Latent profiles of substance use, early life stress, and attention/externalizing problems and their association with neural correlates of reinforcement learning in adolescents.

BACKGROUND: Adolescent substance use, externalizing and attention problems, and early life stress (ELS) commonly co-occur. These psychopathologies show overlapping neural dysfunction in the form of reduced recruitment of reward processing neuro-circuitries. However, it is unclear to what extent these psychopathologies show common v. different neural dysfunctions as a function of symptom profiles, as no studies have directly compared neural dysfunctions associated with each of these psychopathologies to each other. METHODS: In study 1, a latent profile analysis (LPA) was conducted in a sample of 266 adolescents (aged 13-18, 41.7% female, 58.3% male) from a residential youth care facility and the surrounding community to investigate substance use, externalizing and attention problems, and ELS psychopathologies and their co-presentation. In study 2, we examined a subsample of 174 participants who completed the Passive Avoidance learning task during functional magnetic resonance imaging to examine differential and/or common reward processing neuro-circuitry dysfunctions associated with symptom profiles based on these co-presentations. RESULTS: In study 1, LPA identified profiles of substance use plus rule-breaking behaviors, attention-deficit hyperactivity disorder, and ELS. In study 2, the substance use/rule-breaking profile was associated with reduced recruitment of reward processing and attentional neuro-circuitries during the Passive Avoidance task (p < 0.05, corrected for multiple comparisons). CONCLUSIONS: Findings indicate that there is reduced responsivity of striato-cortical regions when receiving outcomes on an instrumental learning task within a profile of adolescents with substance use and rule-breaking behaviors. Mitigating reward processing dysfunction specifically may represent a potential intervention target for substance-use psychopathologies accompanied by rule-breaking behaviors.

Working memory-related brain activity in cannabis use disorder: The role of cross-cultural differences in cannabis attitudes.

Cannabis legislation and attitudes towards use are changing. Given that evidence from cultural neuroscience research suggests that culture influences the neurobiological mechanisms underlying behaviour, it is of great importance to understand how cannabis legislation and attitudes might affect the brain processes underlying cannabis use disorder. Brain activity of 100 dependent cannabis users and 84 controls was recorded during an N-back working memory (WM) task in participants from the Netherlands (NL; users = 60, controls = 52) and Texas, USA (TX; users = 40, controls = 32). Participants completed a cannabis culture questionnaire as a measure of perceived benefits (positive) and perceived harms (negative) of cannabis from their personal, friends-family's and country-state's perspectives. Amount of cannabis use (grams/week), DSM-5 CUD symptoms and cannabis use-related problems were assessed. Cannabis users self-reported more positive and less negative (personal and friends-family) cannabis attitudes than controls, with this effect being significantly larger in the TX cannabis users. No site difference in country-state attitudes was observed. TX cannabis users, compared with NL cannabis users, and those cannabis users perceiving more positive country-state attitudes showed a more positive association between grams/week and WM-related activity in the superior parietal lobe. NL cannabis users, compared with TX cannabis users, and those cannabis users with less positive personal attitudes showed a more positive association between grams/week and WM-load-related activity in the temporal pole. Both site and cultural attitudes moderated the association of quantity of cannabis use with WM- and WM-load-related activity. Importantly, differences in legislation did not align with perceived cannabis attitudes and appear to be differentially associated with cannabis use-related brain activity.

Use of Marijuana: Effect on Brain Health: A Scientific Statement From the American Heart Association.

Marijuana is perceived as a harmless drug, and its recreational use has gained popularity among young individuals. The concentration of active ingredients in recreational formulations has gradually increased over time, and high-potency illicit cannabinomimetics have become available. Thus, the consumption of cannabis in the general population is rising. Data from preclinical models demonstrate that cannabinoid receptors are expressed in high density in areas involved in cognition and behavior, particularly during periods of active neurodevelopment and maturation. In addition, growing evidence highlights the role of endogenous cannabinoid pathways in the regulation of neurotransmitter release, synaptic plasticity, and neurodevelopment. In animal models, exogenous cannabinoids disrupt these important processes and lead to cognitive and behavioral abnormalities. These data correlate with the higher risk of cognitive impairment reported in some observational studies done in humans. It is unclear whether the effect of cannabis on cognition reverts after abstinence. However, this evidence, along with the increased risk of stroke reported in marijuana users, raises concerns about its potential long-term effects on cognitive function. This scientific statement reviews the safety of cannabis use from the perspective of brain health, describes mechanistically how cannabis may cause cognitive dysfunction, and advocates for a more informed health care worker and consumer about the potential for cannabis to adversely affect the brain.

