Cannabis-Derived Agent May Offer Type 2 Diabetes Benefit

Miriam E Tucker

A nonpsychoactive analog of a cannabis component may represent a new agent for treating type 2 diabetes, early research suggests.

Findings from a randomized, double-blind, placebo-controlled phase 2a trial investigating two different phytocannabinoids in type 2 diabetes patients were published online August 29 in Diabetes Care by Khalid A Jadoon, of the University of Nottingham, Derby, United Kingdom, and colleagues.

Chronic overactivation of the endocannabinoid system (ECS) has previously been identified in obesity and type 2 diabetes, while marijuana use has been linked to lower fasting insulin and greater insulin sensitivity, the authors note.

Also in the past, modulation of the cannabinoid receptors with the synthetic cannabinoid rimonabant led to significant reductions in body weight, waist circumference, and triglycerides and increased HDL cholesterol. That drug was approved for weight loss in Europe but then removed from the market in 2008 due to adverse psychiatric events.

Now, attention has turned to two other potentially safer cannabinoid receptor modulators: cannabidiol (CBD) and Δ⁹-tetrahydrocannabivarin (THCV), the former derived from the cannabis plant and the latter a naturally occurring analog of Δ⁹-tetrahydrocannabinol (THC), but with different pharmacological effects. In animal models, CBD demonstrated anti-inflammatory and antioxidant properties, while THCV caused hypophagia and weight loss.

Unlike the related — and better-known — cannabis constituent THC, CBD and THCV don't activate CB₁ receptors in the brain and therefore lack the psychotropic actions of THC, Dr Jadoon and colleagues explain.

In this first clinical study of both compounds in people with type 2 diabetes and dyslipidemia, THCV improved glycemic control, whereas CBD failed to show any detectable metabolic effects, although it did produce desirable changes in some adipokines and gut hormones. Adverse events were similar between groups and no new safety concerns arose.

"These findings suggest that THCV may represent a new therapeutic agent for glycemic control in subjects with type 2 diabetes," the authors write.

Major Effects Seen With THCV, Fewer for CBD
A total 62 subjects with non–insulin-treated type 2 diabetes were randomized to one of five treatment arms: CBD (100 mg twice daily), THCV (5 mg twice daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13 weeks.

Although THCV had no effect on the primary end point — change in HDL cholesterol from baseline — or on LDL-cholesterol levels, it did significantly increase apolipoprotein A (apoA) concentrations from baseline (P < .05). In contrast, CBD alone and in combination with THCV did not affect any of the lipid parameters.

Fasting plasma glucose was also lower with THCV from baseline compared with placebo, from about 133 mg/dL to 121 mg/dL (P < .05), along with a significant concurrent increase in beta-cell function (P < .01). But again, neither CBD alone nor in combination with THCV affected glycemic parameters.

Adiponectin concentrations were also significantly increased from baseline with THCV and significantly reduced with placebo (P < .01 for the difference).

There were some significant effects for CBD, including a reduction in the adipokine resistin (P < .05), which is associated with obesity and insulin resistance, and an increase in the concentration of the gut hormone glucose-dependent insulinotropic peptide, which appears to have beta-cell–preserving properties (P < .05). But CBD had no effect on leptin or adiponectin levels.

Neither agent appeared to influence cardiovascular parameters, plasma markers of vascular function, plasma markers of inflammation (C-reactive protein, tumor necrosis factor-alpha, and interleukin-6), or anthropomorphic parameters (body weight, waist circumference, waist-to-hip ratio, or skinfold thickness), visceral adiposity, or appetite.

Safety Profile Favorable
Adverse events were reported by majorities of all groups, including placebo, and were mostly mild to moderate. Reduced appetite was common with the cannabinoids, reported in 9% to 33% of the treatment groups vs none in placebo. Two people reported diarrhea with THCV vs none in the other groups. There were no deaths or treatment-related serious adverse events.

"THCV improved glycemic control and therefore warrants further investigation in this therapeutic area," the authors conclude.