Effect of combined doses of Δ9-tetrahydrocannabinol and cannabidiol or tetrahydrocannabinolic acid and cannabidiolic acid on acute nausea in male Sprague-Dawley rats.

RATIONALE: This study evaluated the potential of combined cannabis constituents to reduce nausea. OBJECTIVES: Using the lithium chloride (LiCl)-induced conditioned gaping model of nausea in male rats, we aimed to: 1) Determine effective anti-nausea doses of cannabidiol (CBD) 2) Determine effectiveness and the mechanism of action of combined subthreshold doses of CBD and Δ9-tetrahydrocannabinol (THC) 3) Determine effective doses of synthetic cannabidiolic acid (CBDA) 4) Determine effective doses of synthetic tetrahydrocannabinolic acid (THCA) 5) Determine the mechanism of action for THCA 6) Determine effectiveness and the mechanism of action of combined subthreshold doses of CBDA and THCA RESULTS: CBD (0.5-5 mg/kg, intraperitoneal [i.p.]) reduces LiCl-induced conditioned gaping (but 0.1, 20, 40 mg/kg are ineffective). Combined subthreshold doses of CBD (0.1 mg/kg, i.p.) and THC (0.1 mg/kg, i.p.) produce suppression of conditioned gaping, and this effect is blocked by administration of either WAY100635 (a serotonin 1A [5-HT1A]) receptor antagonist or SR141716 (SR; a CB1 receptor antagonist). THCA (0.01 mg/kg, i.p.) reduces conditioned gaping and administration of MK886 (a peroxisome proliferator-activated receptor alpha [PPARα] antagonist) blocked THCA's anti-nausea effect. Combined subthreshold doses of CBDA (0.00001 mg/kg, i.p.) and THCA (0.001 mg/kg, i.p.) produce suppression of conditioned gaping, and this effect is blocked by administration of WAY100635 or MK886. CONCLUSION: Combinations of very low doses of CBD + THC or CBDA + THCA robustly reduce LiCl-induced conditioned gaping. Clinical trials are necessary to determine the efficacy of using single or combined cannabinoids as adjunct treatments with existing anti-emetic regimens to manage chemotherapy-induced nausea.

Effect of steady-state methadone on high fructose corn syrup consumption in rats.

Patients undergoing methadone maintenance treatment self-report enhanced preferences for, and excessive consumption of, foods rich in sugar. However, it is unclear whether these are direct pharmacological effects of methadone or the consequences of metabolic dysfunctions induced by addiction to illicit opiates. Hence, the current study in drug-naïve male Sprague-Dawley rats explored the effects of steady-state methadone delivered by osmotic mini-pumps (13 days; 0, 10, 30 mg/kg/day) on consumption of rat chow and a palatable, sweet, liquid high fructose corn syrup solution. Six days after the removal of the pumps, mRNA expression of genes involved in responses to stress and rewards were quantified: pro-opiomelanocortin in the hypothalamus, mu-opioid receptor in the nucleus accumbens, and dopamine D2 receptor in the dorsal striatum. Taste reactivity and locomotion tests were also performed throughout the study. It was found that methadone increased caloric intake from high fructose corn syrup and reduced caloric intake from chow, effects that could not be directly ascribed to changes in high fructose corn syrup taste reactivity or motor functions. However, the changes in caloric intake displayed significant tolerance, and mRNA expression analysis suggested that methadone attenuated the effect of high fructose corn syrup on pro-opiomelanocortin mRNA, and possibly on dopamine D2 receptor mRNA. These findings in rats suggest that the pharmacological effect of methadone, administered to achieve steady-state maintenance, may not be the primary cause of dietary alterations reported by patients maintained on methadone.