The role of sex in the association between cannabis use and working memory-related brain activity.

Although cannabis use patterns differ between men and women, studies on sex differences on the effects of cannabis on the brain and cognitive control are largely lacking. Working memory (WM) is a component of cognitive control believed to be involved in the development and maintenance of addiction. In this study, we evaluated the association between cannabis use and WM (load) related brain activity in a large sample, enabling us to assess sex effects in this association. The brain activity of 104 frequent cannabis users (63% men) and 85 controls (53% men) was recorded during an N-back WM task. Behavioral results showed a significant interaction between WM load and group for both accuracy and reaction time, with cannabis users showing a relatively larger decrease in performance with increasing WM load. Cannabis users compared to controls showed a relatively smaller reduction in WM (load) related activity in the precuneus and posterior cingulate cortex at higher WM load. This WM (load) related activity was not associated with performance nor cannabis use and related problems. An exploratory analysis showed higher WM-related activity in the superior frontal gyrus in men compared to women. While cannabis users showed higher WM (load) related activity in central nodes of the default mode network, this was not directly attributable to group specific worsening of performance under higher cognitive load. Further research is necessary to assess whether observed group differences increase with higher cognitive load, how group differences relate to measures of cannabis use, and how sex affects these group differences.

Residual Effects of Cannabis Use on Effort-Based Decision-Making.

OBJECTIVE: Acute Δ9-tetrahydrocannabinol (THC) administration in humans (Lawn etal., 2016) and rats (Silveira, Adams, Morena, Hill, & Winstanley, 2016) has been associated with decreased effort allocation that may explain amotivation during acute cannabis intoxication. To date, however, whether residual effects of cannabis use on effort-based decision-making are present and observable in humans have not yet been determined. The goal of this study was to test whether prolonged cannabis use has residual effects on effort-based decision-making in 24-hr abstinent cannabis using adults. METHOD: We evaluated performance on the Effort Expenditure for Reward Task (EEfRT) in 41 adult cannabis users (mean age = 24.63 years, 21 males) and 45 nonusers (mean age = 23.90 years, 19 males). A mixed 2x3x3 ANOVA with age as a covariate was performed to examine the effect of group, probability of winning, and reward amount on EEfRT performance. EEfRT performance was operationalized as % of trials for which the hard (vs. easy) condition was chosen. Pearson's correlations were conducted to test the relationship between EEfRT performance and measures of cannabis use, anhedonia and motivation. RESULTS: We found that cannabis users selected hard trials significantly more than nonusers regardless of win probability or reward level. Frequency of cannabis use was positively correlated with amount of % hard trials chosen. There were no significant correlations between % hard trials chosen, self-reported anhedonia, or motivation. CONCLUSIONS: These results suggest that unlike acute effects, residual effects of cannabis following 24 hrs of abstinence are associated with greater effort allocation during effort-based decision-making.

Unraveling the role of cigarette use in neural cannabis cue reactivity in heavy cannabis users.

Cue reactivity is an important biomarker of cannabis use disorder (CUD). Despite high rates of cigarette and cannabis co-use, its role in cannabis cue reactivity remains unclear. Using a visual functional magnetic resonance imaging cue reactivity paradigm, we investigated interactive effects of cannabis and cigarette use on cannabis cue relative to cigarette and neutral cue reactivity in a priori regions of interest-the amygdala, striatum, anterior cingulate cortex (ACC), ventral tegmental area (VTA), and orbitofrontal cortex-and a whole-brain analysis. In our sample of cannabis users and controls closely matched on cigarette use, significant interactions between cannabis and cigarette use status emerged in the amygdala, striatum, ACC, frontal pole, and inferior frontal gyrus. Cannabis-only users showed heightened cue reactivity in the amygdala compared with nonusing controls. Co-users did not show heightened cue reactivity compared with cigarette smoking controls, although cue-induced VTA activity was positively correlated with grams per week of cannabis. Cigarette smoking controls showed unexpectedly heightened cue reactivity compared to co-users and nonsmoking controls. These findings and the high prevalence of cannabis and cigarette co-use underscore the importance of considering cigarette smoking status when investigating the role of cue reactivity in heavy cannabis use.

