Using marijuana as a teen could make another drug even more intense — study

There's extra time to reminisce about teenage 4/20s while in quarantine. But a new study may make you view those early weed experiences in a new way: Being exposed to marijuana during teen years can cause fundamental changes in the brain that make other drugs hit different, according to research conducted on rats.

This study suggests that exposure to a synthetic THC-lookalike during adolescence can reprogram key areas of the brain.

Specifically, the scientists found that exposure to a synthetic cannabinoid made adolescent rats more sensitive to the effects of cocaine, and changed gene expression in the pre-frontal cortex, an area of the brain involved in planning and complex behavior.

The prefrontal cortex is already a messy environment for teens. As some connections are strengthened and others are pruned, our executive functions (circuits in the brain that make you think twice before being foolish) are offline. Adding marijuana to the mix makes things more chaotic: Weed can negatively affect working memory and change the brain's normal development pattern in teens, previous studies suggest.

Now, researchers suggest that the effects of a synthetic cannabinoid can cause changes in the brain that ultimately makes cocaine an even more intense experience than it already is. This finding was published Wednesday in the journal Proceedings of the National Academy of Sciences.

While most studies on rats and marijuana focus on THC, this study used a synthetic cannabinoid called WIN 55,212-2 (WIN), which has similar effects to THC but has a different chemical structure.

Philippe Melas is the study's last author and a postdoctoral researcher at the Karolinska Institutet in Sweden. He tells Inverse that past studies suggest that WIN and THC have similar neurochemical changes in the brain. However, WIN does bind more strongly to cannabinoid receptors in the brain than natural THC does.

One group of pubescent rats and another group of adult rats received increasing doses of WIN for 11 days. The researchers intentionally increased the doses of the drug to replicate "heavy" cannabis use during adolescence (they describe this intent in their supplemental material).

Because of that these findings "may not apply to single or occasional cannabis use of low THC doses," Melas adds.

For these rats, the highest dose was two WIN doses of 8mg/kg per day. Then, after letting the rats dry out for a week, they gave them their first taste of cocaine.

Ultimately, the team found that the adolescent rats were "cross-sensitized" to that first cocaine dose, which means that they were hypersensitive to the effects of the drug and wild out — aka, moved around a ton in their cage.

The team doesn't go into detail about what that "cross-sensitization entails." But previous studies have shown that THC exposure during adolescence can cause rats to pick up a cocaine habit more quickly. Other studies have shown that rats become more hyperactive when they take cocaine if they've been exposed to THC first.

However, the adult rats didn’t appear hypersensitive to cocaine — even though they were exposed to synthetic THC too. This suggests that there's something unique happening when cocaine meets a teenage brain with prior exposure to THC.

The rats were sacrificed soon after their drug experiences, which allowed the researchers to look for changes in their brains that might explain their intense reactions.

While they found numerous small changes in gene expression, one of their most powerful findings was an attachment of additional chemical groups to histones (histones are collections of proteins that DNA is wrapped around).

Scientists have already proposed that cocaine use can add tiny chemical tails to these spools of proteins, which change the way genes are expressed. Those histone-related changes spike when cocaine-addicted mice are deprived of cocaine, which scientists believe may be the precursor to a drug relapse.

In this study, they saw the bulk of these changes in the prefrontal cortex (dysfunction in that area of the brain is linked to compulsive drug use).

Their results suggest that in, taken in tandem with other changes in gene expression, these changes contribute to the rats' hyperactive reactions to cocaine.

If the results hold up in humans, Melas adds that they could underpin a "favorable" reaction to cocaine for teens that use a lot of marijuana. However, this study can't prove this connection exists on its own.

Is marijuana actually a gateway drug?

It might be easy to paint these results as further evidence of a "gateway drug hypothesis" or the idea that marijuana use can cause the use of harder drugs later on. While there is evidence that some marijuana users do go on to use other drugs later on, that's not enough evidence to say marijuana use drives that decision.

"Although favorable first encounters with a drug of abuse are known to predict repeated use of that drug in the future, we need to remember that additional environmental, social or genetic vulnerabilities are also needed for an addiction to develop," Melas says.

For instance, one 2015 study found that 44.7 percent of 6,624 marijuana users went on to use other drugs. But that progression was influenced by socioeconomic demographics and psychiatric disorders. Other research suggests there are lots of reasons that people might choose to use drugs in the first place. And as other drugs come onto the radar, like cocaine, those same social or environmental factors may make using those drugs more likely too.

Marijuana may not be a gateway drug in that there's some nefarious characteristic that guides someone down the path to other drugs. Rather, it might just be more readily available, as the NIH notes.

That said, research like this study does show that weed can reshape the brain, especially during adolescence, suggesting that there is some biology to consider as well. Using a drug may not drive you to use another, but it could change the way that your brain responds to further substances.

Abstract: The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain’s initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phos- phoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross- sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2. Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK- targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC–NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN pre-exposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine.