Cannabis Dependence is Associated with Reduced Hippocampal Subregion Volumes Independently of Sex: Findings from an ENIGMA Addiction Working Group Multi-Country Study.

Background: Males and females who consume cannabis can experience different mental health and cognitive problems. Neuroscientific theories of addiction postulate that dependence is underscored by neuroadaptations, but do not account for the contribution of distinct sexes. Further, there is little evidence for sex differences in the neurobiology of cannabis dependence as most neuroimaging studies have been conducted in largely male samples in which cannabis dependence, as opposed to use, is often not ascertained. Methods: We examined subregional hippocampus and amygdala volumetry in a sample of 206 people recruited from the ENIGMA Addiction Working Group. They included 59 people with cannabis dependence (17 females), 49 cannabis users without cannabis dependence (20 females), and 98 controls (33 females). Results: We found no group-by-sex effect on subregional volumetry. The left hippocampal cornu ammonis subfield 1 (CA1) volumes were lower in dependent cannabis users compared with non-dependent cannabis users (p<0.001, d=0.32) and with controls (p=0.022, d=0.18). Further, the left cornu ammonis subfield 3 (CA3) and left dentate gyrus volumes were lower in dependent versus non-dependent cannabis users but not versus controls (p=0.002, d=0.37, and p=0.002, d=0.31, respectively). All models controlled for age, intelligence quotient (IQ), alcohol and tobacco use, and intracranial volume. Amygdala volumetry was not affected by group or group-by-sex, but was smaller in females than males. Conclusions: Our findings suggest that the relationship between cannabis dependence and subregional volumetry was not moderated by sex. Specifically, dependent (rather than non-dependent) cannabis use may be associated with alterations in selected hippocampus subfields high in cannabinoid type 1 (CB1) receptors and implicated in addictive behavior. As these data are cross-sectional, it is plausible that differences predate cannabis dependence onset and contribute to the initiation of cannabis dependence. Longitudinal neuroimaging work is required to examine the time-course of the onset of subregional hippocampal alterations in cannabis dependence, and their progression as cannabis dependence exacerbates or recovers over time.

Decision-making, somatic markers and emotion processing in opiate users.

RATIONALE: Opiate use is associated with deficits in decision-making. A possible explanation for these deficits is provided by the somatic marker hypothesis, which suggests that substance users may experience abnormal emotional responses during decision-making involving reward and punishment. This in turn may interfere with the brief physiological arousal, i.e. somatic markers that normally occur in anticipation of risky decisions. To date, the applicability of the somatic marker hypothesis to explain decision-making deficits has not been investigated in opiate users. OBJECTIVES: This study assessed whether decision-making deficits in opiate users were related to abnormal emotional responses and reduced somatic markers. METHODS: Opiate users enrolled in an opiate substitute treatment program (n = 28) and healthy controls (n = 32) completed the Iowa Gambling Task (IGT) while their skin conductance responses (SCRs) were recorded. Participants' emotional responses to emotion-eliciting videos were also recorded using SCRs and subjective ratings. RESULTS: Opiate users displayed poorer decision-making on the IGT than did controls. However, there were no differences between the groups in SCRs; both groups displayed stronger SCRs following punishment than following reward, and both groups displayed stronger anticipatory SCRs prior to disadvantageous decisions than advantageous decisions. There were no group differences in objective or subjective measures of emotional responses to the videos. CONCLUSIONS: The results suggest that deficits in emotional responsiveness are not apparent in opiate users who are receiving pharmacological treatment. Thus, the somatic marker hypothesis does not provide a good explanation for the decision-making deficits in this group.

Prospective memory impairment in long-term opiate users.

RATIONALE: Opiate use is associated with a range of neurological and cognitive deficits. However, to date, no studies have assessed whether these cognitive deficits extend to the ability to perform intended actions in the future (i.e. prospective memory). Reduced ability in this area might be anticipated due to impaired executive functions and episodic memory associated with long-term opiate use. OBJECTIVES: The main objectives of this study are to assess the performance of long-term opiate users on a laboratory measure of prospective memory which closely simulates the types of prospective memory tasks encountered in everyday life ('Virtual Week') and to investigate the extent to which prospective memory performance is related to executive functions and episodic memory ability. METHODS: Twenty-six long-term heroin users enrolled in an opiate substitution program, and 30 controls with no previous history of drug use were tested on Virtual Week. Retrospective memory and executive functions were also assessed. RESULTS: Long-term opiate users were significantly impaired on prospective memory performance compared with controls (p = 0.002, η(2) p = 0.17), and these deficits did not vary as a function of prospective memory task type (regular, irregular, event, time). The findings also suggest that retrospective memory difficulties contribute to the prospective memory difficulties seen in opiate users (r s = 0.78, p < 0.001) but that executive dysfunction is less influential. CONCLUSIONS: Prospective memory is sensitive to long-term opiate use. Importantly, opiate users suffer from generalised deficits in prospective memory, regardless of the task demands, which may have significant implications for day-to-day functioning. These results may therefore contribute to the development of clinical intervention strategies to reduce the negative impact of prospective memory failures in daily life.