Participants were chosen to reflect typical perspectives: they were recruited from common spaces where most participants gathered, almost all participants approached during recruitment agreed to participate, and service staff at recruitment sites helped identify participants who were representative of their clientele. For each of the eight venues, staff chose random days and time periods for recruitment. During the allotted time for recruitment at each of the eight study sites, staff screened clientele for eligibility and invited eligible participants to enroll into the study. All participants who were approached and were eligible were included in the study; we did not gather information on the total number of participants approached at each session. On each recruitment day, study staff reviewed the list of individuals recruited to ensure there were no duplicate records. On instances where there were duplicates, we retained only the first record for that participant. Staff administered a 20-minute questionnaire on a tablet computer. Participants who completed the questionnaire received a $15 gift card for their participation. All study procedures were approved by the University of California, San Francisco Committee on Human Research.We calculated the mean and standard deviations or median and interquartile range for continuous variables. We calculated proportions for categorical variables. We showed differences in demographics, cigarette smoking characteristics, patterns and frequency of use of flavored and unflavored ATPs, and perceptions of risk, addictiveness and harmfulness of ATPs between cigarette-only users and ATP users. We used logistic regression to examine the bivariate and multi-variable associations between ATP use and past-year quit attempts,cannabis grow indoor adjusting for covariates shown to be associated with quit attempts in prior studies with homeless adults including demographics, substance use disorders, depression, and cigarette use characteristics.

We conducted all analyses using Stata, Version 12.1 .Among participants, 34.5% were cigarette-only users and 65.5% were ATP users . Compared to ATP users, cigarette-only users were more likely to be older, White and American Indian/Alaska Native; ATP users were more likely to self-identify as Hispanic/Latinx. ATP users were more likely to report depressive symptoms, PTSD and past 30-days use of other substances compared to cigarette-only users. Compared to cigarette-only users, ATP users were more likely to report use of menthol cigarettes. ATP users reported high rates of use of cigars and bluntsin the past 30 days. In comparison, rates of use of e-cigarettes , smokeless tobacco , or tobacco pipe were low . ATP users were more likely to perceive cigars and blunts as addictive compared to cigarette-only users , and were more likely to perceive cigars and tobacco pipes as harmful compared to cigarette-only users . Cigarette-only and ATP users did not differ in their perception of risk of developing a smoking-related illness .In this study of current smokers who experienced homelessness, we found that 65.5% concurrently used an ATP. This estimate is similar to that reported in studies of adult homeless daily smokers in Oklahoma City, OK and Boston, MA , but higher than that reported among homeless adult smokers in Dallas, TX . Consistent with prior studies, we found that cigars, e-cigarettes, and blunts were the most commonly used ATP . Cigar use is common among individuals experiencing homelessness, perhaps due to their lower cost relative to cigarettes . Hispanic/Latinx participants were slightly more likely to report ATP use, in contrast to the general population where Hispanic/Latinx individuals have reported lower rates of use . ATP use is common among cigarette smokers experiencing homelessness, highlighting a need for providers to be aware of and screen for ATP use in this population. Contrary to our hypothesis and findings from a previous study , the use of ATP in the past 30 days was not associated with a past-year quit attempt.

We did not observe an association between ATP use and number of cigarettes smoked or time to first cigarette after waking, which are other metrics of nicotine dependence and predictors of quit attempts. These findings suggest that the frequency of ATP use or motivations of use may be more significant predictors of cigarette quit attempts than use of an ATP in the past 30-days. The type of ATP may also make a diference. Compared to other non-combustible tobacco products like cigars, which may carry equivalent risk to cigarettes, ecigarettes may be considered less risky and more likely to be used for cigarette quit attempts . However, we found no independent association between e-cigarettes and quit attempts in bivariate and multi-variable analysis. Amphetamine use in the past 30-days was associated with a lower odds of making a quit attempt after adjusting for other covariates. Our findings highlight a specific group of individuals who may have high levels of nicotine and co-ocurring substance use dependence that might pose challenges for cigarette smoking cessation. In contrast, hazardous alcohol use was associated with higher odds of past-year quitting. Our results are in contrast to previous studies that indicated that smoking cessation was significantly associated with fewer drinking days, fewer drinks consumed on drinking days, and lower odds of heavy drinking among individuals experiencing homelessness . Integrated efforts in treating tobacco and substance use might benefit this population. Consistent with previous studies , we found that ATP users had higher rates of mental health disorders and substance use in the past 30-days compared to cigarette-only users. Given high rates of smoking among individuals with mental health and substance use disorders , the use of ATP among this population may signal a need for higher levels of nicotine to allay symptoms from mental health and substance use conditions . Alternatively, ATP users may use other substances such as cannabis to reduce cravings to smoke, and may be more likely to attempt to quit smoking. While exploring these associations was beyond the scope of this study, our results highlight the need for studies to examine the underlying role of ATP use to curb substance use cravings and/or alleviate mental health symptoms or reduce the urge to smoke cigarettes among cigarette smokers experiencing homelessness.

Among both e-cigarette and cigar users and the general population, fruit flavored products had the highest appeal. This is consistent with a recent study that some adult e-cigarette users initiate use of these products because of their flavors . Studies are needed to examine whether flavored tobacco contributes to the initiation of ATP and/or smoking cessation among populations experiencing homelessness, especially in light of recent momentum to restrict these products. Almost all participants perceived cigarettes to be addictive and harmful, and cigarette only and ATP users did not differ in their perception of risk of developing a smoking-related illness. Most participants perceived cigars and e-cigarettes to be harmful or addictive. These findings have particular salience to the Food and Drug Administration’s regulatory authority, and suggest that efforts to inform the public of the harms associated with ATPs, specifically flavored ecigarettes, are reaching this population. Although ATP users perceived higher levels of addiction and harm from some tobacco products, including cigars and tobacco pipes,vertical farming supplies they also reported high rates of use of some of these products. These findings are consistent with those from a previous study where knowledge of risk was not associated with reduction in product use . Our study has several limitations. Our findings, which are intended to be representative of homeless adults seeking emergency shelter services in San Francisco, may not be generalizable to the general homeless population. The cross-sectional nature precludes us from evaluating a causal association between risk, harm, and addiction perceptions and smoking cessation behaviors. Longitudinal studies are needed to further explore these associations. Measurement error is possible given that tobacco use behaviors were self-reported and not biochemically verified. Residual confounders such as affects toward e-cigarettes and motivations for use of these products were not explored in this study and warrant further exploration.On the remains of an abandoned military base, a few minutes walk from the commercial and political center of Denmark, a village has arisen. Named Christiania after an ancient Viking monarch, this community of little more than a thousand was established thirty-five years ago as an alternative society. Amidst the 1960’s student revolts and critique of modern consumer culture, Christiania was formed as a space of expression and difference. The hope was to create a new society that would allow freedom from the constricting rules of the welfare state, and offer a counter-point and challenge to the homogeneity of Danish culture. Over the years, Christiania has become a key cultural icon in Danish society, recognized as a “social experiment” by the earlier Social Democratic governments and widely known as one of the oldest, most successful and politically active squatter communities in Europe. Christiania lies unobtrusively in the neighborhood of Christians haven, near Copenhagen’s famous walking street.

The enclave comes slowly into view, obscured by the surrounding multistory, grey apartment buildings and busy, car-filled streets. Among the dense rows of monotonous buildings is a surprisingly un-urban space; a vibrant, artistic, car-free and tree-filled village. Set-off from the busy bustle of the surrounding city streets, Christiania remains enclosed by a long colorful wall that separates it from the street. The encircling wall, a relic from the military past, is now a graffiti-filled space that provides running commentary on the current political situation in Denmark and abroad. At one of the few entrances, a gravel path leads away from the monotonous urban side streets towards the infamous Pusher Street; a city block of densely clustered booths illegally selling cannabis products, often joints rolled with different grades of marijuana, hashish blocks on paper plates, and the necessary paraphernalia to complete the smoking experience. Christiania is often represented in the media as a throwback, a place that is out-of-touch, lost in the hopes and dreams of the 1960’s. Once within Christiania, it is difficult to get oriented. There are no street signs and dirt pathways crisscross through the thousand-person community, and the various houses are not numbered. The noticeably formidable, large, grey military buildings dominate the community center. The functional austerity of the military barracks mixes with new age, pot-smoking, hippie style and vibrant hip-hop style graffiti covers the large buildings that once served as military housing and provided storage facilities. Over the past 35 years their functional austerity has been subverted. Some of the large buildings have been divided into communal houses, theaters, or transformed into work spaces such as the all-women smithy. A military base has been transformed into a living space. Christiania is a pastiche; hodge-podge, auto-constructed homes mix with brightly colored wagons that sit dispersed among three-story, massive grey barracks parodying the uniformity of the surrounding city space. Although only one-thousand people live in Christiania, it is also one of the most visited places in Denmark. The Danish Tourist Bureau estimates that several million people come to Christiania each year to see the famous “hippie” commune; purchase cannabis products or sit, enjoy and listen to music; jog on the surrounding canal embankments; or visit the many shops, and eat at the several restaurants and bars. “Pusher Street” is widely known as a tourist magnate, and is the most famous street in Christiania and is listed on tourist maps. The community also boasts a four-star restaurant called Loppen . Christianitter revel in their alterity and boast that their community is a special space, a needed counterpoint to the constricting rule-based limitations of the Danish welfare state and the homogeneity of the Danish culture. The emphasis on difference, and a resistance to incorporation is symbolically marked as you leave Christiania, a wooden arch hangs over the exit, carved in wood the sign proclaims: “You are now entering the European Union.” This paper discusses the connections between urban spaces, police violence, conflict and national identity. I use the case of Christiania, an illegal squatter community in Denmark, and focus on the twin projects of urban renewal and the policing of urban spaces. Christiania is a key cultural icon and widely known as one of the oldest, most successful and politically active squatter communities. It is also the most diverse and policed spaces in Copenhagen.In 2002 a new government, elected on a neoliberal agenda that promised significant reform of the welfare state, began plans to close the squatter community and to capitalize on its countercultural cache.

