Pharmacology: CBD Brings Positive Outlook to Negative Effects of THC

Looking at how different elements of cannabis work together in the brain, researchers from the University of Western Ontario in London, Canada, discovered the molecular mechanisms that can cause CBD to halt the negative psychiatric side effects of THC, the main psychoactive element of the plant.

This finding holds significance for individuals who may be more prone to anxiety and addictive behaviors yet could also benefit from the clinical prescription of medical cannabis.

Another important aspect of this finding is not only how the reaction occurs but also where in the brain it can be blocked.

Earlier research revealed that strains of cannabis plants with higher levels of THC and lower levels of CBD have a greater tendency for increased psychiatric effects such as paranoia, anxiety, and addictive behaviors. However, the reasons for this effect were not clearly understood at that time.

“A big unexplored area is the pharmacology of how CBD and THC work together,” says neuroscientist Steven Laviolette, PhD, a professor at Western’s Schulich School of Medicine & Dentistry and a researcher on this study. “Certain cannabidiols work together better than others. But little is known about where in the brain the interactions happen.”

Laviolette says that these findings have implications for prescribing cannabis as well as for the long-term use of the substance. For individuals who may be more vulnerable to developing psychotic symptoms and addictivelike behaviors with cannabis, but need the drug for therapeutic indications, it’s important to use cannabis strains that are higher in CBD and lower in THC. CBD alone doesn’t have much effect on altering the negative side effects.

“In our research, we could see how the discovery of coadministering CBD and THC opens up opportunities for the development of more effective and safer THC formulations,” Laviolette says.

Researchers at Western, he explains, had been looking at CBD and THC effects separately. But as the makeup of cannabis has changed over the years—from a more balanced level of CBD to THC to a more THC-heavy substance—researchers were seeing more negative side effects among cannabis users. “Now, there are more cases of first-episode psychosis among users, especially with the higher THC exposure,” he says. “There were fewer instances of side effects in the early years of cannabis use.”

This latest study was the first foray into examining effects with the two elements administered together.

According to the findings, published recently in the Journal of Neuroscience, researchers used rats to study to role of extracellular signal-regulated kinase (ERK), a molecule in the brain’s ventral hippocampus that triggers the neuropsychiatric effects of THC. The ventral hippocampus is the area of the brain that relates to stress, emotion, and affect; it’s also known to be more vulnerable to some of the long-term effects of higher concentrations of THC. ERK is the pathway that’s activated by THC and produces certain effects as a result.

As Laviolette explains, the rats were given different cannabinoid compounds. Those given THC had higher levels of activated ERK, exhibited more anxious behavior, and were quicker to develop fear-based learning. However, rats that were given both CBD and THC had more normal levels of ERK and showed fewer anxiety behaviors. The conclusion, then, was that CBD blocked the ability of THC to overstimulate the brain. Researchers achieved the reported positive results using a 1:1 ratio of CBD to THC.

“It boiled down to what happens in the ERK, the signaling pathway,” he says. “We knew that THC triggers a reaction in the ERK, but we didn’t know how much THC was the cause of the negative side effects.

Using rats as subjects, researchers were better able to pinpoint the specific area of the brain they wanted to study, Laviolette says. Once the CBD and THC were administered, they were able to “map out” the results.

“We found that THC was overstimulating the ERK pathway, altering oscillation patterns in the brain linked to schizophrenia and disturbing the dopamine system,” he adds. “We could see that the coadministration of CBD and THC helped to eliminate the negative side effects of cannabis in the brain,” he says.

A Forward View
According to Laviolette, his research team will follow up this study by continuing to identify the specific features of ERK. It will look at ways to formulate THC with fewer side effects, as well as improve the effectiveness of CBD-based solutions.

“We were able to achieve a wide effect on helping to improve the negative effects of THC by looking at just this one area of the brain,” he says. “As we widen our areas of study, the hope is that we will find further benefits of CBD coadministered with THC.”

Laviolette’s research team is studying how THC triggers side effects on the cognitive side, looking at the prefrontal cortex area of the brain, and how CBD can minimize negative effects in that area.

The team’s research in this area is a natural evolution of its efforts to explore how disturbances in the brain’s emotional processing centers can lead to the development of neuropsychiatric disorders such as addiction and anxiety. Called the Addiction Research Group, the team has made numerous discoveries related to how the brain is influenced by chronic drug exposure and how signaling through the brain’s cannabinoid and opioid systems can control emotional processing in specific brain circuits.

Ongoing studies in this area are important, Laviolette says, because determining the biological mechanism for the interaction of THC and CBD in the brain will provide background for eventual studies in humans on how CBD can affect the short- and long-term effects of THC. Attempts to block the psychotropic effects of THC can offer a viable solution to patients looking to use medical cannabis for relief from pain, to reduce anxiety, or to treat conditions such as glaucoma.

In the meantime, he says, “If you want to avoid the possible negative effects of cannabis, you may want to use strains that have a relatively higher CBD content to counteract the side effects of THC.”

— Kathy Hardy is a freelance writer based in Phoenixville, Pennsylvania.