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Cannabis use has been associated with adverse mental health outcomes, the neurochemical underpinnings of which are poorly understood. Although preclinical evidence suggests glutamatergic dysfunction following cannabis exposure in several brain regions including the hippocampus, evidence from human studies have been inconsistent. We investigated the effect of persistent cannabis use on the brain levels of N-acetyl aspartate (NAA) and myoinositol, the metabolite markers of neurons and glia, the site of the main central cannabinoid CB1 receptor, and the levels of glutamate, the neurotransmitter directly affected by CB1 modulation. We investigated cannabis users (CUs) who started using during adolescence, the period of greatest vulnerability to cannabis effects and focused on the hippocampus, where type 1 cannabinoid receptors (CBR1) are expressed in high density and have been linked to altered glutamatergic neurotransmission. Twenty-two adolescent-onset CUs and 21 nonusing controls (NU), completed proton magnetic resonance spectroscopy, to measure hippocampal metabolite concentrations. Glutamate, NAA, and myoinositol levels were compared between CU and NU using separate analyses of covariance. CU had significantly lower myoinositol but not glutamate or NAA levels in the hippocampus compared with NU. Myoinositol levels in CU positively correlated with glutamate levels, whereas this association was absent in NU. Altered myoinositol levels may be a marker of glia dysfunction and is consistent with experimental preclinical evidence that cannabinoid-induced glial dysfunction may underlie cannabinoid-induced memory impairments. Future studies using appropriate imaging techniques such as positron emission tomography should investigate whether glial dysfunction associated with cannabis use underlies hippocampal dysfunction and memory impairment in CUs., (© 2019 Society for the Study of Addiction.)

Stress and cannabis use are risk factors for the development of psychosis. We have previously shown that subjects at clinical high risk for psychosis (CHR) exhibit a higher striatal dopamine response to stress compared with healthy volunteers (HV), with chronic cannabis use blunting this response. However, it is unknown if this abnormal dopamine response extends to the prefrontal cortex (PFC). Here, we investigated dorsolateral PFC (dlPFC) and medial PFC (mPFC) dopamine release using [ 11 C]FLB457 positron emission tomography (PET) and a validated stress task. Thirty-three participants completed two PET scans (14 CHR without cannabis use, eight CHR regular cannabis users [CHR-CUs] and 11 HV) while performing a Sensory Motor Control Task (control scan) and the Montreal Imaging Stress Task (stress scan). Stress-induced dopamine release (ΔBP ND ) was defined as percent change in D 2/3 receptor binding potential between both scans using a novel correction for injected mass of [ 11 C]FLB457. ΔBP ND was significantly different between groups in mPFC (F(2,30) = 5.40, .010), with CHR-CUs exhibiting lower ΔBP ND compared with CHR (.008). Similarly, salivary cortisol response (ΔAUC I ) was significantly lower in CHR-CU compared with CHR (F(2,29) = 5.08, .013; post hoc .018) and positively associated with ΔBP ND . Furthermore, CHR-CUs had higher attenuated psychotic symptoms than CHR following the stress task, which were negatively associated with ΔBP ND . Length of cannabis use was negatively associated with ΔBP ND in mPFC when controlling for current cannabis use. Given the global trend to legalize cannabis, this study is important as it highlights the effects of regular cannabis use on cortical dopamine function in high-risk youth., (© 2019 Society for the Study of Addiction.)

