Key Cannabis Components Have Opposite Effects on the Brain

Fran Lowry

January 09, 2012

January 9, 2012 — The 2 main chemical ingredients in marijuana, δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), can have very different effects on behavior and in the brain, new research shows.

Even a single modest dose of THC can induce psychotic symptoms, whereas CBD can be useful as a treatment for psychosis, according to lead author Sagnik Bhattacharyya, MBBS, MD, PhD, from the Institute of Psychiatry, King’s College London, London, United Kingdom.

"Often, people have polarized views about marijuana. Some consider it to be essentially harmless but potentially useful as a treatment in a number of medical conditions, and others link it to potentially severe public health consequences in terms of mental health," Dr. Bhattacharyya told Medscape Medical News.

"Whilst the results are still preliminary, our study is the first experimental evidence of the effect cannabis has on people’s attribution of salience, or the importance they attach to things they perceive. The results add to the idea that psychotic symptoms may develop through individuals attaching inappropriate prominence to insignificant experiences or stimuli."

The study is published in the January issue of Archives of General Psychiatry.

Psychosis Risk

A number of studies have clearly shown that regular marijuana use in vulnerable individuals is associated with increased risk of developing psychotic disorders such as schizophrenia, in which patients lose contact with reality.

"Paranoid and delusional thinking, when one has false ideas about what is happening, is a key characteristic of schizophrenia. However, how marijuana may make a person paranoid has been unclear," Dr. Bhattacharyya said. "In this study, we investigated the brain mechanisms that may underlie this effect."

The investigators examined 15 healthy men, mean age 26.7 years (range, 20.9 to 32.4 years), who were occasional marijuana users, to look at the effects of THC and CBD on regional brain function.

The researchers used functional magnetic resonance imaging (fMRI) to study each participant on 3 separate occasions after administration of THC, CBD, or a placebo.

The subjects then performed a visual oddball detection task in order that the investigators could understand the importance each individual attached to specific stimuli.

The researchers found that under the influence of THC, the main ingredient in marijuana that is responsible for the "high," the men perceived normally insignificant visual stimuli as more significant and salient.

Paranoia Explained

They also experienced symptoms of psychosis, such as paranoid and delusional thinking, which were associated with an effect of THC on the normal functioning of the striatum and lateral prefrontal cortex.

"These regions of the brain signal whether things that we perceive are salient and significant or not. They are normally activated when the brain processes stimuli that it perceives as salient, significant or relevant," Dr. Bhattacharyya explained.

"For example, how strongly the striatum responds tells us how salient or significant we perceive something. But in this study, THC increased the response of the striatum to insignificant stimuli and decreased its response to those stimuli that would normally be perceived as salient or significant in the context of the task," he noted.

Moreover, the effects in the brain were related to the severity of the psychotic symptoms that were induced by THC, he added.

"The more THC decreased the normal striatal response to salient stimuli, the greater was the severity of the psychotic symptoms, such as paranoid thinking and delusions," he said.

"These findings help explain why smoking marijuana can result in feelings of paranoia, or in the most extreme cases, psychotic episodes, as individuals attach special importance or meaning to normally insignificant experiences or stimuli."

CBD, on the other hand, had the opposite effect, increasing the response of the left caudate, an area of the brain weakened by THC. The finding suggests that CBD may have potential in the treatment of psychosis, Dr. Bhattacharyya said.

He hopes that the results from this study will facilitate a more balanced discussion regarding the health effects of marijuana as well as stimulate further research into the therapeutic potential of CBD.

Another hope is that more research will be done into the genetic basis responsible for the "considerable" variability in individual responses to THC.

Low CBD Concentrations

Killian Welch, MD, from the University of Edinburgh, Royal Edinburgh Hospital, United Kingdom, who recently headed a study that found that smoking marijuana led to a loss of brain volume in people with a strong family history of schizophrenia, told Medscape Medical News that the study by Dr. Bhattacharyya and colleagues was "very good and well-designed."

The fact that the authors also examined the effects of CBD made the study even more interesting, he said.

"As subjects were also given cannabidiol, the impact of this drug on brain function on presentation of salient relative to nonsalient stimuli could also be examined. Administration of cannabidiol was associated with the opposite effects on brain function to THC, a finding which may be of significance in understanding how cannabidiol may counteract the psychotomimetic effects of THC," Dr. Welch said.

He agreed that CBD, which is present in naturally occurring marijuana, may have antipsychotic properties, but he cautioned that concentrations in modern strains of marijuana, which he referred to as "skunk," are very low.

The study was supported by a Joint Medical Research Council/Prior Clinical research training fellowship from the Medical Research Council and the Psychiatry Research Trust, United Kingdom. Dr. Bhattacharyya and Dr. Welch report no relevant financial relationships.

Arch Gen Psychiatry. 2012;69: 27-36. Abstract

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