Alcohol use disorder and cannabis use disorder symptomatology in adolescents is associated with dysfunction in neural processing of future events.

Two of the most commonly used substances by adolescents in the United States are cannabis and alcohol. Cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with impairments in decision-making processes. One mechanism for impaired decision-making in these individuals is thought to be an inability to adequately represent future events during decision-making. In the current study involving 112 adolescents, we used a comparative optimism task to examine the relationship between relative severity of CUD/AUD (as indexed by the CUD/AUD Identification Tests [CUDIT/AUDIT]) and atypical function within neural systems underlying affect-based neural represenation future events. Greater CUDIT scores were negatively related to responses within subgenual anterior and posterior cingulate cortex when processing high-intensity potential future positive and negative events. There was also a particularly marked negative relationship between CUD symptoms and blood oxygen level-dependent (BOLD) responses within visual and premotor cortices to high-intensity, negatively valenced potential future events. However, AUD symptom severity was not associated with dysfunction within these brain regions. These data indicate that relative risk/severity of CUD is associated with reduced responsiveness to future high-intensity events. This may impair decision-making where future significant consequences should guide response choice.

Dynamic functional connectivity between nucleus accumbens and the central executive network relates to chronic cannabis use.

The neural mechanisms of drug cue-reactivity regarding the temporal fluctuations of functional connectivity, namely the dynamic connectivity, are sparsely studied. Quantifying the task-modulated variability in dynamic functional connectivity at cue exposure can aid the understanding. We analyzed changes in dynamic connectivity in 54 adult cannabis users and 90 controls during a cannabis cue exposure task. The variability was measured as standard deviation in the (a) connectivity weights of the default mode, the central executive, and the salience networks and two reward loci (amygdalae and nuclei accumbens); and (b) topological indexes of the whole brain (global efficiency, modularity and network resilience). These were compared for the main effects of task conditions and the group (users vs. controls), and correlated with pre- and during-scan subjective craving. The variability of connectivity weights between the central executive network and nuclei accumbens was increased in users throughout the cue exposure task, and, was positively correlated with during-scan craving for cannabis. The variability of modularity was not different by groups, but positively correlated with prescan craving. The variability of dynamic connectivity during cannabis cue exposure task between the central executive network and the nuclei accumbens, and, the level of modularity, seem to relate to the neural underpinning of cannabis use and the subjective craving.

Interaction of Cannabis Use and Aging: From Molecule to Mind.

Given the aging Baby Boomer generation, changes in cannabis legislation, and the growing acknowledgment of cannabis for its therapeutic potential, it is predicted that cannabis use in the older population will escalate. It is, therefore, important to determine the interaction between the effects of cannabis and aging. The aim of this report is to describe the link between cannabis use and the aging brain. Our review of the literature found few and inconsistent empirical studies that directly address the impact of cannabis use on the aging brain. However, research focused on long-term cannabis use points toward cumulative effects on multimodal systems in the brain that are similarly affected during aging. Specifically, the effects of cannabis and aging converge on overlapping networks in the endocannabinoid, opioid, and dopamine systems that may affect functional decline particularly in the hippocampus and prefrontal cortex, which are critical areas for memory and executive functioning. To conclude, despite the limited current knowledge on the potential interactive effects between cannabis and aging, evidence from the literature suggests that cannabis and aging effects are concurrently present across several neurotransmitter systems. There is a great need for future research to directly test the interactions between cannabis and aging.

Testing the role of the posterior cingulate cortex in processing salient stimuli in cannabis users: an rTMS study.

The posterior cingulate cortex (PCC) and precuneus are hubs in the default mode network and play a role in processing external salient stimuli. Accordingly, activation in these regions has been associated with response to salient stimuli using drug cue-reactivity paradigms in substance using populations. These studies suggest that the PCC and precuneus may underlie deficits in processing salient stimuli that contribute toward the development of substance use disorders. The goal of this study was to directly test this hypothesis using repetitive transcranial magnetic stimulation (rTMS). Using a double-blind, placebo-controlled design, we used rTMS to target the PCC and precuneus with a double-cone coil at 10 Hz (high frequency) and 1 Hz (low frequency) in 10 adult cannabis users and 10 age- and sex-matched non-using controls. Electroencephalography data were collected before and after rTMS during a modified oddball paradigm with neutral, oddball, self-relevant, and cannabis-related stimuli. Cannabis users exhibited increased amplitude in P3 and faster latencies in the P3, N2, and P2 components in response to self-relevant stimuli compared to controls during baseline that normalized after rTMS. These results suggest that cannabis users exhibited heightened salience to external self-relevant stimuli that were modulated after rTMS. PCC dysfunction in cannabis users may be related to abnormalities in processing salient stimuli, such those during cue-reactivity, and provides a potential target for cannabis use disorder intervention.