These analyses used government-run population-based study data, which may limit self-disclosure of sexual minority status, and further relied on a single identity variable to measure sexual orientation, which ignores same-sex sexual behaviors. There is an inextricable yet varied relationship between an individual’s mental health and substance use. Substance use may lead to poorer mental health or, inversely, poor mental health may lead to increased substance use . A variety of substances have been shown to be associated with negative mental health events or symptoms. For example, Clatts, Goldsamt, and Lifound that a third of young MSM who used club drugs on a regular basis reported having attempted suicide, and almost half of those who had attempted suicide, did so multiple times over their lifetime. They also found that more than half of regular club drugs users had high levels of depressive symptoms. McKirnan and colleagues found that GBM who showed signs of depression were nearly twice as likely to smoke. Stall and colleagues identified a “dose-response” relationship between self-rated mental well being and alcohol related problems: GBM who self-rated their mental well-being as low were approximately three times more likely to have alcohol related problems and those who rated it as moderate were nearly twice as likely to have alcohol related problems. Respondents who scored as depressed were also one and half times more likely to report using multiple drugs and nearly twice as likely to report weekly drug use. Syndemics [clusters of mutually reinforcing epidemics that interact with one another to make overall burden of disease within a population worse ] has been used in research with GBM to explain how various psychosocial variables such as polydrug use,flood tray mental health conditions, and intimate partner violence increase the likelihood of acquiring HIV .

However, nearly all of these studies have relied on convenience samples through online and venue-based recruitment; thus, they may not be representative of the larger underlying population of GBM. In order to address issues of representativeness and limitations of non-probability sampling in past research with GBM, we used respondent-driven samplingto estimate population parameters that are more representative than convenience samples . RDS is a type of chain-referral research technique in which participants are asked to recruit individuals from within their social networks in successive waves, and estimates population parameters using measures of network size and recruitment homophily. By utilizing RDS we sought to produce a more representative sample of the GBM population in Metro Vancouver in order to determine the prevalence of mental health issues and substance use as well as the association between these factors.We analyzed cross-sectional data from participants enrolled in the Momentum Health Study, a longitudinal bio-behavioral prospective cohort study of HIV-positive and HIV-negative GBMin Metro Vancouver, Canada. The overall aim of this study was to examine the impact of a biomedical intervention—increased access to highly active antiretroviral therapy for HIV— on HIV risk behaviors among GBM. The present analysis utilized data collected from participants’ first study visit that occurred between February 2012 and February 2014. We used RDS to recruit GBM in the Greater Vancouver area . Initial seeds were selected inpers on through partnerships with community agencies or online through advertisements on GBM socio-sexual networking mobile apps or websites . These seeds were then provided with up to six vouchers to recruit other GBM they knew. All participants were screened for eligibility and provided written informed consent at the in-person study office in downtown Vancouver. A computer-assisted, self-administrated questionnaire was used to collect socio-demographic, psychosocial, and behavioral variables.

Subsequently, a nurse-administered structured interview collected information on history of mental health and substance dependence diagnosis and treatment, and participants provided blood samples to test for HIV and other sexually transmitted infections . Participants received a $50 honorarium for completing the study protocol and an additional $10 for each eligible GBM they recruited into the study. All project investigators’ institutional Research Ethics Boards granted ethical approval. Moore and colleagues have published additional detail on the Momentum Health Study protocol.On the nurse-administered structured interview, participants were asked the following question, “have you ever been told by a doctor that you have any of the following mental health problems?”: depression, anxiety, bipolar disorder, schizophrenia, alcohol use disorder, and other substance use disorders. We collapsed participants indicating any alcohol use disorder and substance use disorder versus neither for the first dependent variable. A second dependent variable was then derived for participants who indicated any other mental health disorder , excluding any participant who also indicated an alcohol or other substance use disorder, versus none. Participants who indicated any lifetime mental health diagnosis were also asked if they were, “ …now under any treatment for any mental health condition?” and if so to, “ …please describe [the] treatment.”We sought to determine the prevalence of doctor diagnosed mental health conditions and self-reported substance use among GBM, as well as the association between these two domains, using cross-sectional data from the Momentum Health Study of GBM living in the Metro Vancouver, British Columbia, Canada. Substance use and mental health conditions were highly prevalent among GBM. As expected, there were strong associations found between a substance use disorder diagnosis and various substances in our study, which corroborate previous research regarding smoking and alcohol-related problems among GBM. Further, cigarette smoking and erectile dysfunction drugs were the only substances associated with any other mental health disorder diagnosis at the univariable level, and did not remain in the multi-variable model.

Our findings suggest that GBM have higher rates of mental health disorders than the overall population. According to the 2012 Canadian Community Health Survey , a third of Canadians reported a mental health or substance use disorder diagnosed in their lifetime , while more than half of the participants in our sample reported any lifetime doctor-diagnosed mental health disorder. Examining depression, anxiety, and drug abuse/dependence more specifically, our study reported population prevalence estimates approximately three times larger than the overall population: 8.7% of Canadian sversus 25.9% of GBM report being diagnosed with anxiety in their lifetime, 11.3% of Canadians versus 42.4% of GBM report being diagnosed with depression in their lifetime, and 4.0% of Canadians versus 14.8% of GBM reported lifetime drug abuse or dependence. This discrepancy is greater than what was reported by Meyer and King et al. , which found the prevalence of mental health conditions in GBM to be approximately two times greater than in heterosexual men across multiple studies. However, neither Meyer nor King et al.included Canadian data in their analyses, nor did previous studies utilize RDS, making our findings more representative, at least for urban GBM in Metro Vancouver, Canada. Our use of respondent-driven sampling to generate population parameter estimates indicated that we had over-sampled White GBM and under-sampled low-income GBM, GBM with less formal education and bisexual-identified men.According to the Canadian Tobacco Use Monitoring Survey , 18.4% of Canadian men are current smokers,which includes those who do not smoke daily ,grow table while in our study, 47.1% of GBM smoked cigarettes in the past 6 months. These percentages fall at the upper end of the 25–50% range in the review conducted by Ryan and colleagues , which looked at the prevalence of smoking across multiple studies of GBM and found that GBM were much more likely to smoke than their heterosexual counterparts. Our study found that recent cannabis use among GBM was higher than lifetime use in the Canadian population: 63.6% recently used in our study versus 41.5% lifetime use in the Canadian Alcohol and Drug Use Monitoring Survey . Other substances, such as cocaine and ecstasy, also had recent prevalence estimates at much greater magnitudes in our study at 29.5% and 18.9%, respectively, versus the 1.1% and 0.6% lifetime estimates found in CADUMS. These findings are consistent with the review by Hughes and Eliason , whom found that GBM are more likely to use substances than heterosexual men.AUDIT and AUDIT Consumption have been used previously in research with GBM to assess alcohol use. A larger proportion of GBM were categorized to be hazardous drinkers or possibly dependent on alcoholin our study versus other studies: 9% among older LGB adults and 15.4% among HIV-positive men who have sex with men . D’Augelli, Grossman, Hersh berger, and O’Connell studied older lesbian, gay, and bisexual people and found a mean AUDIT score of 3.06, which is nearly half the median value of 6.0 in our study. For studies using the AUDIT-C that focused only on consumption patterns, hazardous drinking categorization was more prevalent: 71.4% among gay and bisexual youth aged 13–24 , 65.4% among gay men and 58.8% among bisexual men aged 18–25 , and 58% of adult GBM . These disparities in prevalence may be due to the age group or HIV-status specificity of the samples in other studies, differences in measurement approaches, benefits of using RDS to access hard-to-reach GBM subgroups, or may reflect a local phenomenon among GBM in Metro Vancouver. Few studies have used the Hospital Anxiety and Depression Scale to measure anxiety and depression in GBM, allowing our study to provide some of the first estimates using this scale in a nonclinical population and with RDS-weighted population parameters. However, this also makes it difficult to compare the results of our study with others.

Gray and Hedge found that only 40% of gay men were in the normal range for the HADSAnxiety measure and 77% of gay men were in the normal range for the HADS-Depression measure, which are similar to the percentages found in our study where 42.9% of GBM scored within normal range for the HADS-Anxiety measure and 80.9% scored in the normal range for the HADS-Depression measure. Many studies assessing anxiety and depression in GBM have used the Composite International Diagnostic Interview ; a nonclinical, structured interview often used in epidemiological surveys and is based on the diagnostic criteria outlined in the Diagnostic and Statistical Manual of Mental Disordersas well as the International Classification of Diseases. Cochran et al.found that 69% of GBM were not depressed and 97.1% were not anxious according to the CIDI, which differs from the 80.9% and 42.9% in our study for HADS-Depression and HADS-Anxiety respectively. The percentage of participants who scored within the normal range for the HADS-Depression measure in our study is similar to the percentage by Wang et al. , which was 80.8% versus 80.9% in our study, while the anxiety measure differed greatly which was 78.1% in their study versus the 42.9% in our study. While the HADS is easier to use because it is a self-administered questionnaire, the CIDI has been shown to demonstrate high validity as a diagnostic instrument , which could be useful in future studies of GBM mental health. A number of salient social factors were identified as important determinants of mental health. Our study found that GBM with lower annual incomes were more likely to have been diagnosed with a substance use disorder. Income is considered to be one of the most important social determinants of health because it effects whether one may access nutritious food, housing, transportation, and other basic health prerequisites . This upstream determinant impacts one’s general and physical well being, which in turn may explain this greater burden of mental health disorders. Lastly, we found that participants who were currently students were less likely to have a substance use disorder than participants who were not. This may be due to students generally being younger in age, and as such are biased towards a shorter lifetime reporting period within which to have been diagnosed with any mental health conditions. Specific to being a sexual minority, GBM who were not out about their gay identity were less likely to report having any other mental health condition at the univariable level than those who were open about being gay. We posit that this may be due to the fact that individuals who are public regarding their sexual orientation are easier targets for harassment or discrimination. This is supported by findings from D’Augelli and Grossman , where GBM who came out at an earlier age and GBM who spent more years out of the closet were more likely to experience victimization than individuals who came out later or who spent less time out of the closet.

The development of functional imaging techniques such as Positron Emission Tomography and functional Magnetic Resonance Imaging , has allowed the high-resolution mapping of the brain in-vivo, in people with SUD. This body of work has provided increasing evidence that SUD is associated with alterations in the anatomy and the functional brain pathways ascribed to reward, learning, and EF. Importantly, emerging evidence suggests that neuroimaging versus subjective measures in SUD may predict with greater precision addiction-relevant cognitive processes and treatment outcomes.Functional imaging techniques allowed exploration of whether brain dysfunction is implicated in SUD in humans. These create images of brain function by relying on proxies, including metabolic properties of the brain. The application of functional imaging has been crucial to reveal the impact of SUD on human brain function in areas ascribed to cognitive processes and positive and negative emotions .PET imaging relies on the movement of injected radioactive material to identify whether the metabolic activity of brain regions is related to cognitive functions . PET’s invasiveness and high financial costs have resulted in a limited number of studies using it, and its low temporal and spatial resolutions prevented the identification of subtle brain activity alterations in SUD samples . The development of fMRI provided a way to overcome these limitations. Unlike PET, fMRI is non-invasive, promoting feasibility in unpacking the neural correlates of SUD . Specifically, fMRI generates information about brain activity by exploiting the magnetic properties of oxygenated and deoxygenated blood . Further, fMRI provides information on the brain’s functional activity with higher temporal and spatial resolutions than those of PET, i.e., within seconds and millimeters, respectively . These methodological advantages have allowed many studies to map the neural pathways implicated in SUD,hydroponics flood table while providing information on brain function within a high spatial and temporal resolution.

