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Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol

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Abstract

Background

Chronic cannabis use has been associated with memory deficits and a volume reduction of the hippocampus, but none of the studies accounted for different effects of tetrahydrocannabinol (THC) and cannabidiol (CBD).

Methods

Using a voxel based morphometry approach optimized for small subcortical structures (DARTEL) gray matter (GM) concentration and volume of the hippocampus were measured in 11 chronic recreational cannabis users and 13 healthy controls, and correlated with THC and CBD from hair analyses. GM volume was calculated by modulating VBM using Jacobian determinants derived from the spatial normalization.

Results

Cannabis users showed lower GM volume located in a cluster of the right anterior hippocampus (Puncorr = 0.002; effect size Cohen's d = 1.34). In a regression analysis an inverse correlation of the ratio THC/CBD with the volume of the right hippocampus (Puncorr p < 0.001, Cohen's d = 3.43) was observed. Furthermore Cannabidiol correlated positively with GM concentration (unmodulated VBM data), but not with GM volume (modulated VBM) in the bilateral hippocampus (P = 0.03 after correction for hippocampal volume; left hippocampus Cohen's d = 4.37 and right hippocampus 4.65).

Conclusions

Lower volume in the right hippocampus in chronic cannabis users was corroborated. Higher THC and lower CBD was associated with this volume reduction indicating neurotoxic effects of THC and neuroprotective effects of CBD. This confirms existing preclinical and clinical results. As a possible mechanism the influence of cannabinoids on hippocampal neurogenesis is suggested.

Introduction

A long lasting debate accompanies the use of cannabis. The contra-arguments are impairment of attention, memory and motivation, risk for psychosis and addiction, whereas the pro-arguments emphasize that neuropsychological deficits are transient, and the addictive potential is low (Murray et al., 2007). Neurobiological research is challenged to objectify the debate. The main ingredients of cannabis are delta-9-tetrahydrocannabinol (THC) and the non-psychogenic cannabidiol (CBD). Preclinical research gave evidence that THC acts as a partial agonist of cannabinoid (CB) receptors and CBD as an antagonist of CB-receptor agonists (Pertwee, 2008). Recently a series of fMRI studies with an experimental application of THC and CBD in humans confirmed different and partly opposite effects on brain activation during tasks involving verbal learning, viewing fearful faces, and response inhibition (summarized in Bhattacharyya et al., 2010). THC showed unfavorable effects, but a pretreatment with CBD was able to prevent THC effect, indicating beneficial effects of CBD (Bhattacharyya et al., 2010). Furthermore, especially high THC containing cannabis was associated with psychosis, and hair analyses revealed that cannabis users with high THC and low CBD concentration were more likely to exhibit schizophrenia-like symptoms (Di Forti et al., 2009, Morgan and Curran, 2008).

In search for an explanation of cannabis associated memory alterations, a recent MRI study using manual delineation of hippocampal and amygdala volumes showed decreased bilateral volumes correlating negatively with the self-reported amount of cannabis consumption (Yücel et al., 2008). Of four other studies investigating the hippocampus three failed to show differences between control subjects and cannabis users, even with very heavy and long-term cannabis use (Block et al., 2000, Tzilos et al., 2005, Jager et al., 2007), whereas one study showed lower gray matter density in the right parahippocampal gyrus (Matochik et al., 2005). A methodological limitation of the latter study (Matochik et al., 2005) using VBM was that for group comparison different shapes of the head had to be normalised to the MNI–template. This process stretches or compresses the brain to fit it into a standard intracranial vault size and thereby alters volumes. Resulting unmodulated VBM data indicate the proportion of gray and white matter in each voxel, but do not account for volume changes. To obtain data about the volume, unmodulated VBM data have to be modified using the Jacobian determinants derived from the spatial normalization process, resulting in modulated VBM data allowing the comparison of volume differences.

Based on previous studies mentioned above we hypothesize diminished hippocampal volume in cannabis users and positive effects of CBD and negative effects of THC onto hippocampal volume. In our study, unmodulated and modulated VBM data are presented for comparability with earlier unmodulated VBM studies, and to assess hippocampal volume. For VBM analyses we use a method recently optimized for subcortical structures: the Diffeomorphic Anatomical Registration using Exponentiated Lie algebra registration (DARTEL) (Ashburner, 2007, Yassa and Stark, 2009).

Section snippets

Methods

Eleven healthy male cannabis users (19–25 years old) and 13 age- and IQ- matched male control subjects, all students, were recruited by advertisement at the University of Mannheim. Cannabis was used for 5.4 years in an average daily dose of 0.27 g. Detailed clinical data of the study participants have been published previously (Hermann et al., 2007). The use of other illegal drugs in the previous 3–4 days was excluded by an immunochromatographic urine test. Cannabis users were more likely to

Results

Group comparison of GM tissue composition or concentration (unmodulated data) revealed no differences between healthy controls and cannabis users in whole brain or in hippocampal ROI. Concerning the GM volume (modulated data) cannabis users showed lower volume of the anterior part of the right hippocampus in comparison to healthy controls (cluster size: 41 voxel = 138 mm3, Puncorr = 0.002, PFWE = 0.28, T = 3.3, Z = 2.9, MNI: 36,−9,−27). Cohen's d = 1.34 for the volume difference (estimated from t-value (d = t

Discussion

This study showed lower GM volume in cannabis users located in a cluster of the right anterior hippocampus. A correlation analysis revealed that GM volume was lowest when the THC content in cannabis used had been high or the CBD content had been low. Previous findings of reduced hippocampal volumes in heavy cannabis users with the gold standard of manual delineation of hippocampal volumes (Yücel et al., 2008) are corroborated in our study using modulated VBM-DARTEL analysis. We consider this

Role of funding source

Funding for this study was provided by the Central Institute of Mental Health (CIMH) Mannheim, Germany; the CIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Contributors

Authors Traute Demirakca, Alexander Sartorius, Karl Mann, and Derik Hermann designed the study and wrote the protocol. Authors Nadja Meyer and Helga Welzel managed the literature searches and summaries of previous related work. Authors Derik Hermann and Helga Welzel recruited patients and control subjects. Author Gisela Skopp performed the hair analyses. Authors Traute Demirakca, Alexander Sartorius, Gabriele Ende and Nadja Meyer undertook the statistical analysis, and authors Traute Demirakca

Conflict of interest

All authors disclose any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the work submitted that could inappropriately influence, or be perceived to influence, their work.

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