pts	CBD	n=21/7 Longstanding RA Mean age 61.1±10.7	CBD in DMSO	Up to 72 min	- Concentration-dependent reduction/inhibition of IL-6, IL-8, and MMP3 secretion - High WIN concentration effects partly dependent on media FCS content - WIN influences adhesion to fibronectin (low concentrations <2 μM stimulated adhesion; higher concentrations >2 μM decreased adhesion) - WIN concentrations >1 μM halted cell proliferation - WIN at high concentrations >2 μM changed cell shapes from spread out with fibropodia to sharp-edged with a condensed nucleus and extensive vacuolation - WIN activities were independent of CB1 or CB2 but attenuated by TRPV1 or TRPA1 inhibitors
Lowin et al. (2020)45	Evaluation of anti-arthritic properties of CBD	Investigation of RASF ex vivo from RA pts		32 F and 8 M with long-standing RA fulfilling ACR criteria, mean age 66.9±8.2 years			- CBD reduced cell viability and proliferation of RASF - CBD increased intracellular Ca²⁺, effects enhanced by TNFα - Ca²⁺ mobilization and PoPo3 uptake partly depended on TRPA1 activation - Mitochondrial targets mediate CBD effects
Kotschenreuther et al. (2021)47	Analysis of cannabinoid impact on Th17 differentiation in RA pts	Investigation of T helper cells differentiation ex vivo in peripheral blood cells of RA pts		Healthy donors	RA pts		- CBD and AEA increased Th17 differentiation in CD4⁺ T cells of RA pts but not healthy donors - Adding cytokines TGFβ, IL-1α, IL-6, and IL-23 increased Th17-inducing CBD properties - CBD oil Tx for 4–8 weeks increased Th17 cell expansion - Disease Activity Score 28-joint count C-reactive protein increased during CBD Tx - Immunomodulatory effect of CBD not mediated by CB1, CB2, or GPR55 - CBD increased sgk1 and ahr expression and decreased csf2 expression - Results contrary to results in mice where CBD ameliorated RA

2-AG, 2-arachidonyl glycerol; ACR, American College of Rheumatology; AEA, N-arachidonoylethanolamine; AjA, ajulemic acid; CB1/CB2, cannabinoid 1/cannabinoid 2; CBD, cannabidiol; DMSO, dimethylsulfoxide; F, females; FCS, fetal calf serum; FLS, fibroblast-like synovial cells; GPR55, G protein-coupled receptor 55; M, males; MAPK/ERK1/2, mitogen-activated protein kinase/extracellular-regulated kinase; MEFs, mouse embyonic fibroblasts; MMP, matrix metalloproteinase; OA, osteoarthritis; PPAR, peroxisome proliferator-activated receptor; pts, patients; RA, rheumatoid arthritis; RASF, rheumatoid arthritis synovial fibroblasts; rh, recombinant human; RNA, ribonucleic acid; TNF, tumor necrosis factor; Th17, T helper 17; TRPA1, transient receptor potential cation channel subfamily A1; TRPV1, transient receptor potential cation channel subfamily V1; Tx, treatment; WIN, WIN55,212-2.