Cannabis users exhibit increased cortical activation during resting state compared to non-users.

Studies have shown altered task-based brain functioning as a result of cannabis use. To date, however, whether similar alterations in baseline resting state and functional organization of neural activity are observable in cannabis users remains unknown. We characterized global resting state cortical activations and functional connectivity via electroencephalography (EEG) in cannabis users and related these activations to measures of cannabis use. Resting state EEG in the eyes closed condition was collected from age- and sex-matched cannabis users (N = 17; 6 females; mean age = 30.9 ±â€¯7.4 years) and non-using controls (N = 21; 9 females; mean age = 33.1 ±â€¯11.6 years). Power spectral density and spectral coherence were computed to determine differences in cortical activations and connectivity between the two groups in the delta (1-4Hz), theta (4-7 Hz), alpha (8-12 Hz), beta (13-30 Hz), and gamma (31-50 Hz) frequency bands. Cannabis users exhibited decreased delta and increased theta, beta, and gamma power compared to controls, suggesting increased cortical activation in resting state and a disinhibition of inhibitory functions that may interrupt cognitive processes. Cannabis users also exhibited increased interhemispheric and intrahemispheric coherence relative to controls, reduced mean network degree, and increased clustering coefficient in specific regions and frequencies. This increased cortical activity may indicate a loss of neural refinement and efficiency that may indicate a "noisy" brain. Lastly, measures related to cannabis use were correlated with spectral power and functional connectivity measures, indicating that specific electrophysiological signals are associated with cannabis use. These results suggest that there are differences in cortical activity and connectivity between cannabis users and non-using controls in the resting state that may be related to putative cognitive impairments and can inform effectiveness of intervention programs.

Brain intrinsic network connectivity in individuals with frequent tanning behavior.

BACKGROUND: Emergent studies suggest a bidirectional relationship between brain functioning and the skin. This neurocutaneous connection may be responsible for the reward response to tanning and, thus, may contribute to excessive tanning behavior. To date, however, this association has not yet been examined. OBJECTIVES: To explore whether intrinsic brain functional connectivity within the default mode network (DMN) is related to indoor tanning behavior. METHODS: Resting state functional connectivity (rsFC) was obtained in twenty adults (16 females) with a history of indoor tanning. Using a seed-based [(posterior cingulate cortex (PCC)] approach, the relationship between tanning severity and FC strength was assessed. Tanning severity was measured with symptom count from the Structured Clinical Interview for Tanning Abuse and Dependence (SITAD) and tanning intensity (lifetime indoor tanning episodes/years tanning). RESULTS: rsFC strength between the PCC and other DMN regions (left globus pallidus, left medial frontal gyrus, left superior frontal gyrus) is positively correlated with tanning symptom count. rsFC strength between the PCC and salience network regions (right anterior cingulate cortex, left inferior parietal lobe, left inferior temporal gyrus) is correlated with tanning intensity. CONCLUSION: Greater connectivity between tanning severity and DMN and salience network connectivity suggests that heightened self-awareness of salient stimuli may be a mechanism that underlies frequent tanning behavior. These findings add to the growing evidence of brain-skin connection and reflect dysregulation in the reward processing networks in those with frequent tanning.

Orbitofrontal cortex connectivity as a mechanism of adolescent behavior change.

An increasing number of studies have implicated the role of network functional connectivity in addiction. Yet, none have examined functional connectivity as a potential mechanism of adolescent behavior change. We examined the underlying neural mechanism of a promising treatment for adolescents, motivational interviewing (MI). We began by employing psychophysiological interaction (PPI) to evaluate network response in a sample of adolescent cannabis users (N=30). Next, we examined correlations between network connectivity and clinical metrics of treatment outcome. PPI analyses seeded on the orbitofrontal cortex (OFC) showed significant increases in functional connectivity across the inferior frontal gyrus (IFG), precentral gyrus, anterior and posterior cingulate gyrus, supplementary motor area (SMA), superior frontal gyrus, pallidus, caudate, and parahippocampal gyrus. Further, greater functional connectivity between the OFC and anterior cingulate/medial frontal gyrus was associated with less behavior change (e.g., greater post-treatment cannabis problems). These data support the role of the OFC network as a mechanism of adolescent treatment response.

