Buzzkill: A chat with the researcher behind high-free weed


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The mysterious relationship between cannabis and the brain is something that scientists and stoners alike have been interested in for a while. Whether the question is “how do I convert tetrahydrocannabinol to cannabinol?” or “how do I reach those Oreos?” the driving force behind the drug’s intrigue in the past has been that we just aren’t quite sure why it makes us do what we do.

Recently, however, research into the science behind getting stoned has made interesting progress, particularly in the examination and breakdown of the chemical composition of the isomers behind the effect you feel after smoking a few jazz cigarettes.

Now, through examining effects of drugs on steroid production by the body, a team of French researchers carrying out research on lab rats have found that a steroid hormone, pregnenolone, reduces the activity of a particular brain molecule called the type-1 cannabinoid receptor, which is the main receptor for THC. The hormone can basically “cancel out” the high caused by THC.

This might sound like a massive buzzkill at first, but it could have its uses, primarily in treating marijuana overuse.

I also wondered if these findings might just offer a solution for those who over-indulge and want to cancel out the effects—not everyone loves to get so high they end up watching three hours of Cash in The Attic because the remote is too far away and their Dorito-induced coma is too restricting. Could these recent findings offer a glimpse of a weed ‘off’ switch? Could we be able to wake’n’bake, yet still arrive at work, fresh and on time?

To find out more about the findings and their possible applications, I caught up with the lead author of the research project, Pier Vincenzo Piazza from the French Institute of Health and Medical Research (INSERM).

MOTHERBOARD: What drove your study? Was it conducted with a particular goal of finding how to control cannabis effects or was the aim more vague?

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Piazza: We discovered at the beginning of the 90s that another steroid hormone called cortisol (produced by the adrenal gland and considered the main stress hormone) was very important in determining the vulnerability to develop addiction to cocaine. When it was discovered that the brain produced a subclass of steroids, called neurosteroids, it was natural to go and see if neurosteroids were also controlling drug addiction. This is why we studied the effects of the major classes of drugs of abuse on the brain steroids.

The surprise was that only one drug had a huge effect: THC, and its effect was an increase in pregnenolone, which was a neurosteroid—until then considered an inactive precursor (something that had no biological effects on its own but that was used to produce other steroids, like progesterone, or testosterone).  Since the levels of pregnenolone after administering THC increased by 3,000 percent, we thought it probably had an important role and the vision of this hormone as being inactive was a mistake. We then discovered that pregnenolone blocked the effect of THC… In other words, it is a built-in defence mechanism.

How exactly does the drug control the effects of cannabis? Is it only the ‘high’ sensation that is affected? How would someone feel after taking pregnenolone compared to if they hadn’t taken it?

No, practically all the effects of cannabis (at least the most known ones and all the ones that we have studied) are antagonized. The bad effects such as the craving for the drug, the amount of the drug that would be self-administered, memory loss and excessive demotivation were all affected, as well as the good effects like pain control and increase in food intake. So even though we do not know exactly how a human will feel after he has taken both pregnenolone and cannabis, the prediction is that the effects of the cannabis are probably less desirable and that the drug should be craved less.

For people who use marijuana medicinally, would they still experience the same beneficial effects from the cannabis or would the pregnenolone inhibit those?

Unfortunately they don’t. Most of the medicinal effects of cannabis are stopped by pregnenolone.

How would the drug be taken? Would it be administered as a pill, or an injection?

In animals it was an injection but in humans it will be a pill. However, it won’t be pregnenolone itself. Pregnenolone cannot be used as a therapeutic drug because it is quickly metabolized in other steroids. So if you take pregnenolone even at high doses, you will have a lot of progesterone and testosterone in your body and quite little pregnenolone. It will then be a treatment more likely to cause you to lose your hair and increase the size of your mammary gland than to stop smoking cannabis.

Has the drug been tested on humans as well as mice yet?

No, we haven’t conducted any human tests yet, at least, not for cannabis addiction.

What do you think the predominant uses of the drug could be? I was thinking that maybe if someone had smoked “too much” (I know you can’t actually overdose, but if they felt unwell or something) then it might be able to be given as a sort of antidote.

No, unfortunately the only use we foresee is for individuals that develop cannabis addiction, i.e. that smoke several times per day and it is messing up their life; people who would like to stop but cannot.

What do you see as the future of the drug? Are you doing any more developing, and do you plan for it to be made available commercially?

Since pregnenolone cannot be used as a therapeutic drug, we have developed pregnenolone derivatives that still have the same anti-cannabis effects but are not transformed into other steroids. It is this new class of drug that we will be testing in humans—we hope to start clinical testing in about one and a half years. These drugs also might have other useful applications such as in the treatment of schizophrenia, metabolic disease and some skin diseases. The reason is that cannabis has its effects by activating a receptor, the CB1, that has a lot of other functions.


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