January 3, 2014
French Team Pinpoints Natural Defense Against Cannabis Intoxication
redOrbit Staff & Wire Reports - Your Universe Online
A reported 20 million people worldwide are addicted to cannabis, and regular use of the substance can lead to impaired cognitive function and an overall loss of motivation. When THC acts on the brain through the CB1 cannabinoid receptors, it can bind to them and divert them away from their regular physiological roles.
Among the processes that can be affected include food intake regulation and metabolism, and overstimulation can reduce memory capacity while ultimately leading to dependence on the substance. The development of an effective treatment for cannabis addiction is quickly becoming a top research priority, the investigators said, leading INSERM’s Pier Vincenzo Piazza and Giovanni Marsicano to examine pregnenolone’s potential in this department.
Pregnenolone is a steroid hormone produced in the brain, and previously it was believed to be the inactive precursor used to synthesize other steroid hormones, including estrogen and testosterone. Now, however, Piazza and Marsicano have found that it protects the brain from marijuana intoxication.
“Essentially, when high doses of THC (well above those inhaled by regular users) activate the CB1 cannabinoid receptor they also trigger the synthesis of pregnenolone. Pregnenolone then binds to a specific site on the same CB1 receptors and reducing the effects of THC,” INSERM explained in a statement.
“The administration of pregnenolone at doses that increase the brain's level of this hormone even more, antagonize the behavioral effects of cannabis,” the Institute added. “At the neurobiological level, pregnenolone greatly reduces the release of dopamine triggered by THC. This is an important effect, since the addictive effects of drugs involve an excessive release of dopamine.”
The hormone’s role in protecting the brain from the ill effects of cannabis was originally discovered when rats were given equal doses of several substances (including cocaine, morphine, alcohol and cannabis) and the levels of several brain steroids (including pregnenolone). The researchers found that THC was the only substance that increased the levels of the steroid pregnenolone by as much as 3000 percent for a period of two hours.
“This increase in pregnenolone is a built-in mechanism that moderates the effects of THC. Thus, the effects of THC increase when pregnenolone synthesis is blocked,” INSERM said. “Conversely, when pregnenolone is administered to rats or mice at doses (2-6 mg/kg) that induce even greater concentrations of the hormone in the brain, the negative behavioral effects of THC are blocked.”
Additional experiments conducted using cell cultures that express the human CB1 receptor confirmed that the steroid can also be used to counteract the effects of THC in humans. However, Piazza explained that pregnenolone itself cannot be used as a treatment, because it is poorly absorbed when taken orally and is quickly transformed into other steroids once it enters the blood stream. Even so, Piazza is confident that the discovery will lead to new ways of treating cannabis addiction.
“We have now developed derivatives of pregnenolone that are well absorbed and stable,” he explained. “They then present the characteristics of compounds that can be used as new class of therapeutic drugs. We should be able to begin clinical trials soon and verify whether we have indeed discovered the first pharmacological treatment for cannabis dependence.”