However, a well-described limitation of fMRI analyses is the difficulty to control for multiple tests and related false positive errors . The neuroimaging community has started to implement several strategies to address this limitation , but the use of liberal thresholds has probably inflated false positive rates in earlier studies. Using multi-modal imaging techniques is warranted to further unpack the neural mechanisms of SUD and abstinence. For instance, integrating structural MRIdata with Magnetic Resonance Spectroscopy Imaging, an MRI imaging technique that allows investigation of metabolites in the brain, may provide insight into the biochemical changes associated with volumetric alterations in SUD. Further, conducting brief, repeated task-free fMRI studies during treatment/abstinence could provide a better understanding of the impact of clinical changes on intrinsic brain architecture. An advantage of resting-state functional imaging data is the possibility of investigating patterns of brain function without restrictive “forces” on brain function placed by a specific task. Finally, studying SUD with modalities such as Diffusion Tensor Imaging may reveal alteration in white matter pathways that connect brain regions that are volumetrically altered. This approach may inform the pathophysiology of volumetric alterations in SUD-relevant brain circuits.Table 1 overviews key neurobehavioral pathways implicated by prominent neuroscientific theories of addiction and a growing body of work. These include neurobehavioral systems implicated in positive valence, negative valence, interoception, and EF . Abstinence may recover and mitigate such brain alterations and related cognitive functions, e.g., increase in response inhibition capacity, lower stress and drug reactivity, learning new responses to drugs and related stimuli. This notion is yet to be tested using robust neuroimaging methods that, in conjunction with treatment-relevant clinical and cognitive measures, measure and track the integrity of specific neural pathways during abstinence . The neurobiology of abstinence has been posited to entail two core processes . The first is the restored integrity of brain function, as drug levels in the central nervous system and bloodstream clear out with abstinence. The second is the retraining of neural pathways implicated in cognitive changes that enable abstinence. These include awareness/monitoring of internal psychological/physiological states , withdrawal and craving ; EF ; monitoring conflict between short-term goals versus long-term goals ; motivation to use drugs ; and learning new responses to drug-related and other stimuli.

Most neuroimaging studies to date have mapped dysfunctional neural pathways in SUD. There is a significant lack of work that tracks abstinence-related brain changes over time. This evidence gap prevents neuroimaging studies from informing the identification of treatment targets and clinical practice. It is unclear if abstinence leads to recovery of SUD-related brain dysfunction ,engages additional pathways implicated in abstinence-related cognitive, clinical, and behavioral changes, and is predicted by specific brain measures assessed pre-treatment. Emerging evidence from standard behaviora land pharmacological treatments that directly affect the central nervous system provides preliminary support for these notions, as reviewed in detail in previous work [see ]. This section provides an overview of early neuroimaging evidence for brain changes related to abstinence and novel interventions .Abstinence may “reverse” brain dysfunction and volume loss associated with SUD. Studies have observed increased or normalized volumes in global and prefrontal brain regions related to abstinence in people with alcohol use disorder and cocaine and opiate use disorders . PET and DTI studies of alcohol and cocaine users showed recovery of brain dysfunction and white matter integrity following heterogeneous abstinence durations, e.g., from about a month , to several months and several years . Results from fMRI tasks of response inhibition in abstinent users also showed that reduced brain function typically associated with drug use, was “restored” and increased in prefrontal and cerebellar pathways in former versus current cigarette smokers, and in former cannabis usersversus non-users . Emergingevidence showed that abstinence duration was associated with improved integrity of cortical and prefrontal pathways . Additionally, abstinence related neuroadaptations have been associated with substance use levels [e.g., cocaine dose, and performance was improved during cognitive tasks relevant to addiction e.g., processing speed, memory, EF-shifting. Thus, abstinence-related brain changes may in part drive treatment relevant outcomes.

Several neuroimaging studies have examined whether brain integrity in SUD predicts abstinence, with promising results. Studies of brain structure in people with nicotine and alcohol use disorders reported that increased volume and white matter integrity in prefrontal regions, followed by parietal and subcortical areas, most consistently segregated abstainers versus relapsers . Studies have examined brain function using fMRI tasks that engage cognitive domains relevant to treatment response. These studies provided evidence that the function of fronto-striatal regions in particular, followed by other regions discriminated responders versus nonresponders, relapsers versus non-relapsers in cigarette smokers and people with methamphetamine, cocaine and alcohol use disorders . Also,hydroponic stands the activity of fronto-striatal pathways have been shown to predict alcohol dosage at 6 month follow-up . Studies that used other functional imaging techniques such as spectroscopy and PET imaging consistently reported that frontal blood flow and metabolites and the density of dopamine receptors predicted treatment outcome in alcohol users and relapse in methamphetamine users .Novel training strategies that target core cognitive dysfunctions in SUD have shown promise to restore cognitive alterations and help maintain abstinence . One example includes cognitive bias modification strategies that reduce attentional biases towards substance related cues [see study in tobacco smokers ]. Such strategies may target top-down and bottom-up brain pathway simplicated in addiction . These include increasing the activity of top-down EF regions that enhance inhibitory control and behavioral monitoring , and decreasing reactivity of bottom-up pathways implicated in reactivity to drug stimuli, and craving . Early neuroimaging evidence has examined the neuroadaptations that occur pre-to-post-cognitive bias modification training. These findings are revised and discussed in the COGNITIVE TRAINING AND REMEDIATION section below. There is a paucity of neuroimaging research on other cognitive training and remediation approaches, despite promising evidence of neuroplasticity-related changes after cognitive remediation in brain injury .Mindfulness-based interventions are being increasingly used for the treatment of SUD . Although mindfulness does not use standard cognitive training/remediation approaches, it has shown to improve SUD-relevant cognitive processes such as attention and EFas well as substance use outcomes. Mindfulness-based interventionseng age two key cognitive processes focused attention, which consists of paying attention to a specific stimulus while letting go of distractions and open monitoring, which refers to the being aware of internal and external stimuli with a non-judgmental attitude and acceptance. The effectiveness of mindfulness-based interventions has been ascribed to improved function of prefrontal, parietal, and insula regions that are implicated in EF and autonomic regulation , and down-regulation of reactivity in striatal/amygdala regions implicated in reward, stress, and habitual substance use . Only a handful of neuroimaging studies have examined brain changes that occur with mindfulness-based interventions in SUD. This includes a fMRI study in tobacco smokers that showed a 10-session mindfulness-oriented recovery enhancement versus placebo intervention, decreased activity of the ventral striatum, and medial prefrontal regions during a craving task and an emotion regulation task . Most evidence on mindfulness and SUD consists of behavioral studies that showed robust effects on cognition, substance use, and craving. Given the widespread use of mindfulness-based interventions in clinical settings, we advocate the conduct of active placebo-controlled neuroimaging studies that map the neurobiology of mindfulness in SUD.Overall, there is a paucity of neuroimaging studies of treatment and abstinence in SUD.

The study methods are very heterogeneous which precludes their systematic integration. First, there was significant heterogeneity in treatments, with distinct durations and hypothesized neurobehavioral and pharmacological mechanisms of action, and distinct treatment responses across different individuals, SUD and related psychiatric comorbidities. Second, control groups varied substantially and brain changes related to abstinence were compared to different types of controls . Third, repeated measures study designs had varying data testing points that precluded the integration of the study findings and mapping treatment-related, trajectories of brain changes with abstinence/recovery. More systematic evidence is needed to provide sufficient power to measure brain pathways relevant to treatment response and to inform clinically-relevant treatment endpoints. In order to address this gap, the ISAM-NIG Neuroimaging stream recommends the conduct of harmonized, multi-site, neuroimaging studies with systematic testing protocols of relevance for clinical practice. It is hoped that the ISAM-NIG Neuroimaging approach will generate results that can be readily integrated and that increase the power to detect abstinence-related neuroadaptations. On one hand, the integration of neuroimaging testing into clinical practice can be challenging. MRI scanners are extremely expensive to buy, setup, and run safely, and the acquisition of high-quality brain images requires extensive specialized technical expertise. On the other hand, the availability of MRI scans in many hospitals, universities, and medical institutions, may provide ideal settings to integrate neuroimaging and clinical expertise. MRI scans can be feasible in that they are non-invasive, safe, and can be relatively quick . Outstanding challenges to address remain funding sources, the lack of integration in the theoretical frameworks between basic research, clinical science, and clinical practice. Discipline-specific specialized language and practices can also create barriers. We advocate using team science to develop a harmonized interdisciplinary framework, so that all stakeholders, including clinicians, neuropsychologists, social workers and neuroscientists interact to inform commonly-agreed testing batteries and most profitable directions for future work. The present review has focused on neuroimaging data mainly acquired through fMRI, allowing for visualization of the brain networks involved in certain conditions . However, it should be noted that the coarse temporal resolution of such techniquesimpedes determination of the temporal activation sequence , allowing the specific brain activation patterns to be correlated with the various cognitive stages involved in the investigated processes [e.g., ]. Other tools, such as cognitive event related potentials in particular, might be more suitable for this purpose . Nowadays, different studies reveal that specific ERP components tagging specific cognitive functions may be used as neurophysiological biomarkers for addiction treatment outcome prediction . Such data may be of great value to clinicians for the identification of cognitive processes that should be rehabilitated on a patient-by-patient basis through cognitive training and/or brain stimulation. However, despite technical facilities , several decades of research, and clinical relevance, ERPs like other neuroimaging modalities have yet to be implemented in the clinical management of SUD.Despite recent advances in psychological and pharmacological interventions for SUD, relapse remains the norm. A recent meta analysis of 21 treatment outcome studies conducted between 2000–2015 found that fewer than 10% of treatment seekers were in remission in any given year following SUD treatment .

Given the rapid evolution in e-cigarette products and messaging, there remains a need to inform how smoking cessation treatment can be tailored for SUD clients who use both e cigarettes and tobacco cigarettes. The high rates of tobacco use and tobacco-related mortality among individuals with SUDs, and the complex, emerging questions regarding the effectiveness of e-cigarettes as smoking cessation aids, highlights the need for up-to-date information about e-cigarette use in this population. The purpose of this study was to characterize e-cigarette use among clients in residential SUD treatment and to identify the correlates of e cigarette use as a smoking cessation aid among current cigarette smokers. We conducted a secondary data analysis of 562 participants in 20 residential SUD treatment programs in California who were recruited as part of three separate studies. A description of the full sample of 20 programs can be found in Guydish and colleagues . Among the participating residential SUD treatment programs, some also offered behavioral health services for individuals who had recently been released from prison or individuals who sought treatment for both SUD and mental health diagnoses. All three studies evaluated interventions designed to reduce continued tobacco use and/or use of nicotine containing prod ucts among clients in residential SUD programs. This report uses the baseline data collected during the calendar year of 2019. Research staff collected baseline data in the course of scheduled site visits at the participating programs. Eligible clients were both smokers and non-smokers enrolled in the program on the day of the site visit. All participants provided informed consent and completed the survey using an iPad with a pre-populated unique participant research identification number. Respondents received a $20 gift card for their time. The Insti tutional Review Board of the University of California, San Francis coapproved all research procedures. Demographic characteristics collected for the survey included age, gender, race/ethnicity, and education.

