Molecule that protects brain from cannabis intoxication found

Scientists have found a brain molecule which acts as a natural defence mechanism against the harmful effects of cannabis in animals, paving way for a new class of therapeutic drugs to treat cannabis addiction.
Researchers from INSERM in France discovered that pregnenolone prevents THC, the main active ingredient in cannabis, from fully activating its brain receptor which causes the intoxicating effects of cannabis.
THC acts on the brain through CB1 cannabinoid receptors located in the neurons. THC binds to these receptors diverting them from their physiological roles, such as regulating food intake, metabolism, cognitive processes and pleasure.
When THC overstimulates CB1 receptors, it triggers a reduction in memory abilities, motivation and gradually leads to dependence.

The INSERM researchers led by Pier Vincenzo Piazza and Giovanni Marsicano investigated the potential role of pregnenolone - a brain produced steroid hormone.
Researchers found 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 (see figure) and reducing the effects of THC.
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, researchers found.

In the study, rats were given equivalent doses of cocaine, morphine, nicotine, alcohol and cannabis and the levels of several brain steroids (pregnenolone, testosterone, allopregnenolone, DHEA etc) were measured.
The study found only one drug, THC, raised brain steroids and more specifically selectively one steroid, pregnenolone, that went up 3000 per cent 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.
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 behavioural effects of THC are blocked.

The animals that were given pregnenolone recover their normal memory abilities, are less sedated and less incline to self-administer cannabinoids, researchers said.
Experiments conducted in cell cultures that express the human CB1 receptor confirm that pregnenolone can also counteract the molecular action of THC in humans.
Piazza said that pregnenolone itself cannot be used as a treatment because it is badly absorbed when administered orally and once in the blood stream it is rapidly transformed in other steroids.
However, there is hope of seeing a new addiction therapy emerge from this discovery.
"We have now developed derivatives of pregnenolone that are well absorbed and stable. They then present the characteristics of compounds that can be used as new class of therapeutic drugs," Piazza said.