Marijuana concentrates spike THC levels but don't boost impairment

June 10, 2020

Science Daily/University of Colorado at Boulder

A study of 121 regular users of legal market cannabis found that higher potency does not necessarily mean greater intoxication. It also found that while balance and memory are impaired immediately after use, that impairment fades within in an hour.

Smoking high-potency marijuana concentrates boosts blood levels of THC more than twice as much as smoking conventional weed, but it doesn't necessarily get you higher, according to a new study of regular users published today by University of Colorado Boulder researchers.

"Surprisingly, we found that potency did not track with intoxication levels," said lead author Cinnamon Bidwell, an assistant professor in the Institute of Cognitive Science. "While we saw striking differences in blood levels between the two groups, they were similarly impaired."

The paper, published June 10 in JAMA Psychiatry, is the first to assess the acute impact of cannabis among real-world users of legal market products. It could inform everything from roadside sobriety tests to decisions about personal recreational or medicinal use.

But the study also raises concerns that using concentrates could unnecessarily put people at greater long-term risk of side-effects.

"It raises a lot of questions about how quickly the body builds up tolerance to cannabis and whether people might be able to achieve desired results at lower doses," said Bidwell.

While 33 states have legalized medicinal marijuana use, and 11 have legalized recreational use, both uses remain illegal at the federal level. Researchers are also prohibited from handling or administering marijuana. Some previous studies have used strains supplied by the government, but those strains contain far less THC than real-world products.

In order to study what people really use, Bidwell and her colleagues utilize two white Dodge Sprinter vans, also known as the "cannavans," as mobile laboratories. They drive the vans to the residences of study subjects who use cannabis they purchase on their own inside their homes and then walk out for tests.

"We cannot bring legal market cannabis into a university lab, but we can bring the mobile lab to the people," she said.

For the current study, the team assessed 121 regular cannabis users. Half typically used concentrates (oils and waxes that include the active ingredients without the leaves and stems). The other half typically used flower from the plant. Flower users purchased a product containing either 16% or 24% [tetrahydrocannabinol (THC)], the main psychoactive ingredient in marijuana. Concentrate users were assigned to a product containing either 70% or 90% THC.

On test day, researchers drew the subjects' blood, measured their mood and intoxication level and assessed their cognitive function and balance at three time points: before, directly after and one hour after they used.

Those who used concentrates had much higher THC levels at all three points, with levels spiking to 1,016 micrograms per milliliter in the few minutes after use, while flower users spiked at 455 micrograms per milliliter. (Previous studies have shown that THC levels hover around 160 to 380 micrograms per milliliter after marijuana use).

Regardless of what type or potency of cannabis participants used, their self-reports of intoxication, or "feeling high," were remarkably similar, as were their measures of balance and cognitive impairment.

"People in the high concentration group were much less compromised than we thought they were going to be," said coauthor Kent Hutchison, a professor of psychology and neuroscience at CU Boulder who also studies alcohol addiction. "If we gave people that high a concentration of alcohol it would have been a different story."

The study also found that, among all users, balance was about 11% worse after using cannabis, and memory was compromised. But within about an hour, that impairment faded.

"This could be used to develop a roadside test, or even to help people make personal decisions," said Bidwell.

The researchers aren't sure how the concentrate group could have such high THC levels without greater intoxication, but they suspect a few things are at play: Regular users of concentrates likely develop a tolerance over time. There may be genetic or biological differences that make some people metabolize THC more quickly. And it may be that once compounds in marijuana, called cannabinoids, fill receptors in the brain that spark intoxication, additional cannabinoids have little impact.

"Cannabinoid receptors may become saturated with THC at higher levels, beyond which there is a diminishing effect of additional THC," they write.

The authors caution that the study examined regular users who have learned to meter their use based on the desired effect, and does not apply to inexperienced users. Those users should still be extremely cautious with concentrates, said Hutchison.

Ultimately, the researchers hope to learn what, if any, long-term health risks concentrates truly pose.

"Does long-term, concentrated exposure mess with your cannabinoid receptors in a way that could have long-term repercussions? Does it make it harder to quit when you want to?" said Hutchison. "We just don't know yet."

https://www.sciencedaily.com/releases/2020/06/200610135016.htm

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