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Molecule Discovered That Protects Brain from Cannabis Intoxication

By Phungushead, Jan 19, 2014 | | |
  1. Phungushead
    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 harmful effects 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 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 brain, 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 cannabis dependence."

    Jan. 2, 2014

    Science Daily

    Journal Reference: M. Vallee, S. Vitiello, L. Bellocchio, E. Hebert-Chatelain, S. Monlezun, E. Martin-Garcia, F. Kasanetz, G. L. Baillie, F. Panin, A. Cathala, V. Roullot-Lacarriere, S. Fabre, D. P. Hurst, D. L. Lynch, D. M. Shore, V. Deroche-Gamonet, U. Spampinato, J.-M. Revest, R. Maldonado, P. H. Reggio, R. A. Ross, G. Marsicano, P. V. Piazza. Pregnenolone Can Protect the Brain from Cannabis Intoxication. Science, 2014; 343 (6166): 94 DOI: 10.1126/science.1243985

    Image: 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. (Credit: © Derek Shore, Pier Vincenzo Piazza and Patricia Reggio)



  1. kumar420
    Interesting article about an interesting premise, thanks for posting it. I do have several issues with it though.

    A few things about the way this article has been written:

    This irked me as soon as I read it. The article assumes the 'harmful' effects of cannabis are the intoxicating ones, and makes no mention of the fact that it is impossible to overdose on THC and the more unpleasant side effects are usually only apparent in users with little or no tolerance. No mention whatsoever of the protective and medicinal properties that accompany the intoxication, nor of the widely agreed-upon list of negative effects of cannabis, especially the ones related to smoking (which are the only ones that have been really conclusively proven). Nothing in existence is completely safe, even cannabis, but to write off years of research that intimately relates to the topic is really sloppy work.

    Next up:
    I call bullshit on this one. Considering the boom in the synthetic drug market, combined with the existing problem of alcohol (the most widely abused addictive drug) and the recent rise in the availability of methamphetamine, this claim seems EXTREMELY unlikely. And seriously, rehab for cannabis addiction? If you've been smoking all day, every day for ten years, this might be necessary. Not so for a kid who tokes on the weekends (and is probably only in rehab because of an overly concerned parent or relative).

    While I'd like to fluff this off as reefer madness, I'm going to take it seriously and address it in a serious manner. 'General loss of motivation' is such a nonsense, all round description of a state of mind that could have any number of causes (that may or may not include the weed) and can even be a symptom of a mental disorder or some form of depression. Attributing 'general loss of motivation' to weed is like a mechanic saying that your car isn't working because of 'some problem with the engine'. Vague and useless.

    As for cognitive deficits, the article assumes a hell of a lot and doesn't elaborate much, save to mention 'memory problems' (another all-round term that doesn't identify a specific problem). It seems to me that the person who wrote this article assumes the average cannabis user is a useless layabout pothead, like in one of Hollywood's beloved stoner comedies, who has the short-term memory of a goldfish, athletic ability of a snail and cognitive capacity of a pebble. Which as all of us here should know, simply isn't true. Abusing any drug will have short and long term negative effects on a person's health, but when describing such effects it pays to be specific.

    This discovery is an incredible asset to medical world, because when this drug is perfected, everyone will be able to use cannabis to treat a wide variety of symptoms without having the intoxicating effects that could potentially affect one's performance and judgement during a workday, allowing pain patients, epileptics, chronic MS-suffers and people undergoing chemotherapy to work full days pain-free and without fear of making mistakes due to being intoxicated. Unfortunately if the attitude displayed in this article persists, this marvelous molecule could be turned into a weapon against the legalization movement, and a direct attack on the freedoms of those of us who choose to use cannabis recreationally (and medically). I can see the headlines now:

    'Sick of the smell of burning marijuana leaking from your nextdoor neighbors backyard? Spray his plants with pregnenole so he won't be able to get high anymore!'

    Returning to the article, really badly written, omits all sorts of important material, incredibly biased. I expected better from a source calling itself the 'Science daily' and purports to be 'Your source for the latest research news'. No thanks, I'll stick to google.
  2. Crystal_Queen
    Why would an addict pay for two drugs that cancel each other out?
    How is that better then spending no money on drugs. lol
  3. jazzyj9
    I've never considered the intoxicating effect harmful, unless someone is driving or doing some other activity that requires metal focus and quick reflexes. I don't mean to minimize cannabis addiction. I had a friend who said she was addicted for many years and that it caused a lot of memory problems for her.

    I do know more people who have benefited from cannabis however. It was also great for me when I was getting off of crystal meth and helped for a while when I was depressed. It was kind of a crutch though, which wasn't helping me grow in certain aspects of my life that I had let fall by the wayside. Nevertheless, I really love the plant, and was impressed to find out it also has anti-tumor properties http://norml.org/library/item/gliomascancer

    This is in addition to it's analgesic effects and ability to stimulate appetite for use in people with cancer and other bodily wasting diseases. Overall, I think its a rather benign recreational drug and that the positive effects far outweigh the negative.

    Kumar420 makes about how this discovery may possibly be used as a benefit for people who are using it strictly for it's medicinal effects in the body (excluding the intoxicating effects).

    I think the purpose of the research may be just to prevent people from enjoying the intoxicating effects, which seems like a waste of money and time if used for that purpose.
  4. SIR KIT
    *Throws away bottle of Pregnenolone tablets*
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