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ICOSR 2009—Cur(e)ious Cannabinoids: Implications for Psychosis and Its Treatment

As part of our ongoing coverage of the 2009 International Congress on Schizophrenia Research (ICOSR), 28 March to 1 April 2009, in San Diego, California, we bring you session summaries from some of the Young Investigator travel award winners. We are grateful for this summary by Elizabeth Tunbridge of the University of Oxford, U.K.


8 May 2009. Cannabis is the most widely used illicit substance, and its content of 9-Δ-tetrahydrocannabinol (THC), the primary psychoactive ingredient, has been steadily rising. This is highly relevant to schizophrenia since regular cannabis use is associated with around a 40 percent increase in the risk of developing this disorder; the risk is particularly strong in those that start using cannabis before the age of 15. Furthermore, cannabis use has adverse cognitive and emotional effects, complicating its study, suggested Sagnik Bhattacharyya, who chaired the Monday 30 March afternoon session entitled “Different neural effects of cannabinoids in man—implications for psychosis and treatment.”

Bhattacharyya’s presentation focussed on the mechanisms by which cannabis acutely modulates cognitive function and psychotic symptoms. Cannabis is chemically complex, containing over 60 different cannabinoid compounds. Therefore, he focused initially on the effects of THC, which is thought to be responsible for most of cannabis’s adverse effects. He investigated the effect of THC on brain activation in healthy controls performing a verbal learning task. He showed that THC increased psychosis, anxiety, intoxication, and sedation in healthy volunteers. Under conditions where performance was matched between drug and placebo groups, THC attenuated the learning-related changes in medial temporal and ventral striatal activation with repeated trials, an effect which might reflect inefficiency of adaptive responses. Bhattacharyya also showed that the attenuation of ventral striatal activation induced by THC correlated with the psychotic symptoms that it induced. These data suggest that THC’s effects on medial temporal and ventral striatal function might mediate its effects on verbal learning and psychosis, respectively, in regular cannabis users.

In addition to examining the effects of THC, Bhattacharyya also assessed whether cannabidiol (CBD) affects brain function, since this cannabinoid has been reported to be anxiolytic and neuroprotective, and might even counteract the negative effects of THC. In contrast to the latter, CBD did not induce psychosis, anxiety, or psychomotor symptoms and showed very different effects on brain activation during task performance. It induced opposite effects to THC in a number of regions, including the ventral striatum. Finally, he presented preliminary data from healthy subjects co-administered THC and CBD. Intriguingly, he reported that, so far, CBD has blocked all the psychotic symptoms induced by THC, although stressed that these results must be replicated in a larger cohort.

CBD’s anti-THC properties are in keeping with other observations. Paul Allen pointed out that cannabis has mixed effects on anxiety (it is generally considered to increase it but it can also act as an anxiolytic), which may result from differences in the relative amounts of the different cannabinoid compounds. He described studies examining the effects of THC and CBD on emotional processing. He examined the differential effects of these two compounds on brain activation and the skin conductance response (SCR) during exposure to faces expressing mild or intense fear. Consistent with his hypothesis, he found that THC increased anxiety, as well as sedation and intoxication, whilst CBD did not. Furthermore, CBD attenuated the SCR associated with processing of fearful faces, compared with placebo, while THC increased it, consistent with the respective anxiolytic and anxiogenic effects of these compounds. CBD also attenuated the activation of the amygdala and anterior and posterior cingulate cortices induced by viewing intensely fearful faces. Significantly, the effect of CBD on activation of the anterior cingulate and amygdala correlated with the SCR during fearful face processing, consistent with evidence that amygdala activity modulates the SCR. Furthermore, he presented connectivity analyses which suggested that CBD (but not THC) disrupts the normal coupling of the anterior cingulate to the amygdala during fearful face processing. These effects of CBD on brain activation were markedly different from those of THC, which reduced inferior frontal activation but increased parietal activation. Thus, THC and CBD showed distinct effects on the processing of fearful faces: CBD reduced amygdala and cingulate activation and the associated SCR, while THC increased anxiety and the SCR, and modulated frontal and parietal regions, perhaps consistent with its more widespread detrimental effects on psychosis and cognitive function.

