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In this De-Natured segment of Nature League, Brit breaks down a recent scientific journal article about the effect of cannabidiol on brain regions associated with psychosis.

Article citation:

Bhattacharyya S, Wilson R, Appiah-Kusi E, et al.

Effect of cannabidiol on medial temporal, midbrain, and striatal dysfunction in people at clinical high risk of psychosis: a randomized clinical trial.

JAMA Psychiatry, 2018

Article link:
https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2697762

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On Nature League, we spend the third week of each month exploring a current trending article from the peer-reviewed literature.

Scientific information isn’t just for scientists- it’s for everyone! It just requires a bit of a break down. [CHEERY INTRO MUSIC].

For this month’s De-Natured segment, we’re going to look at an article released in August 2018 in the Journal of the American Medical Association Psychiatry. This month is all about plants, and in this month’s Lesson Plan we began by mentioning that most organisms on Earth depend on plants to live. Not only do plants provide oxygen to the atmosphere, but they serve as the energy starting point for many living food webs.

But in the realm of human medicine, plants and their isolated compounds can yield much more than oxygen and food- especially in the case of cannabis. In this paper entitled, “Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal. Dysfunction in People at Clinical High Risk of Psychosis”, the researchers report the results of a new clinical trial that investigated how cannabidiol, or CBD, can affect individuals at high risk of psychosis.

So here’s what’s already known. Cannabis is a genus of flowering plants- plants that have been used by humans for thousands of years for a multitude of purposes. Two well-known varieties of plants in this genus are commonly known as hemp and marijuana.

Two chemical compounds have contributed to the well-known nature of Cannabis plants. The first is cannabidiol, or CBD, and it’s primarily found in hemp. The second compound is tetrahydrocannabinol, or THC, and it’s primarily found in marijuana.

While both compounds have the exact same molecular formula, THC is psychoactive, meaning it can create a high, or euphoria. But what do cannabis plants have to do with psychiatry? That’s where brain chemistry comes in.

The reason our bodies react to CBD and THC at all has to do with the fact that human brains have an endocannabinoid system. Alterations in this system are associated with the symptom of psychosis, which can be generally defined as a loss of contact with reality. While some research has shown that regular cannabis use can be a risk factor for developing psychosis, especially in teenagers, these findings specifically refer to THC.

The other compound, CBD, can actually have the opposite effect. In fact, some clinical studies have shown that CBD has antipsychotic properties for people with certain mental disorders. Despite a growing body of evidence that CBD can be beneficial to those suffering psychotic symptoms, scientists have yet to figure out how.

To address this, the research team observed the effects of CBD on three specific regions of the brain in people at clinical high risk of psychosis. The first of these regions is the medial temporal lobe, or MTL, and its primary function has to do with new learning. The other regions are the midbrain and striatum, which also contribute to learning in the form of helping to encode and update information in our memory.

To observe the effect of CBD on the brain, the team had participants perform something called the verbal paired associate learning task, or VPA. Participants at clinical high risk of psychosis, referred to as CHR, were recruited as well as healthy control participants who were not at CHR. For the purposes of this video, we’ll refer to CHR participants as high risk participants to get away from being too bogged down in initializations.

In the study, high risk participants were randomly assigned to a CBD treatment or placebo treatment. After taking the assigned drug, participants performed a VPA task while having their brain scanned using functional MRI. The healthy control group didn’t receive any drug treatment, but they still did the tests and imaging.

But what exactly did the VPA task entail? It actually has three separate testing conditions: encoding, recall, and baseline. During encoding, participants answered yes or no to whether a pair of words went well together.

So for example, “sharks” and “awesome” - definite yes! In the recall condition, participants were shown one of the words they saw during encoding and asked to say which word it had been paired with. The baseline bit was a control of sorts where the participant looked at a blank version of the setup they’d seen during encoding and recall.

The response of the brain during the VPA task was measured using fMRI. Specifically, the scan measured the blood oxygen level-dependent, or BOLD, response of the brain. Basically, this allowed the researchers to measure the flow and composition of blood in the brain during the encoding and recall parts of the VPA task.

Then, they could compare these responses to the baseline results. So what did they find? Overall, high risk participants who were assigned a placebo had several regions of the brain activate differently than people in the control group.

