The effects of synthetic cannabinoids (SCs) on brain structure and function

https://doi.org/10.1016/j.euroneuro.2018.07.095Get rights and content

Highlights

  • The purpose of our study was to assess whether chronic use of SC alters brain volume and function.

  • This is the first study showing overall reduced grey matter volume and specific reduced grey matter volumes in chronic SC users.

  • This study showed for the first time impairment in the neural brain mechanisms responsible for working memory in SC users.

  • The results of reduced grey matter density and diminished activation during a working memory task in SC users, may suggest vulnerability of the frontal-parietal network in chronic SC users.

Abstract

There is an increasing use of “Novel Psychoactive Substances” containing synthetic cannabinoids worldwide. Synthetic cannabinoids (SC) are highly addictive and cause severe adverse effects. The purpose of our study was to assess whether chronic use of SC alters brain volume and function. Fifteen SC chronic users and 15 healthy control participants undertook an MRI scan to assess brain volume and function while performing a working memory N-back task and a response-inhibition Go-No-Go task. SC users showed impaired performance on the N-back task but not on the Go-No-Go task. They also showed reduced total gray matter volume compared with control participants, as well as reduced gray matter volume in several cortical regions including the middle frontal gyrus, frontal orbital gyrus, inferior frontal gyrus, insula, anterior cingulate cortex and the precuneus. Moreover, SC users showed diminished brain activations in the precuneus, cuneus, lingual gyrus, hippocampus and cerebellum while performing the N-back task. No differences were found in brain activation while performing the response-inhibition task. This is the first study showing overall reduced grey matter volume and specific reduced grey matter volumes in chronic SC users. Furthermore, this study showed for the first time impairment in the neural brain mechanisms responsible for working memory in SC users. Our results of reduced grey matter density and diminished activation during a working memory task in SC users, may suggest vulnerability of the frontal-parietal network in chronic SC users.

Introduction

There is an increasing worldwide use of new types of novel psychoactive substances (NPS) which contain various psychoactive compounds (Zawilska, 2011, Weinstein et al., 2017). Some of these NPS contain synthetic cannabinoid (SC) compounds that are marketed as a natural herbal mixture under different brand names (Fattore and Fratta, 2011). However, when consumed, they produce various adverse effects that are similar to the effects of cannabis (Seely et al., 2012). Moreover, SC drugs contain other psychoactive substances, of which some are unknown (Fattore and Fratta, 2011).

As the popularity of SC increased, their potentially harmful effects has been recognized, especially affective disorders, psychosis and paranoia, tachycardia, chest pain, tremors, seizures, loss of memory, sedation and higher risk for developing dependence after persistent usage (Castellanos and Thornton, 2012, Winstock and Barratt, 2013, Vandrey et al., 2012, Seely et al., 2012). Moreover, these undesired effects are considered as more intense either in terms of duration and severity than effects induced by non-synthetic cannabis products (Spaderna et al., 2013). The evidence for association between non-synthetic cannabis consumption and impaired cognitive function is mixed (Bossong et al., 2014, Eldreth et al., 2004, Jager et al., 2006). Preclinical studies showed that chronic consumption of SC resulted in impairment of cognitive function (Pattij et al., 2008, Castaneto et al., 2014). We have shown that chronic SC users had poorer performance on working memory, cognitive inhibition and a long-term memory task than non-users and recreational cannabis users in Israel and in Hungary (Cohen et al., 2017).

The purpose of the current study was to assess whether SC display changes in brain structure and neuronal activity associated with working memory and response inhibition. We hypothesized that chronic SC users will have smaller grey matter volume in brain regions associated with chronic cannabis use. We further hypothesized that SC users will show reduced brain activity in areas associated with working memory and response inhibition compared with healthy control participants.

Section snippets

Participants

A total of thirty-three participants were recruited and undertook an MRI scan. Fifteen SC chronic users were recruited from rehabilitation centers of the Ministry of Health in Israel and eighteen healthy controls were recruited from the community to participate in the study.