James Stone attempted to clarify conflicting data on whether cannabis use can increase risk for conversion to psychosis in populations already at greater risk for developing a psychotic disorder. He presented data, retrospectively collected, on cannabis use in an At Risk Mental State (ARMS) population. Although cannabis use was not associated with current symptoms, there was a trend for increased transition to psychosis in regular cannabis users, and this reached significance in those who reported regular use of cannabis before the age of 15. Therefore, regular, early cannabis use may increase the risk of transitioning to psychosis in ARMS populations. Stone also demonstrated an association between lifetime cannabis use and measures of hippocampal glutamate and glutamine, determined using magnetic resonance spectroscopy, in ARMS individuals, and with prefrontal and precuneus gray matter volume in both ARMS and control individuals, suggesting that cannabis may alter brain structure. Taken together, these data support the hypothesis that regular, early cannabis use can increase the risk of transitioning to psychosis in ARMS individuals, and that cannabis might impact on brain structure, both in ARMS individuals and controls.

Finally, José Alexandre Crippa reviewed his group’s research into the effects of CBD in human volunteers, and its potential as a novel antipsychotic and anti-anxiety compound. Using SPECT imaging to measure regional cerebral blood flow, his group found that CBD increased resting activation of the parahippocampal gyrus, but decreased activation of the posterior cingulate, hippocampus, and hypothalamus. He posited that these changes in activation might underlie the anxiolytic effects of CBD that were seen in these individuals. He then explored the hypothesis that CBD might be effective as an antipsychotic drug, since its administration was previously shown to reduce the dissociative effects of ketamine, a compound which can induce psychotic symptoms, in healthy volunteers. His initial open-label trials administering CBD to four patients with schizophrenia proved promising. However, a second trial showed little or no effect in three treatment-resistant cases. CBD was well tolerated in all cases, suggesting that it might be a viable therapeutic target for schizophrenia, but not in treatment-resistant patients. Furthermore, he also presented encouraging data suggesting that CBD might ameliorate psychosis in Parkinson’s disease: CBD administration resulted in a significant decrease in psychotic symptoms in six patients with Parkinson’s disease after one month of treatment in a small open-label trial. These results for psychotic symptoms contrast with those he obtained in two patients with bipolar disorder, in whom CBD administration had no effect on mania. Overall, his data suggest that CBD is well tolerated and might be of use as an antipsychotic compound in certain patient groups.

Taken together, the presentations in this session highlighted the complex neurochemistry of cannabis. The findings presented support the hypothesis that THC is generally detrimental to brain function and is responsible for the psychotic symptoms associated with cannabis use, and that CBD might be protective against some of the negative effects of THC. The speakers showed that CBD appears to have anxiolytic properties in its own right and may even be of benefit as an antipsychotic agent. Given the steady rise of THC content in cannabis, understanding the biology of cannabinoid compounds is likely to be of increasing relevance to the field of schizophrenia research.—Elizabeth Tunbridge.

Comments on News and Primary Papers
Comment by:  Suzanne King
Submitted 25 May 2009
Posted 27 May 2009

Great summary!

The effects of cannabis on psychotic symptoms may be especially great in COMT Val allele carriers. Caspi's data (Caspi et al., 2005) suggested this in his birth cohort study which found that cannabis use predicted schizophreniform disorder (n = 28) but only in subjects with the Val allele.

We reported similar findings at ICOSR (Massé et al., 2009): we found a significant interaction between the estimated amount of premorbid cannabis use and COMT in discriminating between 72 schizophrenia patients and 63 community controls. We also found that, only in Val allele carriers, greater cannabis use explained significant variance in the severity of psychotic (or psychotic-like) symptoms in both patients and controls.

We welcome continued research into Gene-by-Cannabis interactions or correlations, as well as other GxG or ExE associations in psychosis.

References:

Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry . 2005 May 15 ; 57(10):1117-27. Abstract

Massé, M., Liu, A., Joober, R. & King, S. (2009) More Premorbid Cannabis Use with the Val Allele of the Catechol-O-Methyltransferase Gene Associated with Increased Risk for Schizophrenia. International Congress on Schizophrenia Research, San Diego, March 28 – April 1, 2009. Published in Schizophrenia Research, 35: Supplement 1, page 78.

View all comments by Suzanne King