Molecule discovered that protects the brain from cannabis intoxication

January 2, 2014, Institut National de la Sante et de la Recherche Medicale
Credit: P. Reggio, modified by P.V. Piazza

Two INSERM research teams led by Pier Vincenzo Piazza and Giovanni Marsicano (INSERM Unit 862 "Neurocentre Magendie" in Bordeaux) recently discovered that pregnenolone, a molecule produced by the brain, acts as a natural defence mechanism against the harmful effects of cannabis in animals. Pregnenolone prevents THC, the main active principle in cannabis, from fully activating its brain receptor, the CB1 receptor, that when overstimulated by THC causes the intoxicating effects of cannabis. By identifying this mechanism, the INSERM teams are already developing new approaches for the treatment of cannabis addiction.

These results are to be published in Science on 3 January.

Over 20 million people around the world are addicted to cannabis, including a little more than a half million people in France. In the last few years, cannabis addiction has become one of the main reasons for seeking treatment in addiction clinics. Cannabis consumption is particularly high (30%) in individuals between 16 to 24 years old, a population that is especially susceptible to the harmful effects of the drug.

While cannabis consumers are seeking a state of relaxation, well-being and altered perception, there are many dangers associated to a regular consumption of cannabis. Two major behavioural problems are associated with regular cannabis use in humans: cognitive deficits and a general loss of motivation. Thus, in addition to being extremely dependent on the drug, regular users of cannabis show signs of memory loss and a lack of motivation that make quite hard their social insertion.

The main active ingredient in 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.

Increase of dopamine release

Developing an efficient treatment for cannabis addiction is becoming a priority of research in the fiend of drug addiction.

In this context, the INSERM teams led by Pier Vincenzo Piazza and Giovanni Marsicano have investigated the potential role of pregnenolone a brain produced steroid hormone. Up to now, pregnenolone was considered the inactive precursor used to synthesize all the other steroid hormones (progesterone, estrogens, testosterone, etc.). The INSERM researchers have now discovered that pregnenolone has quite an important functional role: it provide a natural defence mechanism that can protect the brain from the of cannabis.

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. Pregnenole then binds to a specific site on the same CB1 receptors (see figure) and reducing the effects of THC.

The administration of pregnenolone at doses that increase the brain's level of this hormone even more, antagonize the behavioral effects of cannabis.

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.

This negative feedback mediated by pregnenolone (THC is what triggers the production of pregnenolone, which then inhibits the effects of THC) reveal a previously unknown endogenous mechanism that protects the brain from an over-activation of CB1 receptor.

A protective mechanism that opens the doors to a new therapeutic approach.

The role of pregnenolone was discovered when, 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. It was then found that only one drug, THC, increased brain steroids and more specifically selectively one steroid, pregnenolone, that went up3000% for a period of two hours.

The effect of administering THC on the pregnenolone synthesis (PREG) and other brain steroids

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 , the negative behavioural effects of THC are blocked. For example, the animals that were given pregnenolone recover their normal memory abilities, are less sedated and less incline to self-administer cannabinoids.

Experiments conducted in cell cultures that express the human CB1 receptor confirm that pregnenolone can also counteract the molecular action of THC in humans.

Pier Vincenzo Piazza explains that pregnenolone itself cannot be used as a treatment "Pregnenolone cannot be used as a treatment because it is badly absorbed when administerd orally and once in the blood stream it is rapidly transformed in other steroids".

However, the researcher says that there is strong 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. We should be able to begin clinical trials soon and verify whether we have indeed discovered the first pharmacological treatment for dependence."

Explore further: Stoners beware: Exercising might lead to a positive drug test

More information: Science 3 January 2014, vol 343

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1.4 / 5 (10) Jan 02, 2014
Thus, in addition to being extremely dependent on the drug, regular users of cannabis show signs of memory loss and a lack of motivation that make quite hard their social insertion.

And yet two U.S. states have now legalized the drug for recreational use. How far we have fallen when our states' governments approve of the widespread use of a destructive, addictive substance.
3.7 / 5 (3) Jan 02, 2014
for all of those who can't seem to get any higher, pregnenolone is to blame. now someone needs to find an investor to fund a study on possible blockers.
4 / 5 (8) Jan 02, 2014
"Participants who spent less than seven hours a day in their later years watching TV were 50 per cent less likely to develop memory loss compared to those who spent more than 7 hours a day in front of the TV."