Recreational and chronic cannabis use has been associated with a range of acute and chronic effects including; anti-nociceptive actions, anxiety, depression, psychotic symptoms and neurocognitive impairments. The mechanisms underlying cannabinoid-based drugs effects are not fully known but given the neuro-modulatory functions of the endocannabinoid system, it seems likely that agonistic activity at the cannabinoid type-1 receptors (CB 1 ) might modulate the functions of other neurotransmitter systems. The present review has summarized the currently available pre-clinical and clinical data on the interactions of CB 1 and cannabinoid type-2 receptors (CB 2 ) with the central neurotransmitters; dopamine, serotonin, noradrenaline, GABA, glutamate and opioids. Acute and chronic exposures to cannabinoids exert pharmacological alterations in the mammalian brain that have profound implications for our understanding of the neuropharmacology of cannabinoid-based drugs and their effects on mental health and the brain. A recent emergence uses of cannabis for medical purpose together with legalization and decriminalization of cannabis and increasing use of highly potent synthetic cannabinoids raise a growing concern over the effects of cannabinoids and their interaction with other neurotransmitters on physical and mental health., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Δ(9) -Tetrahydrocannabinol, the main psychoactive component of cannabis, exerts its central effects through activation of the cerebral type 1 cannabinoid (CB1 ) receptor. Pre-clinical studies have provided evidence that chronic cannabis exposure is linked to decreased CB1 receptor expression and this is thought to be a component underlying drug tolerance and dependence. In this study, we make first use of the selective high-affinity positron emission tomography (PET) ligand [(18) F]MK-9470 to obtain in vivo measurements of cerebral CB1 receptor availability in 10 chronic cannabis users (age = 26.0 ± 4.1 years). Each patient underwent [(18) F]MK-9470 PET within the first week following the last cannabis consumption. A population of 10 age-matched healthy subjects (age = 23.0 ± 2.9 years) was used as control group. Parametric modified standardized uptake value images, reflecting CB1 receptor availability, were calculated. Statistical parametric mapping and volume-of-interest (VOI) analyses of CB1 receptor availability were performed. Compared with controls, cannabis users showed a global decrease in CB1 receptor availability (-11.7 percent). VOI-based analysis demonstrated that the CB1 receptor decrease was significant in the temporal lobe (-12.7 percent), anterior (-12.6 percent) and posterior cingulate cortex (-13.5 percent) and nucleus accumbens (-11.2 percent). Voxel-based analysis confirmed this decrease and regional pattern in CB1 receptor availability in cannabis users. These findings revealed that chronic cannabis use may alter specific regional CB1 receptor expression through neuroadaptive changes in CB1 receptor availability, opening the way for the examination of specific CB1 -cannabis addiction interactions which may predict future cannabis-related treatment outcome., (© 2013 Society for the Study of Addiction.)

The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extrastriatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 ± 5.3 cigarettes/day for 12.1 ± 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 ± 5.3 cannabis joints/day for 8.7 ± 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [11C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from -15 to -30%). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

Aims: To investigate the relationship of life-time and repeated cannabis use with hypothalamic-pituitary-adrenal (HPA) axis reactivity to social stress in a general population sample of adolescents., Design: Adolescents who reported life-time or repeated cannabis use, life-time or repeated tobacco use and never use of either cannabis or tobacco were compared with respect to their HPA axis reactivity during the Groningen Social Stress Task (GSST), which was based on the Trier Social Stress Task., Setting: A large prospective population study of Dutch adolescents [the TRacking Adolescents' Individual Lives Survey (TRAILS) study]., Participants: A total of 591 adolescents (51% male) who participated in the GSST, which was an additional measurement during the third assessment wave., Measurements: HPA axis stress-reactivity was indexed by four cortisol samples collected before, during and after the GSST. Furthermore, all adolescents in our study completed self-reported questionnaires on life-time and repeated cannabis and tobacco use. Models were adjusted for sex, recent alcohol use, experimental session risk status, socio-economic status, mood and time of the experimental session., Findings: Life-time cannabis users had significantly lower stress-reactivity levels when compared to abstainers [odds ratio (OR) = 0.68, confidence interval (CI) = 0.55-0.85, P < 0.01] and life-time tobacco users (OR = 0.79, CI = 0.64-0.98, P < 0.05). In addition, repeated cannabis users also exhibited lower stress-reactivity levels when compared to life-time ever users of either tobacco or cannabis (OR = 0.74, CI = 0.53-0.98, P < 0.05)., Conclusions: Lower hypothalamic-pituitary-adrenal-axis stress-reactivity in adolescents is related specifically to life-time and repeated cannabis use., (© 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.)