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Cannabidiol May Reset Brain Function in Psychosis

A single dose of cannabidiol (CBD) may alleviate psychotic symptoms and normalize brain function, results from a new imaging study suggest.

Using fMRI, investigators found that CBD normalized alterations in the parahippocampal, striatal, and midbrain regions, all of which are clinically implicated in psychosis. The finding may explain the efficacy of CBD in ameliorating psychotic symptoms.

“In this study, we show that a single dose of CBD, a nonaddictive, naturally occurring substance present in the extract of the cannabis plant, can normalize brain function abnormalities in key brain regions — the striatum, medial temporal cortex, and midbrain — which we know are abnormal in people with psychosis and which play a central role in increasing the risk of developing psychosis,” lead author Sagnik Bhattacharyya, MBBS, MD, PhD, reader in translational neuroscience and psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom, told Medscape Medical News.

“The key take-home message at this stage is that this study confirms current evidence suggesting that CBD may be a promising treatment, as it seems to target the brain regions implicated in psychosis. However, further studies are needed before it may be ready for routine clinical use,” he said.

The study was published online August 29 in JAMA Psychiatry.

Urgent Need for Better Treatments

Regular use of cannabis can increase the risk for psychosis. It is also known that psychosis is associated with alterations in the endocannabinoid system, the authors write.

The cannabinoid receptor 1 is “ubiquitous” in the brain; it modulates the function of neurotransmitters, including dopamine and glutamate, which are thought to be disrupted in psychosis.

The constituent of cannabis that increases the risk for psychosis is Δ9-

tetrahydrocannabinol (THC). On the other hand, CBD — one of the major nonpsychoactive constituents of cannabis — has “broadly opposite neural and behavioral effects.”

Previous research has suggested that individuals at clinical high risk (CHR) for psychosis experience clinically significant psychotic symptoms similar to those in patients with frank psychosis, as well as high levels of distress, the authors note.

Several preclinical models have proposed that psychosis may involve perturbed activity in the medial temporal lobe (MTL), which drives subcortical dopamine dysfunction via projections to the striatum and midbrain.

Previous neuroimaging studies in individuals at CHR for psychosis indicate a potential association with alteration in parahippocampal structure and function as well as elevated striatal and midbrain dopamine activity.

“We knew from a couple of small-sized studies in patients with psychosis that CBD has an antipsychotic effect, but its mechanisms in treating psychosis have not been clear until now; hence, we wanted to investigate how CBD might work at the level of brain function to treat psychosis,” said Bhattacharyya.

He called this a “particularly important issue” because “understanding how a drug might work and whether it has effect on the brain’s substrates of disease is a critical step before one moves on to test the drug further in larger and more expensive clinical trials, which are in turn necessary before it can be used in the clinic.”

Another “key motivation was that currently, there are no safe, well-tolerated treatments that work for those who have a clinical high risk for psychosis,” and so there is an “urgent need for treatment for these young people, as currently available antipsychotics or psychological treatments either do not work or are not tolerated very well,” he said.

A Single Dose

To investigate the question, the researchers recruited 33 antipsychotic medication–naive participants who were at CHR for psychosis. Of those patients, 16 (median age, 22.43 years; SD, 4.95 years; 35% female) received a single oral dose of CBD 600 mg, and 17 (median age, 23.35 years; SD, 5.24 years; 59% female) received placebo. In addition, 19 healthy control persons (median age 23.89 years; SD, 4.14 years) also received placebo.

Individuals with a history of psychotic or manic episodes or neurologic disorders, those who had a current diagnosis of substance dependence, those with an IQ <70, or those for whom MRI was contraindicated were excluded.

Participants were required to refrain from consuming cannabis for 96 hours, alcohol for ≥24 hours, and nicotine for 6 hours prior to fMRI scanning. They were also required to refrain from using any other recreational drug for 2 weeks before the study day.

The 600-mg dose was chosen because that dose had previously been found to be effective in individuals with established psychosis.

Three hours after taking a CBD capsule or a placebo capsule identical in appearance, participants underwent fMRI while performing a verbal paired associate learning task consisting of three conditions: encoding, recall, and baseline.

Relative to the baseline condition, the encoding condition was associated with activation in the left anterior cingulate cortex, the right caudate, the left precentral gyrus, and the cuneus in control participants.

In control participants, relative to the baseline condition, the recall condition was associated with activation in the left parahippocampal and the left transverse temporal gyri as well as decreased activation in the left middle occipital, the right lingual, and the inferior frontal gyri.

In participants in the CHR group who received placebo, reduced activation relative to control persons was found in the right caudate during encoding (placebo: median = -0.027; interquartile range [IQR], -0.041 to -0.016; control: median, 0.020; IQR, -0.022 to 0.056; P < .001) and in the parahippocampal gyrus and midbrain during recall (placebo: median, 0.002; IQR, -0.016 to 0.010; control: median, 0.035; IQR, 0.015 – 0.039; P < .001).

However, activation was greater in the CBD group than in the placebo group, although it was lower than in the control group (parahippocampal gyrus/midbrain: CBD: median, -0.013; IQR, -0.027 to 0.002; placebo: median, -0.007; IQR, -0.019 to 0.008; control: median, 0.034; IQR, 0.005 – 0.059).

“The level of activation in the CBD group was thus intermediate to that in the other 2 groups,” the authors comment.

There were no significant group differences in task performance.

“We found that under placebo conditions, participants at CHR showed differential activation relative to controls in several regions…that included the 3 areas thought to be critical to the pathophysiology of the CHR state: the striatum (during verbal encoding) and the MTL and midbrain (during verbal recall),” the authors summarize.

“We were extremely impressed with the fact that even a single dose of cannabidiol had an effect on brain regions implicated in psychosis in a manner consistent with its role as an antipsychotic,” said Bhattacharyya.

Important Neuromodulator

Commenting on the study for Medscape Medical News, Amresh Shrivastava, MD, DPM, professor emeritus, Western University, London, Ontario, Canada, who was not involved with the study, said that brain scans are “very important, although they are only one way to understand the neurobiology and trajectory of psychosis.”

He noted that “convergence to psychosis is usually complex and includes psychosocial factors, not only biological ones.”

Nevertheless, the study highlights the importance of focusing on the cannabinoid system because it investigates an “important neuromodulator” and is a step toward the “potential use of cannabinoid-based antipsychotics in treating psychosis,” which “will be a huge advantage, given the metabolic side effects of the currently available agents,” Shrivastava said.

Bhattacharyya reported that, “based on this work, we have now obtained funding to carry out a large-scale, multicenter clinical trial to test whether cannabidiol may be useful in treating symptoms experienced by those who have a clinical high-risk state for psychosis in the UK.

“If successful, it will provide definitive proof of cannabidiol’s role as an antipsychotic treatment and pave the way for its use in the clinic,” he added.

The study was supported by a grant from the Medical Research

Council. Dr Bhattacharyya was supported an award from the

National Institute for Health Research. The other authors relevant financial relationships are listed in the original article. Dr Shrivastava has disclosed no relevant financial relationships.

JAMA Psychiatry. Published online August 29, 2018. Full text

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