"...there is a link between dementia and elevated blood sugars in the non-diabetic range," says study author Dr. David Nathan, a Harvard Medical School professor... helpful is cutting back your intake of highly refined carbohydrates, especially foods with added sugars such as sucrose, high fructose corn syrup, and also molasses, cane sugar, corn sweetener, raw sugar"

"Common symptoms associated with a diagnosis of PCS are related to cognition,[19] problems with attention, memory, especially short-term memory which can also worsen other problems such as forgetting appointments or difficulties at work"

"Poor quality sleep... can cause significant memory loss and brain deterioration, according to a recent study..."

-It is EASY to screw up our brains. Pot is benign.
4.4 / 5 (7) Jan 02, 2014
Yet another subversive attempt to indicate that marijuana is addictive. However many many many more independent none government financed studies show it is not. Habit forming is not an addiction. I have a habit of driving to work using the same route. I am not addicted to that route. I smoked pot every day multiple times a day from 12 years old to 30. I stopped one day because I did not want to spend money on it. No adverse effects or withdrawals just as the valid studies prove. P.S. have not smoked it since and have had no desire. I am 41.
4.7 / 5 (7) Jan 02, 2014
Weed isn't addictive. Sugar is as strong an addiction as crack. Why is there no outcry to ban sugar?
3 / 5 (2) Jan 02, 2014
this has all the usefulness of ......... Politician discovered that prevents the economy from economic growth........somehow I am not shocked that the same liberals that believe in AGW think that this is a good thing.
4.3 / 5 (6) Jan 02, 2014
"How far we have fallen when our states' governments approve of the widespread use of a destructive, addictive substance."

Yes, terrible, it causes birth defects, liver disease, violence, car crashes, heart disease . . . you were talking about alcohol, weren't you?
5 / 5 (4) Jan 02, 2014
Sooooooooo marijuana is addictive? Excuse me while I LOL. I've smoked for 45 years now when the mood strikes me. Finished University, Own and run a successful business. Have a wonderful Daughter and 2 beautiful granddaughters. I'm spending the winter in Florida this year, scuba diving and fishing. So now I'm a addicted loner with no social life and no motivation? Excuse me, the laughter is bubbling back up. Let me guess, these "researchers", who funded them? Pfizer? Roche? Eli Lily maybe?
Whydening Gyre
5 / 5 (1) Jan 02, 2014
While cannabis consumers are seeking a state of relaxation, well-being and altered perception, there are many dangers associated to a regular consumption of cannabis. Two major behavioural problems are associated with regular cannabis use in humans: cognitive deficits and a general loss of motivation.

That two associated behavioural problems - just sounds like when you get old....
Whydening Gyre
5 / 5 (1) Jan 02, 2014
a lack of motivation that make quite hard their social insertion.

TO be "socially inserted", simply means "to be useful to the reigning society". In other words a good little consumer.

And yet two U.S. states have now legalized the drug for recreational use. How far we have fallen when our states' governments approve of the widespread use of a destructive, addictive substance.

You're just kidding, right? You'd prefer lhat age group have a bottle of Jack Daniels instead? (Not that I have anything against a good whiskey - taken in moderation, of course...)
Kids are kids... they're gonna not do what you tell 'em to, cuz' that's their job... to test previous "theories" against the real thing. First hand experimentation and observation.
not rated yet Jan 02, 2014
Wow!! Cannabis is addictive? I don't think so. Perhaps demotivating for people with under developed minds (read NOT ADULTS). Also note that this article suggests that humans have a built in mechanism to PREVENT addiction. So I don't know what drugs the OP is on, but it isn't cannabis. For those who think cannabis is deadly, then how about you give prisoners on death row the option of death by cannabis smoking or lethal injection. Wonder which one they would pick? Cannabis CAN be a wonderful motivator for the right people. Personally I have written some of my best computer programs on cannabis as it blocks out all distractions. Sure I may have had to use pen and paper to keep track of my thoughts (damn short term memory loss), but for me, it keeps me striving for the best solution to computational problems.
Try to keep in mind that ANY drug is bad for children, or the dimwitted.
I've never seen a street brawl from cannabis smokers, or ppl prostituting themselves for weed!!
5 / 5 (1) Jan 02, 2014
I'd also like to point out, that many studies regarding cannabis focus on the active ingredient THC, and completely ignore the WHOLE plant ingredients. Do some research and you will see that consuming the PLANT, also gives you CBD, which is NOT considered to be a psychoactive. However CBD mediates the effect of THC. This is one of the reasons that different strains of marijuana have different effects. So the plant itself comes with its own control mechanisms. My preference is NOT for high THC, but a nice balance between THC and CBD. Education makes the difference, not an enforced ignorance due to illegality.
5 / 5 (2) Jan 03, 2014
I find it hilarious here that people citing that Cannabis is addictive and bad NEVER question Alcohol. I wonder how many people on drugs if surveyed said they drunk alcohol before trying drugs, in fact Alcohol is probably the gateway to all recreational drug/substance abuse not weed. I also find it funny that anti-Cannabis/weed studies are popping out more than ever since the beginning of mass-legalization in some of the largest states in the US and some south american countries. Before 2010, hell in 2000 and the 90s there was little to no studies at all putting this much villainy on cannabis. It seems to me this is a last ditch effort to try to stop Cannabis from progressing to all. The government(s) [ Because majority of anti-cannabis comes from government studies] are being pressured more than ever by their lobbiest buddies to stop this. Yet at the same time our crack pipe smoking,pill-popping, coke snorting politicians love to do drugs themselves and want us to be regulated.
vlaaing peerd
not rated yet Jan 03, 2014
Luckily over here we have 50 years of research on the social, health and criminal aspects of various usages. There is a clear consensus, of all various types of drugs (including alcohol, nicotine and other socially accepted drugs) that were popular in the Netherlands over the last 40 years, THC is the least problematic on all 3 aspects.