Race/ethnicity was categorized as Hispanic/Latino, African American/Black, White/Caucasian,grow rack systems and other or multiple races. We dichotomized education as less than or equal to high school or general equivalency diploma versus some college or more. In all three studies respondents were asked to report the reason they sought treatment. In two studies they were asked whether they sought treatment mainly for a substance use problem, for both substance use and mental health problems, or for some other problem. One study included the same item but with an added response code for mental health problems. Self-reported reason for currently seeking treatment was coded into four categories: 1) SUD; 2) mental health disorder; 3) SUD and mental health disorder; or 4) other. Respondents were asked to report the primary drug for which they sought treatment: alcohol, amphetamines/methamphetamines, marijuana/cannabis, crack/cocaine, heroin, methadone, other opiates/ analgesics, other drug, and not in treatment for any SUD. Primary drug was coded into these categories: alcohol, stimulants , cannabis, opiates , other drugs, and not in treatment for a SUD. Current cigarette smokers were participants who reported having smoked at least 100 cigarettes during their lifetime and also reported being a current smoker at the time of the survey. Current smokers re ported the number of days per week they smoked cigarettes, number of cigarettes they smoked per day , whether they had a serious quit attempt in the past year , and whether they wanted help quitting smoking . They were also asked about their attitudes toward quitting smoking by rating items on a five-point Likert scale ranging from strongly disagree to strongly agree about the extent to which they: a) had the required skills to quit smoking, b) were concerned about their smoking, and c) believed that counseling by a clinician would help them to quit smoking . The sample for this analysis comprised 332 participants who re ported current cigarette smoking. Bivariate analyses were used to compare those who had ever used e-cigarettes for smoking cessation to those who had never used e-cigarettes for smoking cessation, on de mographic variables, substance use, smoking behaviors, readiness to quit smoking, and perceptions of the harms of e-cigarettes. For the questions that asked about attitudes toward quitting smoking, we combined the strongly agree and agree categories to describe percent agreement for each item.

For the readiness to quit smoking variable, we collapsed the precontemplation and contemplation stages of change categories. We used the Student’s t-test for continuous variables and the Pearson’s chi-square test or Fisher’s exact test for categorical variables. Next, we conducted a multivariable logistic regression analysis to examine independent associations between predictor variables and the dependent variable of ever use versus never use of e-cigarettes for smoking cessation. All variables were included in the model if they were significant at a p ≤ 0.10 in the bivariate comparisons .The generalized estimating equation methodwas applied for correlated data. SAS software was used to conduct all analyses . In this study of clients in residential SUD treatment, almost half of current cigarette smokers had ever used e-cigarettes to quit smoking. Results of the multivariable logistic regression showed that smokers who sought treatment for both a SUD and mental health dis order were more than twice as likely to have ever used e-cigarettes as asmoking cessation aid compared to those who sought treatment for an SUD alone. Our finding is consistent with other studies that have found higher rates of e-cigarette ever use among individuals with versus without a mental health disorder . Current smokers who have a mental health disorder may perceive e-cigarettes as an alternate nicotine option compared to traditional to bacco cigarettes. For example, a national survey of US adults found that current smokers with as compared to those without a mental health disorder reported thinking more about the health benefits of using electronic nicotine delivery devices , and a study of chronic smokers with serious mental illness and history of failed treatment-facilitated quit attempts who were provided with e-cigarettes for 4 weeks found high ratings of enjoyment, satisfaction, and willingness to buy e-cigarettes . It is also possible that individuals with mental health disorders may be using e-cigarettes to self-medicate psy chiatric symptoms or to alleviate the side effects of psychiatric medi cations. A qualitative study of social media posts that examined the use of e-cigarettes among people with mental illness found that vapers used e-cigarettes to alleviate stress and psychiatric symptoms such as anxiety, depression, intrusive thoughts, and to offset the side effects of prescribed psychotropic medications . Other noteworthy results included that current cigarette smokers who perceived that e-cigarettes were not as harmful or equally as harmful as tobacco cigarettes were more likely to have ever used e cigarettes as a smoking cessation aid. The finding that some current smokers perceived e-cigarettes to be as harmful as tobacco cigarettes yet used them to quit smoking may appear counterintuitive.

However, a possible explanation for this finding may be that beyond perceived risk, having more positive affect toward e-cigarettes may have motivated its use for quitting smoking. In a nationally representative sample of US adults who were aware of e-cigarettes, Popova and colleagues found that images related to risk and disgust were frequently associated with cigarettes ,rolling flood tables but were less common for e-cigarettes . Moreover, they found that lower perceived risks of using e-cigarettes daily was associ ated with having more positive affect toward e-cigarettes, which in turn was associated with a higher likelihood of being a current e-cigarette user. Thus, in weighing the risks and benefits, a favorable attitude to ward e-cigarettes may influence cigarette smokers’ decision-making about whether to use e-cigarettes for quitting smoking. Our finding that younger cigarette smokers were more likely to use e cigarettes for smoking cessation is consistent with previous studies conducted with individuals receiving SUD treatment that have found younger age to be associated with ever using e-cigarettes . Although our findings for education and race/ ethnicity have wide confidence intervals, these findings are consistent with results of recent population studies demonstrating a greater reach of e-cigarette use among older adolescents and younger adults, those with higher education attainment, and people of White ethnicity . Future research among patients in SUD treatment focusing specifically on e-cigarette users to examine the sociodemographic and substance use characteristics of those who have successfully quit smoking would be helpful inmonitoring potential disparities in smoking cessation outcomes . Dual use of e-cigarettes and tobacco cigarettes was higher than what has been documented among some other samples of individuals with SUDs . Dual use of e-cigarettes and tobacco cigarettes among vulnerable populations such as those with SUDs and mental illness has raised concerns about the potential of e-cigarettes to maintain nicotine dependence . Dual users have higher exposure to nicotine and tobacco-related toxicants , and an increased risk for the adverse health effects asso ciated with the combined use of these products as compared with smoking alone . Moreover, users of nicotine delivery systems including e-cigarettes who also use other tobacco products are less likely to discontinue all tobacco use as compared with exclusive users of electronic nicotine delivery systems . A recent randomized clinical trial that compared the effectiveness of e cigarettes and nicotine replacement therapy , including product combinations for smoking cessation found that the 1-year abstinence rate was 18.0% in the e-cigarette group, as compared with 9.9% in the NRT group . However, among participants with 1- year abstinence, those in the e-cigarette group were more likely than those in the NRT group to use their assigned product at the 1 year follow up . Given the high prevalence of dual use of e-cigarettes and tobacco cigarettes among SUD treatment patients, it is critical for clinicians to ask patients not only about cigarette smoking but about all tobacco product use . Counseling messages for patients in SUD treatment programs should also include information about the potential harms of the dual use e-cigarettes and tobacco cigarettes and use of other tobacco products, and evidence of the effectiveness of FDA-approved smoking cessation medications that have proven effective in helping individuals quit smoking, particularly when used in combination with behavioral counseling . Limitations of the study should be noted.

The present study consisted mostly of men recruited from residential SUD treatment programs in a single state potentially limiting the generalizability of our findings to smokers living in other geographic regions of the country. However, our findings are similar to other studies of clients receiving SUD treatment , increasing our confidence that use of e-cigarettes is common in this population, and is viewed by SUD clients as an acceptable method for quitting smoking. Our study examined self-reported mental health sta tus, and did not examine differences in prevalence of e-cigarette use for smoking cessation across psychiatric diagnoses, because psychiatric di agnoses were not collected for all participants. Inaccurate medication reconciliation is the source of many medication-related misadventures leading to hospital admissions and patient morbidity and mortality.1 In randomized controlled studies, pharmacist-led discharge medication reconciliation interventions result in hospital cost avoidance and improve patient safety.1 Valproic acid is an antiepileptic medication commonly used to treat seizures, bipolar disorder, and migraine headache.2 Its mechanism of action includes sodium channel inhibition, T-type calcium channel inhibition, suppression of glutamate, and inhibition of γ-aminobutyric acid metabolism. VPA is available in a variety of dosage forms, and peak plasma concentrations are achieved rapidly .3 With toxic ingestions, absorption and subsequent peak may be delayed; one case report reported peak serum levels 17 hours post ingestion.4 Therapeutic concentrations of VPA range from 50 to 100 µg/L, and it is 80–90% plasma protein bound.3 Elimination occurs via first-order kinetics with a half-life of 5-20 hours; however, this can be prolonged up to 30 hours with toxicity.3 At toxic levels, VPA can cause central nervous system depression, respiratory depression, acute kidney injury, anion-gap metabolic acidosis, and electrolyte abnormalities . VPA is also associated with hepatotoxicity, pancreatitis, hyperammonemic encephalopathy, cerebral edema, and blood dyscrasias such as leukopenia, anemia, and thrombocytopenia. Treatment of VPA toxicity is largely supportive; however, it can include enhanced elimination methods such as charcoal hemoperfusion and hemodialysis . HD is known to clear toxins that are water soluble, have low volume of distribution, and are not highly bound to plasma proteins.

The 4 mini-drinks allowed participants to consume up to 0.04 g/dl alcohol in total, and were individualized by participant gender, weight, height, and alcohol content. Participants were also told that they would receive 1 dollar for each drink remaining at the end of the session. At the end of the session, participants were provided a meal and required to stay at the testing center until their BrAC dropped below 0.02 g/dl or to 0.00 g/dl if driving. For the taste cues paradigm, information regarding image acquisition parameters and preprocessing steps are available in Supplementary Materials and are derived from the primary manuscript . The main contrast of interest was the difference in activation corresponding to alcohol taste delivery and water delivery across the two task runs , for each within-subject medication condition. Consistent with previous studies examining relationships among ventral striatum activity, subjective response to alcohol, and drinking behavior , an anatomical bilateral ventral striatum region of interest was defined using the Harvard-Oxford atlas in standard MNI space and was transformed into participants’ respective native space using FSL’s FLIRT . This ROI was selected because ventral striatum is most consistently elicited in alcohol cue and taste reactivity paradigms, as well as most frequently associated with behavioral measures and treatment response . ROI selection was limited to one due to insufficient power to detect incremental model improvement with multiple ROIs. The mean contrast estimate values were extracted from this region for each subject and used in mixed models for group-level analysis . The self-administration paradigm yielded two outcome measures: latency to first drink , and total number of drinks consumed during the session . To examine the relationship between alcohol taste-induced neural activation and self-administration, multilevel mixed poisson and cox proportional hazard models were the primary analyses for total number of drinks and latency to first drink, pot drying respectively. Frailty models were fitted using a penalized partial likelihood approach available in SAS 9.4 .