Similar to previous studies, these regions included the three thought to be associated with psychosis. The specific hypothesis the team was testing was whether participants at high risk who were given CBD would have a level of brain activation in between the activation levels of the control group, and the high risk group who were given placebo. The team did find this middle ground activation in the striatum during encoding, and in the parahippocampal cortex and midbrain during recall.

These results suggest that for these specific brain regions, CBD may help normalize brain responses in individuals at clinical high risk of psychosis. This article was published in the one of the most prestigious families of medical journals. In addition to academic circles, the results have made headlines in the news as well.

Here are some reasons why I think this study is capturing both scientists and citizens. First of all, the results are directly relevant to helping humans. Unlike some other articles that we’ve discussed on De-Natured, this study has a direct human end use, and an important one.

Mental health disorders affect people in every walk of life, and in the case of psychosis, as many as 3 in 100 people in the U. S. will experience the symptom of psychosis at some point in their lives. Another reason I think this study made the cut is because the research team was the first to do something.

In this case, they are the first to give evidence of how CBD acts in the brain to reduce psychotic symptoms. This is a major level up from just knowing that CBD can reduce these symptoms. And of course, whenever there’s a promising discovery in the medical field, there’s the potential for profit.

There is a growing body of literature supporting the use of CBD for medicinal purposes. And that means major money for those involved in supplying the product. In the United States alone, hemp-derived CBD is predicted to soon become a billion dollar market, and that’s without federal legalization.

There is undoubtedly a lot to gain from using this particular plant product for medical treatments, and money is certainly part of that gain. The devil is in the methods section when it comes to issues in experimental design. However, this research team did a great job of removing potentially confounding variables and removing bias where possible.

For example, the study design was parallel-group, double-blind, placebo-controlled, and randomized. Randomization allows the researchers to remove the bias that comes from assigning specific people to specific treatments. It’s picking names out of a hat instead of, say, because you like their asymmetrical haircut.

Double blind trials are ones where the participant and the researcher aren’t in on who was assigned which treatment. That way, the researchers are less likely to be looking for certain associations. If a researcher knew a participant had been given the CBD, they might start looking for some kind of result, or jump to conclusions unintentionally.

We just can’t help ourselves when it comes to investigating things- it’s impossible to not start explaining what we see, and double-blinding a trial is a great way to avoid that. What about the “parallel groups” bit of the research design? This piece is actually more of a limitation of the study.

In parallel group studies, each participant only receives one of the treatments, and then those people are compared to separate individuals who received the other treatment. In this study, this meant that the high risk participants either received the CBD or the placebo, but none of them were actually observed under the effects of both. With a non-crossover design, the baseline is a bit iffy.

I mean, just think about how different we all are when it comes to chemical reactions! Take alcohol, for example. Comparing you sober to a friend who’s had a bit to drink might be a completely different story than if you reversed the roles.

Luckily, the researchers do an awesome job of pointing out limitations like this in the discussion section of the paper. They mention the issue of the parallel design structure, and suggest that a study be done where each high risk participant be tested with both the placebo and CBD treatment. That said, they mention that the two high risk groups were reasonably similar in terms of demographics and baseline health measures.

This does, however, lead me to another critique of the study, and that is the sample pool of participants. One potential problem area has to do with sample size. There were 15 high risk participants assigned CBD, 16 high risk participants assigned the placebo, and 19 age matched healthy controls.

While these numbers do allow for testing statistical significance at the cutoff levels the team was interested in, more is almost always better when it comes to determining the strength of an effect. There’s also the issue of diversity. In the table showing sociodemographic measures, the paper only reports age, sex, and education level.

However, there’s no mention of variables like race and ethnicity, meaning that this could be yet another psychiatry study done on a Caucasian sample. Conducting research on participants of varied backgrounds is essential to understanding the full picture of drug-brain interactions. Here’s the thing.

Humans and non-human animals have been using plants for medicinal purposes throughout the history of their time on Earth. Understanding how the chemicals in certain plants can affect our brains is a really complicated area of research, and a study like this one is just a single piece of that journey. As the research team put it themselves, this wasn’t so much of a clinical study as it was a proof of concept, pilot study.

It’s exciting to imagine what we might find next when it comes to this amazing kingdom of life on Earth. Thanks for watching this episode of De-Natured here on Nature League. Nature League is a Complexly production: head over to our sister channel SciShow Psych if you’d like to learn more about the complicated and amazing nature of the human brain.