Inclusion criteria for SC users were chronic use of SC, age 18 + years and age at admission < 45 who had used SC for at least 1 year prior to enrollment in the study. Participants were diagnosed as having cannabis use

fMRI working memory N-back task

A widely used task in fMRI studies of working memory (WM) in healthy individuals is the n-back procedure {Owen, 2005 #2}, in which, for each stimulus in a continuous series, participants indicate whether the item matches a stimulus presented ‘n’ (1,2 or 3) stimuli previously. Our n-back task uses letter stimuli presented at two different memory load conditions (1-, 2-back) to facilitate examination of the effect of increased load. The 1- and 2-back conditions alternated with a 0-back condition

fMRI response-inhibition Go-No-Go task

Rapid, event-related task was performed in two runs of 10 minutes each, with a total of 480 trials, 360 Go and 120 No-Go trials in each run; thus, the probability of No-Go trials was 25%. Stimuli were projected in sequence in which each stimulus was presented for 1250 Ms. Go and No-Go trials were randomly interspersed throughout the whole task. Participants were instructed to focus on the screen on which the words letters would appear. They were told to press a button with their right index

Voxel based morphometric analysis

The Voxel Based Morphometry (VBM) (Ashburner and Friston 2000) procedure was used to analyze the T1 weighted anatomical images for each subject. The image processing and statistics were accomplished with VBM extension tools developed by Gaser (http://www.fil.ion.ucl.ac.uk/spm/ext/#VBMtools) implemented in Statistical Parametric Mapping (SPM8) software. This procedure included automated iterative skull stripping, segmentation of the images into grey matter (GM), white matter, and cerebrospinal

Results

Thirty-three male participants were recruited for this study. The SC users group consisted of fifteen participants who have been using SC for a minimum period of one year. The control group consisted of 18 healthy male who had no history of neurological or psychiatric disorders and use of any psychoactive drug. Three healthy volunteers were excluded from the study due to incidental brain abnormal findings in their MRI scans.

Structural changes associated with chronic SC use

Synthetic cannabinoid users showed an overall reduced grey-matter volume than control participants. The brain's gray matter is a major component of the central nervous system made up of neuronal cell bodies and it is involved in motor control, perception, memory, emotions, and speech. Specifically, ROI analysis showed that regional grey matter volume in the right middle frontal gyrus, anterior cingulate cortex, the inferior frontal gyrus, insula, and the precuneus were significantly reduced in

Limitations

While interpreting the results of the presented study some potential limitations should be taken into account. The sample size is not large and the cross-sectional design does not allow for causal inferences. Factors such as psychiatric symptoms (depression and anxiety), demographic, socio-economic, specific addictive behaviors and cognitive performance may have a significant role in neural changes of the addictive brain. Chronic users of SC are a very unique and rare cohort and therefore

Conflict of interests

The authors have no interests or activities that might be seen as influencing the research (e.g., financial interests in a test or procedure, funding by pharmaceutical companies for research).

Disclosure

Funding for this study was provided by the National Institute for Psychobiology in Israel. The National Institute for Psychobiology in Israel had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Authors AL and AW designed the study and wrote the protocol. Authors AL and AW managed the literature analyses. Author KC recruited participants and assisted in testing. Authors AL and NT undertook the statistical analysis, and authors AL and AW wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. PR provided access to the patients and was involved in the study design.

Acknowledgment

We would like to thank the managers of the treatment centers of the Ministry of Health in Israel (Ashdod, Lifta, Haderech, Tamra, and Malcishua) for allowing access to patients, Sapir Vigotsky and Michal Levy for assistance in recruitment of participants. The study was presented the 13th meeting of the World Federation of Biological Psychiatry in Copenhagen in June 2017 and in the 5th meeting on Novel Psychoactive Substances in Vienna October 2017.

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