Primary analyses examined effects of variables of interest, including medication condition , alcohol consumption , and OPRM1. Due to concerns of over parameterization given the limited sample size, additional covariates of interest medication randomization order, gender, alcohol abstinence days prior to scan, smoking status, consumption of preferred alcohol choice in scanner were individually included in separate models to determine whether main effects of ventral striatum would be altered. Alpha corrections were not utilized in this exploratory study due to limited sample size and constrained power. Tests of proportional hazards are included in Supplementary Materials and Figures S1a-S1d. Survival plots for latency to first drink, controlling for covariates within the final model , were generated to further explore ventral striatum activation in predicting latency to first drink. Of note, a dichotomous median-split ventral striatum variable was created for ease of visualization of these relationships, but ventral striatum activation was included as a continuous variable in all models. Characteristics for the final sample of 41 participants who completed both fMRI and self administration tasks are presented in Table 1. Study participants were, on average, younger adult heavy drinkers of Chinese or Korean descent, and a minority reported recent cigarette smoking and/or cannabis use. Fisher’s exact tests tested the association between medication condition and 24 possible side effects as indicated by the SAFTEE checklist . These tests indicated a significant association between medication and nausea , such that 20% of individuals on naltrexone and 0% of individuals on placebo reported experiencing nausea. Similarly, there was a significant association between medication and fatigue , such that 25% of individuals on naltrexone and 0% of individuals on placebo reported experiencing fatigue. There were no other significant associations among the remaining 22 side effects and medication. Ventral striatum activation and self-administration outcomes are also presented in Table 1 by medication condition. Of note, the two primary manuscripts from which this data is derived did not identify significant effects of naltrexone on ventral striatum activation or self administration outcomes . Ventral striatum activation demonstrated moderate reliability and are consistent with other studies examining striatum in fMRI . The distribution of latencies to first drink was non-normal. Across medication conditions, 52% of individuals refrained from drinking throughout the paradigm, 29% consumed a drink within the first three minutes of the paradigm, and 19% of individuals consumed their first drink at some point during the remainder of the session.Other covariates of interest were not associated with latency to first drink .

This study examined the relationship between alcohol cue-induced ventral striatum activation and alcohol self-administration in the laboratory. Results from this heavy-drinking sample of East Asians indicated that higher ventral striatum activation was associated with a shorter latency to first self-administered drink. Similarly, ventral striatum activation was positively associated with the total number of drinks consumed during the self-administration paradigm in this sample. These results remained significant after controlling for severity of drinking patterns, OPRM1, and medication condition. Overall, this is the first study to examine whether neuroimaging outcomes of interest can predict responses within laboratory paradigms commonly used in the alcohol literature. This foundational work adds important validity to the hypothesized interplay between neural bases of alcohol craving and behavioral measures of alcohol seeking, namely alcohol self-administration in the human laboratory. These associations contribute to a growing literature on the translational value of neuroimaging paradigms in alcohol treatment, particularly in elucidating potential mechanisms through which self-administration paradigms in AUD research are related to real world alcohol consumption . Such work is aligned with current efforts in behavioral treatments utilizing neuroimaging to study mechanisms of behavior change for substance use disorders; identifying those individuals with severe orbitofrontal cortex deficits, for instance, may be useful in guiding them away from treatments focused on increasing the salience of future negative consequences of substance use . In a similar fashion, adjunctive fMRI has been used to train individuals with substance use disorders through resonance-based breathing to reduce visual processing of drug cues and increase activation in areas implicated in internally directed cognition . Elucidating the translational value of these various experimental paradigms is strongly indicated, as AUD medications can exhibit differential results based on the utilized paradigm e.g. alcohol challenge or self-administration; and such variability may in turn inform precision medicine efforts. Expanding the study of interexperimental paradigms may also shed light on aspects of alcohol consumption unique to individual paradigms. For instance, a greater understanding of individuals’ experiences in the transition between the first and subsequent drinks may be an important point of clinical interventions when discussing naltrexone use. While the primary aim of this study was not focused on genetic determinants of self administration, it is notable that genotypes encoding the binding potential of mu-opioid receptors were associated with self-administration outcomes.

While it is theorized that individuals with at least one copy of the G-allele for OPRM1 exhibit greater vulnerability to developing AUD, meta-analyses have been mixed, with findings that such an association may not be reliable , are population specific , or that G-allele confers a modest protective effect on general substance dependence in European ancestry cohorts . In this study, G-allele carriers of OPRM1 exhibited lower total consumption relative to A-allele carriers at a statistical trend level, as well as slower latency to first drink. This finding is consistent with the primary analyses for this data , which indicated that G-allele carriers of OPRM1 also reported less severe drinking history and lower AUDIT scores compared to Asn40 homozygotes and may, in turn,cannabis drying help to explain these findings. In sum, we accounted for genetic factors in these analyses given their theoretical and practical salience , particularly in this population . And while the genetic findings are notable and largely consistent with the literature, the primary focus on the study is on the fMRI to human laboratory association. This is the area in which the present analyses make a substantive contribution to the literature by supporting a long hypothesized, yet rarely tested, association between brain and behavior. Finally, this study identified significant effects of naltrexone in increasing latency to first drink and decreasing total alcohol consumption. Notably, while these contrast the primary study results from which the data are derived the current study is a secondary analysis of a sub-sample of participants who had completed both neuroimaging sessions. While inclusion of VS activation may have helped to improve model fit, the primary study had greater power in order to test pharmacogenetic effects. For these reasons, while it is possible that consideration of neuroimaging outcomes help elucidate AUD pharmacotherapy effects, replication using larger samples is warranted. On balance, this study should be interpreted in light of its strengths and limitations. Strengths included assessment of multiple experimental procedures used in the medication development literature and consideration of multiple psychiatric and genetic predictors of self-administration in the statistical analyses. Another strength is the test of hypothesis at the within subjects level of analysis. As argued by Curran and Bauer , several psychological processes which are inherently within-person processes, such as the relationship between how one’s brain processes alcohol cues and how much s/he wants to drink in the future, are presumed to be explained in between-subjects models, when in fact, within-subject analyses provide a more representative test of the process at hand . Thus, a within-subjects approach represents a more robust, and methodologically adequate, test of the association between brain and behavior. One of the most important limitations of the current study is a constrained sample and power; given the exploratory nature of this study, alpha corrections were not implemented. A limitation of the taste cues fMRI paradigm used in this study is that it was modified to reduce trial duration in order to increase the number of trials for analysis; in contrast to the original task , a whole-brain analysis of the task did not elicit significant clusters of mesocorticolimbic, including ventral striatum, activation.

Therefore, replication using other tasks that more strongly elicit ventral striatum activation are needed, both to induce significant enough variability to test medication effects and also to translate such effects into another subsequent experimental modality. Variations of the Monetary Incentive Delay task that administer beer may be particularly useful in disentangling whether anticipation, relative to receipt, of alcohol taste are differently discriminant in predicting self-administration Relatedly, the taste cues paradigm was limited to the choice of red or white wine, which did not always correspond with participants’ drink of choice; while this correspondence was not a significant covariate in self-administration outcomes, administering drink of choice may increase external validity of the imaging task. Another potential weakness is that medication effects from the primary manuscripts were null; future studies are needed to corroborate that medication effects are consistent across paradigms, particularly in identifying significant such effects. An additional warranted question is whether such consistency of medication effects in laboratory studies would translate directly to clinical outcomes and treatment-seeking populations. Lastly, the “priming dose” that preceded the self-administration period was higher than the usual 0.03 g/dl reported in the literature. While the higher priming dose of alcohol in this study did not suppress alcohol self-administration, it may be interpreted differently in that participants were seeking to self-administer to reach high levels of BrAC, perhaps binge-like levels. If that was the case, results would remain highly relevant and consistent with recent efforts to phenotype binge-drinking in the human laboratory . Limitations notwithstanding, the present findings provide proof-of-concept that neuroimaging and laboratory paradigms may be closely linked. Further, neuroimaging may be a useful tool to explore in greater detail how different paradigms are related to real world consumption behavior. Future studies are warranted to replicate the current results and to identify, refine, and implement translational paradigms in AUD research.

The condition has been estimated to affect *1:4000 males and 1:7000 females.Although both sexes are susceptible, males with FXS typically exhibit more severe symptoms compared with females because the single X chromosome in males is usually fully methylated and not producing FMRP6 ; females typically have some FMRP expression from the FMR1 gene on their second unaffected X chromosome.Males with FXS are far more likely than females to exhibit significant intellectual and developmental disabilities .Among individuals with the full mutation , symptoms of FXS vary by age and sex, but often include anxiety , social avoidance , stereotyped behaviors , attention-deficit/ hyperactivity disorder , autism spectrum disorders , intellectual disability , aggression , disrupted sleep patterns , and epilepsy , as well as macroorchidism , prominent ears , long faces , soft skin , and hyper extensible joints .Traditional allopathic treatment of these patients may involve medications to address issues with sleep , anxiety , hyperactivity and deficits in attention , and seizures .Yet, for many patients with FXS, the aforementioned pharmacotherapies, when used alone or in combination, have sub-optimal efficacy and tolerability,suggesting a persistent unmet medical need for novel, interventional treatment approaches for patients with FXS. Because the clinical abnormalities in these patients have been linked, at least in part, with dysregulation of the endocannabinoid system, we briefly review recent research characterizing the involvement of the endocannabinoid system in FXS and present the cases of three individuals with FXS who experienced functional benefit after treatment with cannabidiol – enriched preparations.The endocannabinoid system consists of receptors in the brain and peripheral tissues that are involved in numerous physiological processes as well as the endocannabinoids, N-arachidonoylethanolamine and 2-arachidonoylglycerol . The endocannabinoids bind to the G-protein-coupled receptors, cannabinoid 1 and 2 ,and modulate synaptic transmission throughout the central nervous system.Receptors are distributed throughout the body, with CB1 receptors abundantly expressed in the brain and present at lower concentrations in a variety of peripheral tissues and cells and CB2 receptors expressed primarily in the immune and hematopoietic systems, as well as in the brain, pancreas, and bone.CBD, the primary, noneuphoric exogenous phytocannabinoid in cannabis, may attenuate the loss of endogenous cannabinoid signaling observed in preclinical models of FXS, allowing a component of the FMRP deficiency inherent in FXS to be bypassed. Specifically, many abnormalities seen in FXS appear to be rooted in dysregulation of the endocannabinoid pathways in the central nervous system, with a reduction of endogenous stimulation of endocannabinoid receptors.CBD has the capacity to interact with an FXS-compromised endocannabinoid system. Indeed, deletion of FMRP within a mouse model of FXS led to reduced production of 2-AG, decreasing activation of CB1 receptors in the central nervous system.CBD has been shown to increase 2-AG availability,cannabis square pot potentially attenuating or reversing one of the biological mechanisms of abnormal cellular function in FXS.

