Smoking Marijuana Without Getting High: Hormone Pregnenolone Offsets THC Effect

Pregnenolone is a naturally occurring substance that moderates the psychoactive effect of THC, the main active component of marijuana. Photo Courtesy of Shutterstock

If you love smoking marijuana but hate the high that follows, you’re in luck. In a new study, French scientists describe a naturally occurring molecule that appears to block the effect of cannabis in mice. The compound could come to benefit individuals struggling with addiction.

Pregnenolone, a hormone produced in the brain, has in previous research efforts been identified as an inactive precursor used to synthesize other hormones.  However, during a recent attempt to quantify the influence of steroid hormones on biological responses to drugs, Pier Vincenzo Piazza and Giovanni Marsicano noticed something peculiar: when lab mice were exposed to tetrahydrocannabinol (THC), the main active component in cannabis, their brains initiated a temporary 3,000 percent increase in the production of pregnenolone. The current study, which is published in the journal Science, sought to explain why.

THC and Pregnenolone

In order to induce its psychoactive effect, THC must interact with so-called CB1 cannabinoid receptors located in the brain’s neurons. The compound will bind with these receptors and interrupt their usual business. When the receptors become overstimulated, they fail to perform their assigned tasks, and the user begins to experience cognitive restrictions like memory loss and lack of motivation.

What Piazza, Marsicano, and their colleagues have shown is that pregnenolone antagonizes this effect by binding to the exact same site, effectively crowding out the psychoactive compounds. As the surge in production only occurs in response to very high levels of THC, the researchers theorize that the hormone is the active component in a biological defense mechanism. Essentially, pregnenolone “caps” a marijuana user’s response to the drug.

To test their hypothesis, the team designed an experiment with mice. When subjects were administered both THC and pregnenolone, the behavioral effects otherwise associated with the drug were moderated. Subsequent experimentation with human cell cultures yielded similar results.

Treating Addiction

The clear results notwithstanding, it may take some time before pregnenolone becomes a household name in psychiatric treatment and diagnosis. For example, the researchers are well aware of the difficulties of administering this type of hormone. "Pregnenolone 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,” Piazza said, adding that any therapy would have to use a derivative.

Some experts have also expressed concern that a purely pharmacological treatment strategy may undermine the complex nature of the addiction. According to Scott Krakower, assistant unit chief of psychiatry at Zucker Hillside Hospital in Glen Oaks, N.Y., very few current therapies for marijuana addiction involve drug treatments. “Right now, the treatments for marijuana addiction are therapy," Krakower said, speaking to HealthDay. "Research like this leads to hope that one day we are going to have drugs to help those suffering from marijuana addiction."

That said, others praise the current study as an elegant explanation for the apparent absence of a lethal THC dose. Mitch Earleywine of the University of Albany, State University of New York, told reporters that, "although the authors pitch this as a novel way to treat cannabis abuse, it's actually a superb — if partial — explanation for why cannabis appears to have no potential lethal dose and why its capacity for creating addiction is more like caffeine's than that of any illicit drug.”

Source: Monique Vallée, Sergio Vitiello, Giovanni Marsicano, Pier Vincenzo Piazza et al. “Pregnenolone Can Protect the Brain from Cannabis Intoxication.” Science 3 January 2014: 343 (6166), 94-98. [DOI:10.1126/science.1243985]

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