Yet in contrary to both some posters opinions, THC + CBD is slightly physically addictive (anything that releases dopamine usually is, but negligible in comparison to alcohol or nicotine). What the research on the other hand completely misses out is that the physical addictiveness is not relevant to solving the most common problematic behaviour related to cannabis use (harm to yourself or others, socially, law and health wise).

Now since we stopped criminalizing users and health risks of usage are well within an acceptable range (in rare cases even very beneficial), the only real problems found are mostly socially. ->
vlaaing peerd
not rated yet Jan 03, 2014

there is an amount of users that after several years of usage that do exclude themselves from social participation so much that it over the years it becomes more and increasingly difficult to "get back" into every day social events as school (most problematic users are school going kids), work, sports, culture or just generally maintaining a healthy and social lifestyle.

In the 80's most reintegration aid (usually ones house/family doctor or a psychologist/social worker) was based on getting the user to rid extreme cannabis use, yet left the social situation of the user untouched. Since there was hardly any social change, many users usually reverted back to their old doses and their old situation.

Only after helping problematic users to get back "into society" it also started having a positive effect on extreme usage too.

All in all there aren't a lot of problems and even ridiculously negligible in comparison to alcohol and other drug issues, but I'd say thinking that the ->
vlaaing peerd
5 / 5 (1) Jan 03, 2014
use of cannabis is completely "trouble free" is perhaps the biggest danger. We find especially teenagers and young adults are susceptible to easily getting in to vast daily usage and with it neglecting their social life, school career and other aspects.

So perhaps it is better to educate people about responsible usage, possible dangers and give them enough information to make a well educated decision themselves instead of standing on one end of each of the poles.
5 / 5 (1) Jan 03, 2014
I'm neutral on this. Not into monkeying around with my brain's chemistry, but if others so desire and it doesn't harm the society in which I have to live, . . . whatever.

I'm less than convinced by all these "look at me, 40 years of pot smoking and no problems" single-data-points, though. Sounds too much like those "40 years of tobacco smoking and no cancer" stories we used to hear. Wake me up again when you have the results of some sort of rigorous scientific study of a population.
5 / 5 (3) Jan 03, 2014
@Returner: "How far we have fallen when our states' governments approve of the widespread use of a destructive, addictive substance?"

It wasn't state governments that "approved" cannabis --- it was citizens' demands to legalize this relatively non-toxic, broadly therapeutic, non-addicting drug that were finally (finally!) met. The public is way out in front of the reporters, the doctors and the legislators on this one. As for your characterization of pot as destructive and addictive, I think you are confusing the truly destructive, addicting drug that was re-legalized in 1934 with the one that took its place in the Prohibition Hall of Shame in 1937.
5 / 5 (4) Jan 03, 2014
"How far we have fallen when our states' governments approve of the widespread use of a destructive, addictive substance."

Cannabis or organized religion?

5 / 5 (1) Jan 03, 2014
My one bad result of cannabis use was getting arrested for growing it after it had kept me healthy and active while on chemotherapy. Otherwise I enjoyed its ability to give me focus while studying for a degree, writing code, designing electronics and circuit boards, and learning to play several musical instruments. Knowing exactly how much to ingest to achieve precise levels of focus for the job at hand is key. I smoked while studying calculus and electronics, aced my tests and graduated with high honors.

If you can't get motivated to begin with then THAT is your problem. Cannabis and a predisposition for laziness are certainly no worse than if you drink alcohol to accompany your lax attitude. Except, unlike alcohol, the addiction to cannabis is primarily psychological.

I always cringed at those old anti-reefer ads that said:
"If you smoke marijuana you're not being responsible"

When the correct message we knew should have been:
"If you smoke marijuana - BE RESPONSIBLE!"

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