Molecule discovered that protects brain from cannabis intoxication

January 2, 2014

Science Daily/INSERM (Institut national de la santé et de la recherche médicale)

Two INSERM research teams recently discovered that pregnenolone, a molecule produced by the brain, acts as a natural defense 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."

https://www.sciencedaily.com/releases/2014/01/140102142012.htm

How does resolving cannabis problems differ from problems with alcohol or other drugs?

Those resolving cannabis problems do so at younger ages, with less assistance than those resolving other substance-use problems

March 5, 2018

Science Daily/Massachusetts General Hospital

Individuals who report having resolved a problem with cannabis use appear to have done so at younger ages than those who resolved problems with alcohol or other drugs, report investigators from the Recovery Research Institute at Massachusetts General Hospital (MGH). While study participants also were much less likely to use any formal sources of assistance or support in resolving problems with cannabis than those whose problems were with other substances, that finding was less common in those who resolved a cannabis problem more recently, which may reflect the increased availability and potency of cannabis in recent years.

"Very little has been known about recovery from cannabis use problems, and this is the first study to examine that on a national basis," says John Kelly, PhD, director of the Recovery Research Institute, who led the study published in the March issue of the International Journal of Drug Policy. "Compared with alcohol and other drugs, cannabis holds a unique place in federal and state policies -- continuing to be illegal federally but with medical and recreational use legalized at the state level. Due to this increased availability and the proliferation of a for-profit cannabis industry, understanding the needs of individuals with cannabis problems will be increasingly important."

The current study analyzes data from the National Recovery Survey, conducted by Kelly's team. A nationally representative sample of nearly 40,000 U.S. adults who participate in the Knowledge Panel of the market research company GfK were asked "Did you used to have a problem with drugs or alcohol, but no longer do?" Of more than 25,000 respondents, a little over 2,000 indicated they had resolved such a problem and were sent a link to the full study survey, which asked a variety of questions such as the specific problem substances and details regarding how and when they had resolved their problem. As reported in a paper published last year in Drug and Alcohol Dependence, more than half of all respondents reported resolving their problem with no assistance.

The current study focused on participants who indicated having resolved a cannabis problem, who made up around 11 percent of respondents, reflecting around 2.4 million U.S. adults. Compared with those resolving problems with alcohol or other drugs, those resolving cannabis problems reported starting regular use -- once a week or more -- at younger ages but also resolving the problem at younger ages, an average of 29 compared with 38 for alcohol and 33 for other drugs.

Cannabis-primary respondents were even less likely to have used formal treatment or support services than were those resolving problems with illicit drugs -- 18 percent versus 42 percent -- but were more likely to have participated in drug courts than those who had resolved alcohol problems -- 24 percent versus 8 percent. Cannabis users also reported "addiction careers" -- the years between their first use and problem resolution -- that were significantly shorter than those of the alcohol group -- 12 years versus 18 years, which may reflect the greater physical and mental health impairment associated with alcohol and the continuing illegality of cannabis.

"We did expect that the cannabis-primary individuals would be less likely than the illicit drug group to use formal treatment; but very little is known about the magnitude or nature of such differences, " says Kelly. "That may be due to fewer physiological and other life consequences compared with the impairments caused by drugs like alcohol or opioids. For example, while there is a documented withdrawal syndrome related to cannabis dependence, withdrawal from opioids or alcohol is notoriously more severe and often requires medically-managed detoxification."

Given the increased levels of THC -- the psychoactive component of cannabis -- in products available today, the team investigated whether the use of formal support services had changed over time. Indeed, they found that utilization of outpatient services was more common in those resolving their problems within the past 5.5 years, while use of inpatient services was actually more common in those who resolved their problem around 20 years previously.

The Spallin Associate Professor of Psychiatry in Addiction Medicine at Harvard Medical School, Kelly explains that brain changes caused by the higher THC content in marijuana today -- 15 to 20 percent, versus 1 to 5 percent 10 or 20 years ago -- could make it harder for individuals using this more potent cannabis to stop on their own. While inpatient treatment was considered first-line treatment for addiction two decades ago, it is much less common today, and insurance companies often require attendance at outpatient treatment first.

"In the current landscape of higher potency cannabis and the greater availability and variety of cannabis products, it is more likely that individuals will need to seek help in resolving problems with cannabis," he says. "Now it will be important to determine whether the recovery timeline from high-potency cannabis will be different and more challenging. And since so many of the cannabis-primary group resolved their problem without either formal treatment or mutual help organizations like Marijuana Anonymous or Narcotics Anonymous, it will be critical to understand the changes in their lives that helped make recovery possible."

https://www.sciencedaily.com/releases/2018/03/180305160204.htm