Importantly, CB1 protein expression appears unaffected in FMR1 knockout mice, suggesting that the downstream elements of endocannabinoid signaling can be engaged, even in the absence of FMRP.In addition to the role of 2-AG, recent work has begun to highlight the potential importance of AEA in addressing social impairment as well as deficits in learning and memory among those with FXS. In an FMR1 KO mouse model of FXS, Qin et al. demonstrated that increased levels of AEA were associated with greater cognitive performance.Similarly, Wei et al. utilized mouse models of FXS to show that AEA-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward and that increasing AEA activity resulted in reductions in social impairment.Much like its impact on 2-AG, CBD has been shown to increase levels of AEA by binding to fatty acid-binding proteins, which transport AEA to the catabolic enzyme fatty acid amide hydrolase, an enzyme that breaks down AEA.Binding to fatty acidbinding proteins is thought to increase AEA availability and CB1 activation.The mechanisms underlying the potential benefits of CBD for FXS span far beyond the endocannabinoid system. Beyond providing benefit to patients with FXS through increases in 2-AG and AEA availability, CBD may positively affect synaptic plasticity. Studies of FMR1 KO mice have identified discrete alterations in synaptic plasticity in specific brain regions, including an increase in long-term depression in the hippocampus,and preclinical data suggest that reducing LTD in FMR1 KO mice requires activation of endocannabinoid receptors.Therefore, it is hypothesized that CBD may increase synaptic plasticity in FXS, facilitating one of the basic cellular mechanisms thought to be associated with learning and improvements in cognition.More recent work has also begun to identify deficits in GABA receptor expression among those with FXS. As FMRP has been shown in animal models to enhance expression of GABA receptors, the lack of FMRP among those with FXS has been associated with fewer GABA receptors.Indeed, preclinical studies in FMR1 KO mice have consistently shown down regulation of the GABA system.As CBD acts as a positive allosteric modulator of GABA-A receptors,CBD may also act to enhance the binding affinity for GABA. The impact of CBD on serotonin represents a mechanism by which CBD may aid in reduction of social anxiety and resulting avoidance experienced by patients with FXS. Indeed, the anxiolytic effects of CBD have been reported in over 30 preclinical studies, using multiple models of anxiety ,as well as in a growing number of human studies, including within-social anxiety.Several preclinical studies have identified the serotonin 1A receptor as one mechanism through which CBD exerts its anxiolytic effects.He was born full-term following an uncomplicated pregnancy and delivery at seven pounds six ounces. In the newborn period, he began having problems latching for breastfeeding, and he was fed pumped breast milk and formula from a bottle; he had frequent gagging and spitting up.

By 6 months of age, with introduction of soft baby foods, he was often dysphagic, choked easily, and was intolerant of chunky or textured foods. Testing for food allergies was negative, and his formula was changed multiple times over his first year of life. He grew slowly at the third to fifth percentile for weight and the 50th percentile for length until 15 months of age. He was also hypotonic with delays in gross motor skills. He had behavioral concerns, including atypical motor movements, frequent repetitive moving, stiffening and shaking of his legs, body rocking, and repetitive finger stereotypies while touching his ears. He displayed difficulty adjusting to new or noisy places and changes in routine,trim tray as well as trouble making eye contact and a short attention span during play and in social interactions; he would sometimes stare off and seem disconnected for 10 to 30 sec. At 15 months of age, he was evaluated and underwent a brain magnetic resonance imaging , electroencephalography , creatine kinase, plasma amino acids, and thyroid and genetic testing. His MRI, EEG, microarray, and laboratory parameters were normal. His FXS DNA test results showed a full mutation for FXS with 260 to 650 fully methylated CGG repeats. At this time, the patient’s parents independently obtained and began administering an oral paste comprising 18% to 23.5% CBD and trace amounts of delta-9-tetrahydrocannabinol that delivered 50 mg of CBD per day . They combined the CBD paste with coconut oil, heated the mixture until it liquefied, and then used a syringe to administer the liquid preparation orally. During the first month of CBD+ treatment, the family noticed behavioral improvements. After 1 month of CBD+ monotherapy, the then 16- month-old patient began specialized care in the form of speech and language therapy and occupational therapy for FXS. Over the next 3 months of daily 50-mg CBD+ treatment with adjunctive therapy, the family noted continued improvements in a wide range of clinical parameters. Feeding improved markedly with increased willingness to eat solid foods and increased intake overall. His parents also noted improvements in motor coordination, more frequent vocalizations, less rocking and kicking during feeds, more frequent and longer eye contact, an increase in positive interactions with other children, greater willingness to explore new places, and less self-stimulatory behavior. Many of the parental observations were also confirmed by the patient’s occupational and speech therapists, some of whom were unaware of the initiation of CBD+ treatment.

At the 4-month follow-up visit, the patient’s weight had increased to the 15th percentile, while his length remained at the 50th percentile. Developmental progress included improved fine and gross motor skills, decreased repetitive rocking, improved social interest/ engagement, improved vocalizations, and decreased hyperactivity. The patient began a regimen of sertraline due to preliminary evidence of improved language and development in young children with FXS treated with sertraline.Subsequent follow-up visits showed continued improvement in language and developmental skills. The patient started walking and self-feeding independently, exhibited more frequent and varied vocalizations, fewer repetitive and motor behaviors, fewer sensory sensitivities , and more frequent initiation of joint attention with pointing. Weight increased to the 25th percentile. He continued using CBD+ solution and remained in a strong early intervention program: 1 h per week of occupational, speech, and physical therapy; 6 h per week of Early Start Denver Model behavioral therapy and applied behavioral analysis. When the patient was 30 months of age, his parents chose to discontinue CBD+ treatment to instead explore minocycline, shown to improve behavioral symptoms in some patients with FXS.The initiation of 25 mg per day of minocycline coupled with cessation of CBD+ treatment resulted in increased anxiety, more frequent meltdowns, and more difficulty falling and maintaining sleep. During a clinic visit when the patient was 3 years of age, it was noted that the patient continued to engage and make slow progress, although anxiety, frequent meltdowns, and difficulties with sleep persisted, and increasing challenges with transitions and attention span were observed. The patient’s medical treatments included a daily regimen of 4 mg of sertraline and 25 mg of minocycline. He also continued to receive intensive early intervention services . At 3 years of age, an updated adaptive behavior assessment was obtained . After discussion with his family and medical team, the patient was restarted on CBD+ treatment, 50 mg per day. Following reinitiation of CBD+ treatment, his parents noted reductions in anxiety, fewer meltdowns, and improvements in his ability to fall and stay asleep. The patient has now transitioned into a small preschool where he is continuing to do well and has remained on his CBD+ treatment.Patient 2 is a 26-year-old male with full-mutation FXS and an IQ score in the mid-50s. Despite a medication regimen that included 60 mg of methylphenidate hydrochloride , 2.5 mg of aripiprazole, 100 mg of sertraline, 200 mg of minocycline, and 0.2 mg of clonidine , the patient experienced significant symptoms of attention-deficit/ hyperactivity disorder, including hyperactivity, inattention, and impulsivity. He also suffered from anxiety, which led to avoidant behavior and sleep disturbances, and some significant features of autism, including social avoidance, poor eye contact, perseverative behavior, hand stereotypies, and tactile defensiveness. Due to ongoing symptomatology, the patient began taking a liquid preparation containing 63.9% CBD, 4% cannabichromene, 3.4% THC, and 0.7% phenylbiguanide, delivered orally by a 1-mL syringe. The patient’s parents obtained the solution independent of their physician. Between 0.05 and 0.1 mL of the oral solution was delivered in the morning, once per day for 6 weeks, during which time other therapies remained unchanged. During the  first week of treatment with the CBD+ solution, the patient’s family noticed that his anxiety level was reduced and he was able to explore and participate in more activities with less social avoidance. His facility with language increased, as shown by greater capacity to engage in longer more meaningful conversations. The quality and duration of his sleep also improved; he no longer awoke and wandered in the middle of the night. His symptoms of anxiety and linguistic skills continued to improve over the 6-week course of treatment with the CBD+ solution. His parents have continued him on a stable dose of 0.1 mL daily now for 2 years and have observed sustained symptom improvement.Patient 3 is a 22-year-old female who was diagnosed with FXS at 9 years of age with a full mutation of >200 CGG repeats. She met all of her early milestones appropriately, but at around 3 to 4 years of age, she developed quite significant anxiety and panic attacks.

Decisions regarding the portion of youth participants tested for recent SU is informed by national estimates of prevalence of use . Youth must be naïve to alcohol and recreational drugs at in-person study enrollment, while prescription drug use is permitted in youth participants at the initial baseline visit . Bio-specimens addressing recent, past 3-month and lifetime SU exposures are assessed. Tests of recent drug use will provide the opportunity to evaluate the reliability of self-reports of current drug use. Given potential alcohol or drug effects on test results , youth participants testing positive for recent drug exposure at any follow-up onsite visit, will be asked to reschedule, and to return for testing on another date, drug and alcohol free. Youth reporting a history of non-prescription drug use, or participants suspected of substance intoxication, once they arrive to the lab for study assessments, will be tested for recent drug use, even if they have not been selected randomly for testing before their arrival. Because the effects of drug exposure and misuse of prescribed drugs on brain and cognitive development in youth is a primary focus of the ABCD Study, a reported history of use is not exclusionary at follow-up annual visits, and the assessment of past 3-month and lifetime SU exposures are of high value. The ABCD research team is in the process of developing protocols for future bio-specimen collection, but, have not yet formalized additional bio-specimens. Given the protocol for future onsite visits beyond 1-year follow-up remains undetermined, it is not included in this report.Oral fluid will be collected for toxicology testing of 7 drugs. In follow-up years, urine will be collected and tested at the beginning of each onsite visit, supplemented by breathalyzer testing for a random selection of subjects, to rule out recent non-prescription drug, nicotine, and alcohol use prior to neurocognitive assessment. Onsite drug testing will be completed for alcohol use and a broad range of commonly used substances at 1-year follow-up. At baseline, a positive drug test is exclusionary for initial enrollment into ABCD, as are self or parent/guardian report of youth ingestion of more than 1 whole drink,cannabis grow racks more than one whole cigarette or the equivalent amount of another tobacco product, any marijuana, or misuse of any drug .

