Among the manifold roles of the mammal endocannabinoid (eCB) system is the regulation of metabolism and energy expenditure. This function extends to pathological conditions, as evidenced by previous research showing this system to be over-activated in conditions of obesity and diabetes type 2. A synthetic cannabinoid – Rimbonant – that interacts with cannabinoid type 1 (CB1) receptors, was temporarily marketed for these two conditions, before being withdrawn in 2008 due to its severe psychiatric side effects.
Researchers kept examining other cannabinoids, hoping to find a drug with a safer profile that was also effective in these metabolic disorders. Two compounds, cannabidiol (CBD) and THCV (an analogue of THC with different pharmacological effects) had good results in animal models of obesity and diabetes. Instigated by these findings, a team of researchers from the UK launched a pilot clinical trial to study their effects in type 2 diabetes patients. The results were recently published in the journal Diabetes Care.
The trial followed a randomized, double-blinded, and placebo-controlled design. Sixty-two adults from four centers of the United Kingdom were divided among five conditions, receiving one of the following dosages twice daily for the duration of 13 weeks: 100mg of CBD; 5mg of THCV; 5mg of CBD plus 5mg of THCV; 100mg of CBD plus 5mg of THCV; or placebo. Exclusion criteria included recent use of cannabis, depression diagnosis, and certain genetic profiles that could interfere with the analysis.
The primary assessment was the change in serum HDL-C concentration, the so called “good cholesterol” that is reduced in diabetes type 2. Neither drug, alone or in combination, had an effect on this marker. However, THCV treatment led to an increase in protein Apo A (a major constituent of the HDL-C) concentrations compared to baseline and placebo. On secondary and tertiary endpoints, THCV was associated with a reduction in plasma glucose concentration, which was in line with significant increases in other measures of insulin and blood glucose response.
No treatment led to changes in body weight, waist circumference, or subjective appetite. These findings are apparently contradictory to those of animal studies, but the authors hypothesize that it could be attributed to the lower concentrations of medication given in the trial that might have been insufficient to fully engage the eCB system. The same rationale is proposed for the fact that measurements of circulating endocannabinoids or markers of inflammation were not altered by either CBD or THCV.
More than two thirds of patients reported mild or moderate adverse effects in every treatment group (including 92% of those on placebo). Two patients receiving THCV reported diarrhea. No severe adverse effects were reported, except for two cardiac incidents that were judged to be unrelated to the treatment. The results suggest that THCV is well-tolerated and could have significant therapeutic effects in the control of blood glucose of patients with type 2 diabetes. Larger clinical trials are now warranted to fully assess its therapeutic and adverse effects over a larger period of time.
Investigators’ conflicts of interest: The study was supported by GW Pharmaceuticals. One of the authors has been a member of GW’s Speaker’s Board and has also received previous funding for clinical studies.