Neurosteroid Levels in Patients With Bipolar Disorder and a History of Cannabis Use Disorders.

PURPOSE/BACKGROUND: In animal models, levels of the neurosteroid pregnenolone increase after tetrahydrocannabinol (THC) administration and pregnenolone appears to attenuate the brain effects of THC. Given these interactions between pregnenolone and THC, we evaluated baseline neurosteroid levels in participants with a history of a cannabis use disorders (CUDs). METHODS/PROCEDURES: Bipolar depressed participants were enrolled in a randomized placebo-controlled clinical trial to evaluate the efficacy of add-on pregnenolone for depression and before receiving pregnenolone or placebo. Baseline serum levels of neurosteroids (pregnenolone, allopregnanolone, pregnanolone, and androsterone) were analyzed in 53 participants with highly sensitive and specific gas chromatography/mass spectrometry. Current, active substance use disorders, or a positive baseline urine drug screen, were exclusionary. Participants were classified by past cannabis abuse or dependence diagnosis using the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Data were analyzed by independent t tests for separate neurosteroids. FINDINGS/RESULTS: Participants with a history of CUD had higher serum pregnanolone, lower allopregnanolone, a higher pregnanolone to allopregnanolone ratio, and a lower pregnenolone to pregnanolone ratio compared with those without a history of cannabis use. Similar findings were not observed based on a history of other substance use disorders with the exception of lower allopregnanolone in those with opioid use disorders. Notably, the majority of those with an opioid use disorder also had a CUD (75%). IMPLICATIONS/CONCLUSIONS: These findings potentially suggest either enduring changes in neurosteroids in people with past CUDs or represent a vulnerability marker for a CUD.

Long-term effects of marijuana use on the brain.

Questions surrounding the effects of chronic marijuana use on brain structure continue to increase. To date, however, findings remain inconclusive. In this comprehensive study that aimed to characterize brain alterations associated with chronic marijuana use, we measured gray matter (GM) volume via structural MRI across the whole brain by using voxel-based morphology, synchrony among abnormal GM regions during resting state via functional connectivity MRI, and white matter integrity (i.e., structural connectivity) between the abnormal GM regions via diffusion tensor imaging in 48 marijuana users and 62 age- and sex-matched nonusing controls. The results showed that compared with controls, marijuana users had significantly less bilateral orbitofrontal gyri volume, higher functional connectivity in the orbitofrontal cortex (OFC) network, and higher structural connectivity in tracts that innervate the OFC (forceps minor) as measured by fractional anisotropy (FA). Increased OFC functional connectivity in marijuana users was associated with earlier age of onset. Lastly, a quadratic trend was observed suggesting that the FA of the forceps minor tract initially increased following regular marijuana use but decreased with protracted regular use. This pattern may indicate differential effects of initial and chronic marijuana use that may reflect complex neuroadaptive processes in response to marijuana use. Despite the observed age of onset effects, longitudinal studies are needed to determine causality of these effects.

fMRI study of neural sensitization to hedonic stimuli in long-term, daily cannabis users.

Although there is emergent evidence illustrating neural sensitivity to cannabis cues in cannabis users, the specificity of this effect to cannabis cues as opposed to a generalized hyper-sensitivity to hedonic stimuli has not yet been directly tested. Using fMRI, we presented 53 daily, long-term cannabis users and 68 non-using controls visual and tactile cues for cannabis, a natural reward, and, a sensory-perceptual control object to evaluate brain response to hedonic stimuli in cannabis users. The results showed an interaction between group and reward type such that the users had greater response during cannabis cues relative to natural reward cues (i.e., fruit) in the orbitofrontal cortex, striatum, anterior cingulate gyrus, and ventral tegmental area compared to non-users (cluster-threshold z = 2.3, P < 0.05). In the users, there were positive brain-behavior correlations between neural response to cannabis cues in fronto-striatal-temporal regions and subjective craving, marijuana-related problems, withdrawal symptoms, and levels of THC metabolites (cluster-threshold z = 2.3, P < 0.05). These findings demonstrate hyper-responsivity, and, specificity of brain response to cannabis cues in long-term cannabis users that are above that of response to natural reward cues. These observations are concordant with incentive sensitization models suggesting sensitization of mesocorticolimbic regions and disruption of natural reward processes following drug use. Although the cross-sectional nature of this study does not provide information on causality, the positive correlations between neural response and indicators of cannabis use (i.e., THC levels) suggest that alterations in the reward system are, in part, related to cannabis use. Hum Brain Mapp 37:3431-3443, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

The hyper-sentient addict: an exteroception model of addiction.