Hair samples will be collected from youth subjects during each annual onsite visit for future confirmation of the presence or absence of SU. Hair provides an extended window of drug metabolite detection , and therefore can help confirm drug use despite irregular and/or infrequent drug ingestion. While not without some disadvantages , hair is relatively easy to handle and store, less susceptible to adulterants, and provides longer detection times compared to other biological matrices that have shorter detection windows . By banking hair samples for future testing, results can be used in combination with oral fluid and self-report to ensure that a ‘clean’ baseline is confirmed. This is especially important for the sub-sample of individuals who escalate to substantial levels of drug use by an early age , as these individuals will provide the most crucial test for neurocognitive and brain structure/function differences predating their escalation, or emerging after that escalation.Oral fluid will be collected for toxicology testing using a Draeger 5000 Drug Test Unit, which provides a qualitative test for 7 drugs. Oral fluid drug screening has advantages over conventional methods including reduced biohazard generation, ease of collection, and less susceptibility to adulteration . Oral fluid concentrations are also more tightly correlated to blood than urine concentrations allowing inferences of impairment and flexible detection windows. The Dräger Drug Test 5000 screening device is used to test oral fluid at baseline and each follow-up year to identify recent use of amphetamine, benzodiazepines, cannabis , methamphetamine, cocaine, methadone, and 3,4-methylenedioxymethamphetamine. The Draeger unit was selected over other on-site testing devices because of the high sensitivity for THC, one of the most common substances of abuse. The Draeger provides a lower THC cut-off concentration compared to other testing devices and therefore higher sensitivity and detection accuracy. The Dräger Drug Test 5000 is increasingly utilized for roadside testing . The Dräger system consists of an analyzer, test cassette oral fluid collector, and buffer cartridge. To perform a screening test, the participant refrains from eating or drinking for 10 min.

The test cassette contains a cellulose pad that is moved from one side of the mouth to the other for approximately one minute until the volume adequacy indicator turns blue to confirm a sufficient volume. The sample is then inserted into the Dräger analyzer with 3 mL buffer for drug stabilization. All drug results are displayed on the analyzer device within 5–8 min as “positive” or “negative.” The test is repeated for cases in which the results are unexpected based on self-report and/or clinical observation; repeat test results, and whether results are in-line with self-report and clinical observation are coded. Oral fluid drug testing can be influenced by several factors, including frequency of SU, body fat, and method of ingestion, however work by Huestis and colleagues suggest that 5 ng/mL concentration cut-off provides high diagnostic sensitivity, specificity, and efficiency for oral fluid cannabinoid detection .In addition to the screening measures for SU at the time of lab visits, the ABCD consortium is also collecting hair samples from all participants at each on-site lab visit for a wider detection window to provide longer-term information on history of drug consumption. Approximately 10 percent of participants will have hair analysis conducted at baseline, as the cost would be prohibitive to analyze every sample at every time-point. However, all hair samples are archived for each participant at each site, and future analyses can be done on hair samples for participants who endorse drug use as it becomes more prevalent as the ABCD cohort progresses through adolescence. Participants are instructed that we will cut a sample that is ½ inch wide by two strands deep from the back of the head below the crown. After collection, the sample is placed in foil tightly and sent to Psychemedics. Gas chromatographymass spectrometry and liquid chromatography-mass spectrometry procedures are used to test for the following parent drugs and metabolites: alcohol ethyl glucurolide , cannabis (11-Nor-9-carboxy-THC and cannabidiol , methamphetamine and methylenedioxy-methamphetamine , amphetamine, opiates , and cocaine/benzoylecgonine . Commonly used hair procedures do not impact quantitative results, and samples are relatively easy to collect and store compared to other biological matrices.

Limitations include hair that is too short . This is particularly a challenge in testing pre-pubertal children, where hair on other parts of the body are less available than in older youth and young adults.A hallmark of adolescence is reproductive maturation, known as puberty. Puberty heralds the onset of adolescence, and the hormonal surges that occur during this period of time impact the ‘environment’ of the developing brain. Pubertal maturation influences trajectories of, and sex differences in, brain development and behavior , including SU during adolescence . While much has been discovered in the last decade about the impact of pubertal hormones on adolescent brain and cognitive development (for a review, see , much is yet to be learned, particularly in connection with resilience or risk for SU during adolescence, and related mental health problems. To the best of our knowledge, the ABCD study is the largest most comprehensive study collecting pubertal hormone data longitudinally across adolescence,cannabis grow system and the ability to connect them to brain development, cognition, behavior, genetics and SU. Differences in onset of pubertal timing and maturation, and associations with SU and mental health vary as a function of sex, race and region . Thus, investigating these important hormone associations with neuro development across the United States in a representative sample, both racially and regionally, is essential. Important to the ABCD project, behavioral risk factors begin to emerge during pubertal onset and do so in a sex-specific fashion, with an increased prevalence of SU and externalizing disorders in boys compared to girls . Adolescence is a period of prolonged sensitivity to environmental factors, when the maturing central nervous system is particularly sensitive to insult . How SU impacts the relationships between pubertal onset, mental health, and neuro development remain unclear, and is therefore an objective of the ABCD Study. DHEA, testosterone and estradiol is being assessed each year spanning across both pre- and well past post- pubertal stages of development. It is important to note that pubertal maturation is assessed independently of gonadal hormone measures , and is a key interacting factor for understanding relationships between hormone levels, brain development and SU.Pubertal hormones are assessed in participating adolescents through the collection of a single salivary bio-specimen each year throughout the 10-year duration of ABCD.

This method provides a quick, accurate and reliable method for measuring numerous key gonadal hormones from a single sample. The source of pubertal hormones found in saliva come from several glands in or near the mouth . Compared to collecting blood, the non-invasive nature of the salivary method requires less training for the administer, and eliminates the need for coordination with a phlebotomist. Saliva contains lower levels of pubertal hormones compared to levels found in blood, yet saliva levels are highly correlated with the free blood serum levels that typically exert biophysiological effects .Like serum hormone levels, salivary hormone levels exhibit circadian patterns, making participant waking time , and time of day of saliva collection important variables for statistical analyses and interpretation of results. Oral hygiene, injury resulting in bleeding or inflammation, and food particles can alter levels of hormones in the sample, and/or interfere with accuracy of the assays to assess hormone levels. To adjust for these confounds, notes on the color of the sample should be taken into consideration when running statistical analyses with salivary hormone data . The amount of time it takes a participant to produce a saliva sample can influence the concentrations of hormone levels. The duration of collection time can be impacted by the flow rate of saliva production, which may vary as a function of certain medications, making duration of sample collection an important factor to consider for analyses and interpretation of results. The average sample collection time for the ABCD cohort of 9–10 year olds is approximately 5.25 min . For girls, additional fluctuations in gonadal hormones occurring across the menstrual cycle are captured by collecting key factors, such as: age of onset of menstruation, type of contraceptives used, regular or irregular cycles, length of cycles, and date of last menstrual cycle. Given the cyclic nature of estradiol, factors relating to menstruation are key for understanding possible decreases in estradiol levels across years.Researchers examining ABCD hormone data should be aware that approximately 4% of the currently existing hormone data is affected by some type of experimental error. Many of these errors can be found within the ABCD data set under the research associates’ notes, or become obvious upon close inspection of the data entered relating to factors described in above sections. Bacterial growth in the saliva sample is blocked upon freezing of the sample. However, logistical challenges can sometimes prevent immediate freezing . Errors in data entry occur. As can be seen in Fig. 3, some participants are listed as waking up after 15:00 ; however participants typically arrive much earlier in the day for testing/scanning, making this a data entry error. All saliva samples are stored at −20 to −80 °C before shipping on dry ice for analyses. The deep freezers are subject to malfunctioning ; thus notes about samples thawing, which can significantly impact hormone levels, need to be considered. Upon receipt of frozen samples shipped from each ABCD site, Salimetrics completes all notes on sample quality and thawing, conducts assays, and the initial data entry of hormone levels. Samples are run in replicates, and key details of each hormone assay can be found on their website . Given the sheer quantity, saliva samples shipped from each site every 2 months, and subsequently analyzed in batches at Salimetrics; thus initial assessment for possible batch effects should be conducted before moving on with further analyses within a selected ABCD sub-sample.Genetics plays a crucial role in personality traits , psychiatric illness, including substance abuse disorders.

The COI 2.0 is a national contemporary measure of neighborhood opportunity, comprising a comprehensive dataset that aggregates 29 indicators of neighborhood conditions for 72,000 census tracts in the United States. Beginning with the ABCD 4.0 data release, the ABCD Study provides scores for the COI 2.0 overall index, and the three domain indices that comprise the overall index: education , health and environment , and social and economic opportunities.Detailed documentation describing the indicators that comprise each of the domains as well as the dataset source and year for each of the 29 indicators can be found in Supplemental Table 4 and the COI 2.0 technical documentation . Given the diverse demographics of the ABCD Study participants, linking the COI 2.0 gives us objective measures of neighborhood opportunities for participants so that we can assess the influence of neighborhood quality on adolescent health and potential emerging health disparities. Crime rates are an important neighborhood characteristic that can cause distress on individuals’ mental well-being and has been linked with various children’s developmental outcomes . However, the impact of crime within the context of other neighborhood variables and how these impact neural mechanisms during children’s development is less clear. To empower researchers to investigate the impact of local crime rates in the broader context of the built environment, we obtained county-level crime statistics from Uniform Crime Reporting Data . In addition to the total crime rates, we also provided subcategories of the crime, including violent crimes, drug violations, drug sales, cannabis grow racks sales, drug possessions, and DUIs.

The LED Environment Working Group strives to include additional information about the built and natural environments of all participants in the ABCD Study. These data provide an additional perspective about differences both between study sites and individual differences among children within even a single given study site location. Integrating these external environmental factors are likely important in considering both mediating and moderating effects and allows for important questions to be asked with implications for policies that may help ensure all children can thrive. That is, given the wealth of additional data collected in the ABCD Study, the addition of understanding the built and natural environment in ABCD provides the opportunity to think more broadly about how these factors may influence neuro development of children within the established social determinants of health framework of public health . Specifically, health outcomes, including neuro development, cognition, and mental health as measured extensively by the ABCD Study, have been recognized to be influenced by complex interactions among environmental, social, and economic factors that are ultimately closely tied to one another . Dahlgren and Whitehead provided a visual representation of such complex processes as a model of the main determinants of health and well-being in public health, which has since helped shape public health policy at both national and global scales . Thus, capturing the broader physical environment makes the ABCD Study an ideal resource for researchers interested in studying how various distal and proximal factors may impact developing children and their health. While a number of development cognitive research studies have focused on individual factors, including socio-demographic factors , lifestyle , and social environments , additional natural and built environmental factors including neighborhood quality, community-level access to resources and opportunities, and exposure to harmful substances, provides an additional layer as to understanding and identifying key factors of neuro development and to promote policies that lead to better health outcomes for all children across America.

