PubMed Central, : RMMJ Rambam Maimonides Medical Journal Rambam Health Care Campus 2023 October; 14(4): e0022. ISSN: 2076-9172Published online 2023 October 29. doi: 10.5041/RMMJ.10509

Table 1.

Preclinical Trials—Animal Studies.

Reference Research Question/Goal Induction of Arthritis Experimental Approach Outcome
Zurier et al. (1998)32 Evaluation of anti-inflammatory activities of a non-psychoactive synthetic derivative of THC (DMH-11C) Acute Inflammation: Induction of acute inflammation in dorsal air pouches with injection of IL-1β and TNFα
Chronic polyarthritis: Intradermal injection of Freund’s complete adjuvant (2 mg Mycobacterium butyricum in 0.1 mL mineral oil)
Pouches placed on backs of male Lewis rats, inflammation induced with intradermal Freund’s adjuvant, and arthritis visually assessed in all four paws.
Lewis rats assigned to groups and treated 3 days after adjuvant Tx:
  • untreated
  • treated with safflower oil
  • treated with 0.1 mg/kg DMH-11C three times a week for 35 days
Oral administration of DMH-11C:
  • Acute inflammation: reduced accumulation of pouch-filled polymorphonuclear leukocytes
  • Chronic polyarthritis:
    • - diminished arthritis severity
    • - prevented severe joint tissue injury
    • - chronic polyarthritis rats remained active with no weight loss compared to arthritic control rats
    • - developed only mild joint synovitis
Smith et al. (1998)34 Effectiveness of Δ9-THC and anandamide in blocking nociception or chronic inflammation Intradermal injection of Freund’s complete adjuvant (2 mg Mycobacterium butyricum in 0.1 mL mineral oil) Freund’s adjuvant was injected into the plantar aspect of the paw in male Sprague-Dawley rats Intraperitoneal administration of Δ9-THC or anandamide:
  • - anti-nociceptive effect of Δ9-THC and anandamide
  • - SR141716A (CB1 inhibitor) blocked THC, but not anandamide-induced nociception
  • - no potential contribution of endogenous anandamide in arthritis
Malfait et al. (2000)35 Anti-arthritic properties of non-psychoactive CBD Murine CIA model in complete Freund’s adjuvant Intradermal injection at tail base of male DBA/1 mice of CII emulsified in complete Freund’s adjuvant
Animals assigned into two groups:
  • Intraperitoneal administration at clinical signs onset for 10 days, at different concentrations 20 mg/kg (n=12), 10 mg/kg (n=17), 5 mg/kg (n=15), 2.5 mg/kg (n=9) dissolved in ethanol:cremophor:saline (1:1:18); or vehicle alone (n=23)
  • Oral administration at clinical signs onset for 10 days, CBD dissolved in olive oil at 10 mg/kg, 25 mg/kg, and 50 mg/kg (n=6 per group); control mice fed olive oil (n=6)
Intraperitoneal or oral administration of CBD:
  • - blocked progression of RA
  • - protected joints from severe damage
  • - diminished CII-specific proliferation of lymph nodes and IFNγ-production ex vivo
  • - decreased release of TNFα by knee synovial cells
Sumariwalla et al. (2004)37 Anti-inflammatory and immunosuppressive effects of synthetic cannabinoid HU-320 Murine model of CIA HU-320 or vehicle control (mixture of cremophor-EL, absolute ethanol, and PBS) administered peritoneally for 10 days to arthritic mice at different doses from day 1 of clinical signs appearance at 0.5, 1, and 2 mg/kg body weight Daily intraperitoneal administration of HU-320
  • - ameliorated CII-induced arthritis
  • - protected foot joints from pathological damage
  • - down-regulated CII-specific and polyclonal responses of murine lymphocytes
  • - suppressed serum TNFα levels
Cox et al. (2007)36 Anti-nociceptive effect of Δ9-THC Freund’s adjuvant-induced arthritis in Sprague-Dawley rats Male Sprague-Dawley rats injected intradermally at the tail base with 0.1 mL vehicle or Freund’s adjuvant
  • - arthritic or non-arthritic rats intraperitoneally injected with SR144528 (CB2 inhibitor), SR141716A (CB1 inhibitor), or vehicle (1:1:18, emulphor:ethanol:saline)
  • - arthritic and non-arthritic rats intraperitoneally injected with Δ9-THC
  • - paw pressure test to evaluate nociception
Intraperitoneal administration of Δ9-THC:
  • - anti-nociceptive effect
  • - SR144528 attenuated anti-nociceptive effect in arthritic but not in non-arthritic rats
  • - SR141716A attenuated anti-nociception in arthritic and in non-arthritic rats
Hammell et al. (2016)38 Anti-inflammatory and anti-nociceptive effects of CBD gels Freund’s complete adjuvant-induced arthritis in Sprague-Dawley rats Sprague-Dawley rats (n=54) assigned to three groups and treated as follows:
  • non-treated (n=21)
  • one knee joint injected with Freund’s complete adjuvant
  • vehicle or gel containing 1% or 10% CBD administered to backs of each animal for four consecutive days after arthritis onset
Transdermal administering of CBD gels:
  • - significantly reduced joint swelling
  • - reduced immune cell infiltration and thickening of the synovial membrane
  • - paw withdrawal latency recovered to near baseline
  • - dose-dependent reduction of pro-inflammatory biomarkers
  • - did not alter exploratory behavior
Palomares et al. (2020)33 Evaluation of anti-arthritis properties of Δ9-THCA-A Murine model of CIA 7-week-old DBA/1 mice treated twice with 100 μL type II bovine collagen, injected intradermally at tail base
Mice assigned to groups (n=9) and treated with:
  • Δ9-THCA-A ± PPARγ inhibitor,
  • ± CB1 receptor antagonist, or
  • vehicle
Paw edema evaluation on scale of 0–4
Intraperitoneal injection of Δ9-THCA-A prevents:
  • - arthritis in CIA mice
  • - infiltration of inflammatory cells
  • - synovium hyperplasia
  • - cartilage damage
  • - the expression of inflammatory and catabolic genes in knee joints
  • - anti-arthritic activity mediated by CB1 receptor and PPARγ pathway

CB1, cannabinoid 1; CBD, cannabidiol; CIA, collagen-induced arthritis; CII, type II collagen; DBA/1 mice, strain of mice, DMH-11C, dimethylheptyl-THC-11-oic acid; IFN, interferon; IL, interleukin; PBS, phosphate-buffered saline; PPAR, peroxisome proliferator-activated receptor; RA, rheumatoid arthritis; THC, tetrahydrocannabinol; THCA-A, tetrahydrocannabinolic acid; TNF, tumor necrosis factor; Tx, treatment.

RMMJ Rambam Maimonides Medical Journal Rambam Health Care Campus 2023 October; 14(4): e0022. ISSN: 2076-9172
Published online 2023 October 29. doi: 10.5041/RMMJ.10509