BACKGROUND: Exteroception involves processes related to the perception of environmental stimuli important for an organism's ability to adapt to its environment. As such, exteroception plays a critical role in conditioned response. In addiction, behavioral and neuroimaging studies show that the conditioned response to drug-related cues is often associated with alterations in brain regions including the precuneus/posterior cingulate cortex, an important node within the default mode network dedicated to processes such as self-monitoring. OBJECTIVE: This review aimed to summarize the growing, but largely fragmented, literature that supports a central role of exteroceptive processes in addiction. METHODS: We performed a systematic review of empirical research via PubMed and Google Scholar with keywords including 'addiction', 'exteroception', 'precuneus', and 'self-awareness', to identify human behavioral and neuroimaging studies that report mechanisms of self-awareness in healthy populations, and altered self-awareness processes, specifically exteroception, in addicted populations. RESULTS: Results demonstrate that exteroceptive processes play a critical role in conditioned cue response in addiction and serve as targets for interventions such as mindfulness training. Further, a hub of the default mode network, namely, the precuneus, is (i) consistently implicated in exteroceptive processes, and (ii) widely demonstrated to have increased activation and connectivity in addicted populations. CONCLUSION: Heightened exteroceptive processes may underlie cue-elicited craving, which in turn may lead to the maintenance and worsening of substance use disorders. An exteroception model of addiction provides a testable framework from which novel targets for interventions can be identified.

Age-related increase of resting metabolic rate in the human brain.

With age, many aspects of the brain structure undergo a pronounced decline, yet individuals generally function well until advanced old age. There appear to be several compensatory mechanisms in brain aging, but their precise nature is not well characterized. Here we provide evidence that the brain of older adults expends more energy when compared to younger adults, as manifested by an age-related increase (P=0.03) in cerebral metabolic rate of oxygen (CMRO2) (N=118, men=56, ages 18 to 74). We further showed that, before the mean menopausal age of 51years old, female and male groups have similar rates of CMRO2 increase (P=0.015) and there was no interaction between age and sex effects (P=0.85). However, when using data from the entire age range, women have a slower rate of CMRO2 change when compared to men (P<0.001 for age×sex interaction term). Thus, menopause and estrogen level may have played a role in this sex difference. Our data also revealed a possible circadian rhythm of CMRO2 in that brain metabolic rate is greater at noon than in the morning (P=0.02). This study reveals a potential neurobiological mechanism for age-related compensation in brain function and also suggests a sex-difference in its temporal pattern.

MRI assessment of cerebral oxygen metabolism in cocaine-addicted individuals: hypoactivity and dose dependence.

Long-term cocaine use is known to negatively impact neural and cerebrovascular systems. However, the use of imaging markers to separately assess these parameters remains challenging. The primary reason is that most functional imaging markers, such as cerebral blood flow, functional connectivity, and task-evoked functional MRI, are known to reflect a complex interplay between neural and vascular components, thus the interpretation of the results is not straightforward. The goal of the present study is to examine neural-activity-specific changes in cocaine addiction, using cerebral metabolic rate of oxygen (CMRO2) as a surrogate marker of aggregated neural activity. We applied a recently developed CMRO2 technique in 13 cocaine-addicted subjects and 13 age- and gender-matched control subjects, and examined the impact of long-term cocaine use on CMRO2. Our results showed that CMRO2 in cocaine-addicted subjects (152 ± 16 µmol/100 g/min) is significantly lower (p = 0.031) than that in controls (169 ± 20 µmol/100 g/min). Furthermore, the severity of this decreased metabolism is associated with lifetime cocaine use (p = 0.05). Additionally, the CMRO2 reduction was accompanied by a trend of decrease in cerebral blood flow (p = 0.058), but venous oxygenation was unaffected (p = 0.96), which suggested that the CMRO2 change may be attributed to a vascular deficiency in chronic cocaine users. To our knowledge, this is the first study to measure CMRO2 in cocaine-addicted individuals. Our findings suggest that CMRO2 may be a promising approach for assessing the long-term effects of cocaine use on the brain.