A cannabis extract and morphine: increased analgesia without increased respiratory depression

K. Taheri, J. Padam, C. Bayley, B. A. MacLeod, E. Puil. Anesthesiology, Pharmacology, & Therapeutics, University of British Columbia, Vancouver, Canada.

Introduction: Δ⁹-Tetrahydrocannabinol (THC), a major psychoactive component of cannabis, enhances the thermal analgesic properties of morphine¹. Studies have also shown possible potentiated effects of THC using combinations of different cannabinoids². Therefore, we aimed to study the thermal analgesic properties and respiratory effects of cannabis extract in combination with morphine.

Methods: Cannabis extract was prepared from cannabis flowers using hexane liquid-liquid extraction in vehicle (18:1:1 saline: ethanol: ethoxylated castor oil). The cannabinoid content was quantified using HPLC. Morphine was dissolved in saline. Adult female CD1 mice (25-30 g) were randomly assigned to treatment groups. Animals were injected intravenously with extract (0-0.8 mg/kg THC; n = 5/group), morphine (0.2-12 mg/kg; n = 8), extract (0-0.8 mg/kg THC) and 6 mg/kg morphine (n = 8), or saline (n = 8). Mice were habituated to their environment for 60 min prior to pre- and post-treatment tests. Thermal stimulus response was measured using a ramped hotplate³ with a temperature range of 32.1°C to 52.1°C. Withdrawal latencies were measured at 5 min after treatment. Mice were then placed in modified Falcon tubes and videotaped for 10 min. Respiratory rate (min^-1) was measured during the 9-10th min interval (19-20 minutes after treatment). ANOVA or Kurskal-Wallis followed by Dunnett’s or Dunn’s multiple comparison test was performed (α = 0.01) as appropriate. Delta latencies were calculated by subtracting pre-treatment from post-treatment latencies. Data are shown as mean with SD.

Results: Extract did not affect withdrawal latency or respiratory rate at any dose tested (P > 0.01 compared to vehicle). Compared to saline, morphine increased latency at 6 and 12 mg/kg (-0.4±6.7 s vs. 36.8±18.3, 60.4±19.3 s; P = 0.0009, <0.0001) and decreased respiratory rate at 1-12 mg/kg (186±19 min^-1 vs. 147±15, 125±17, 125±17 min^-1; P = 0.0063, 0.0001, 0.0001). Significant increases in delta latency were seen between 6 mg/kg morphine with vehicle, and combinations of 0.2, 0.4, and 0.8 mg/kg extract and 6 mg/kg morphine (20.0±8.9 s vs. 54.8.8±21.5, 66.8±8.6, 64.9±13.3 s; P = 0.0005, 0.0001, 0.0001) without increased respiratory depression (132±15 min^-1 vs. 122±16, 111±13, 119±24 min^-1; P= 0.77, 0.16, 0.59).

Conclusion: Non-analgesic doses of a cannabis extract combined with a fixed dose of morphine produced an increase in thermal analgesia without added respiratory depression.

References:

1. Smith F et al. (1998). J Pharmacol Exp Ther 60(2): 559-566.

2. Karniol IG and Carlini EA (1973). Psychopharmacologia 33(1): 53

3. Hunskaar S et al. (1986). Behav Brain Res 21(2): 101