Specifically, these data can allow for researchers to examine if upstream built and natural factors might account for and/or moderate associations between physical activity and brain development, understanding the link between screen-time and mental health, determining how neighborhood conditions may impact the formation of peer groups, or exploring how recreational activities may moderate the relationship between adverse neighborhood conditions and mental health. In doing so, not only may we have a better understanding of the complex associations between the various factors contributing to neuro development across childhood and adolescence, but research findings may also point to possible public health targets for intervention and treatment. While there are clear strengths in mapping the environmental context of today’s youth in the ABCD Study, there are also several important technical limitations as well as considerations for researchers planning to use and interpret these data. A vital consideration to this type of geospatial research and the variables derived from it, is the accuracy of the assignment of the exposure assessment at any given time. Several challenges arise in trying to maximize this accuracy. Any given geospatial database has both a spatial and temporal component. How these data were derived, and the degree of resolution is important to consider. For example, census tracts can be rather large, whereas in urban areas drastic differences in the environment can sometimes be noted to vary from street to street. Furthermore, individuals who live in the same census tract should not be considered to have the same experiences or the same amount of exposure in the neighborhood as others with similar demographics. Moreover, many times, geospatial databases are compiled after data is available from other sources, such as the American Community Survey or the Environmental Protection Agency. Thus, exposure estimates can often reflect a snapshot in time that may or may not overlap directly with the time period that the child was at that residential location; requiring the researcher to consider if the exposure of interest can or cannot be assumed to be stable beyond the temporal domains of the dataset.

For example, many databases may create variables using 5-year averages that have then been linked to the baseline residential addresses which were collected in 2016–2018. Another technical challenge is that retrospective address collection is hindered by recall bias, or the differences in the accuracy or completeness of caregivers in the ABCD Study to recall address details over the 9–10 years prior to study enrollment. In addition, exposure assessment based on residential geospatial location also fails to capture individual data on percentage of time in which children in the current study spend time at their primary address versus other daily activities and/or various locations, such as in school. Of course, it is important to note that misclassification of exposure may be lower for children in that they may spend more of their time around the home, as compared to other populations such as adults who may spend more time commuting, time at work, or so forth. Although children do spend a substantial period of time at school, which may or may not be in a similar geographical location to that of their primary residence. Lastly, there is not a direct correlation between external environmental exposures to chemicals and internal exposure doses. For some environmental toxins, internal biomarkers exist to determine internal dose , whereas others, like air pollution, do not. Nonetheless, these geospatial factors can lead to misclassification, or information bias, which can severely affect observed associations between the exposure and the outcome. Therefore, given these limitations, it is important to note that while the current LED Environment measures may help provide a snapshot as to the built and natural environment surrounding ABCD participants’ residential homes, the current data fall short of fully characterizing participant exposomes. Thus, while continued efforts by the LED Environment Working Group aim to mitigate these challenges, findings should be interpreted considering these potential pitfalls, and misclassification should be acknowledged and discussed when necessary. Another potential challenge for researchers using these data is conceptual and/or statistical collinearity and potential confounders. Environmental variables included from various databases can greatly overlap in terms of theoretical construct. For example, various factors may represent broad constructs of economic advantage, and many variables from the same databases may be highly collinear. It is also important to note that although some estimates may draw from similar linked databases , they may implement any number of transformations or operations when computing measures. In addition to considering the exposure of interest from these data, a number of spatial contextual variables may also be important to consider as source of confounding. For example, ecological variables,cannabis grow system such as air pollution, may be an important spatial confounder in examining associations between neighborhood socioeconomic factors and child health outcomes in ABCD. Some models of exposures may also include other important geospatial or socioeconomic factors in establishing estimates of exposure, such as temperature and humidity in estimating ambient air pollution, or age of housing in compiling a metric for lead risk. Therefore, it is vital in the early stages of planning analyses with these data to consider the choice of which variables to use for a given construct, identifying potential ecological or spatial confounders, and understanding the raw datasets that were utilized in calculating various environmental and societal variables included in the ABCD Study. Additional sensitivity analyses should always be considered to evaluate the impact of potential confounds and the specificity of the tested environments.

Lastly, researchers should note that the environmental estimates do not represent the ‘lived’ or subjective experience of these exposures, with careful consideration given to the potential interpretation of any effects seen between these variables and brain and cognitive outcomes of interest. For example, these data are derived from outside databases that may capture an objective perspective of a given geospatial location, as they do not rely on the subjective report of the participants. However, these objective constructs do not necessarily reflect any individual’s subjective experience in a given state, census tract, or even residential neighborhood. It is likely that subjective experiences may moderate or mediate associations of external estimates of exposures. Further, neighborhood socioeconomic factors, environmental exposures, and potential health and behavioral outcomes should also be considered in light of local, state, and federal policies of racism, segregation, and inequality that has resulted in persistent inequalities in social, economic, and educational opportunities . For these reasons, socioeconomic and other family-level factors are likely to also be highly correlated to various built and natural exposure variables. Thus, thoughtful consideration is vital in reporting on potential exposure and outcome associations but also the nexus of neighborhoods, communities, and environmental justice and equity. The LED Environmental Working Group has primarily focused on baseline residential addresses to provide additional contextual information about the places where ABCD Study participants are growing up. In this process, we continually aim to implement ways to reduce exposure misclassification. Current efforts include historical reconstruction of each child’s residential history, which offers the opportunity to create a better understanding about each child’s physical environmental exposures across their lifespan. In doing so, quality assurance of retrospective residential addresses using commercial credit-reporting data is underway to help reduce recall bias . Further, efforts are under way to improve syncing the temporal domains of linked database estimates with temporal changes in residential information for retrospective and prospective addresses. The ABCD Study’s Physical Health Working Group is also collecting biomarkers to measure exposure to some chemical toxins. Beyond improving exposure assessment, both the working group and its discussions with the greater larger scientific community has identified additional important linkage databases with other information regarding environmental toxins, urban settings, and neighborhood factors, such as green space and food deserts. The ABCD LED Environment Working Group envisions an ever-increasing resource for researchers who are keen to understand environmental impacts on the human brain. Given surges in electronic cigarette use among young people in the U.S. and concerns about vaping-related lung injury, federal policy raised the minimum retail tobacco product sales age to 21 in 2019 and in early 2020 prioritized enforcement against the sale of unapproved flavored, cartridge-based e-cigarette products . Individual states and local jurisdictions also have passed retail policies to restrict the sale of e-cigarettes and/or flavored tobacco, including flavored e-cigarettes . For example, in 2019, San Francisco banned direct and online sales of e-cigarettes without Food and Drug Administration Marketing Orders . To date, no e-cigarette company has received FDA Marketing Orders, effectively resulting in a ban on e-cigarette sales for now in San Francisco. Other jurisdictions  prohibit the sale of flavored nicotine vaping products. National youth e-cigarette prevalence in 2020 shows a decline from 2019 to 2018 levels, which were deemed epidemic . An estimated 19.6% of high school students reported past-month e-cigarette use in early 2020, prior to the COVID-19 pandemic shelter-in-place policies .

These latter studies lend initial support for a harm reduction model also in cocaine use disorder treatment. In unpublished neuroimaging studies of 20 PSU patients between 1 and 4 months of abstinence , we found evidence for widespread volumetric change also in individuals who co-abused alcohol and stimulants for more than 20 years: an increase in left caudate volume, a decrease in right superior temporal lobe volume, and trends to decreasing insula and entorhinal cortex volumes . These changes, however, were much less dramatic than observed in short-term abstinent AUD described above. Given that abnormalities in PSU involved both smaller and larger regional tissue volumes , observing both volume increases and decreases across different brain regions during sustained abstinence is not surprising and may relate to the competing morphometric processes and altered functional connectivity postulated among these brain regions. Longitudinal MRS studies have been used to try to further understand the tissue changes that underlie volume changes during recovery. We showed in a series of studies in recovering AUD that after correcting for parallel tissue volume changes, NAA and Cho concentrations throughout the brain recovered significantly, but variably over 5 weeks of abstinence, with some of the metabolite changes related to improvements in specific neurocognitive domains . The brain metabolite recovery was generally greater in nonsmoking than smoking AUD , with less frontal white matter NAA recovery related to longer smoking duration . In an MRS study of recently abstinent methamphetamine abusers, low Glu in ACC recovered over 5 months of abstinence, together with a reduction of craving . Over just 4 weeks of abstinence, however, prefrontal NAA and Cho in intravenous methamphetamine users did not change significantly , in contrast to observations in short-term abstinent AUD. In our small cohort of abstinent PSU, regional metabolite concentrations recovered between 1 and 3 months of abstinence to levels commensurate with controls . Specifically, NAA and Cho in the dorsolateral PFC and GABA and NAA in the ACC significantly increased, while Glu and mI in the ACC and mI in the parieto-occipital gray matter decreased; the NAA increases in ACC and dorsolateral PFC correlated with improvements in visuospatial learning and working memory, respectively. The observed brain tissue volume and metabolite level changes during abstinence from alcohol and/or substances may partially reflect the reversal of maladaptive neuroplastic processes associated with chronic long-term alcohol/substance abuse . While initial significant neurobiological changes have been observed within the first month of abstinence in AUD,cannabis grow setup fewer studies describe such early processes in illicit substance users, reminiscent of the dynamics of potentially related neurocognitive improvements.

Neurobiological improvements are observable over many months, even years after initiation of abstinence. They are likely not the result of a single neural process but of several different processes involving different cell types and populations to various degrees—sometimes potentially with opposing effects on regional MR-based outcome measures and with various temporal dynamics. Given the demonstrated associations between neurobiological and neurocognitive measures, this may give rise to the relatively large variability observed for neurocognitive recovery across different substance-using groups and among individuals in the same substance-using group during abstinence. Data from humans and animal models suggest the tissue volume recovery in AUD during early and extended abstinence is related to increases in neuronal dendritic arbor, soma/cell volume, synaptic density, nonreactive glial proliferation , and remyelination , which are all intrinsic neuroadaptations that are also instrumental in experience-based learning and memory . The metabolite concentration changes that often accompany morphometric changes during abstinence may also be related to these mechanisms. Clinically relevant modulators of the degree of regional volume reduction in adult AUD and of the extent of structural recovery during abstinence have been identified; they include age, gender, family history of problem drinking and genetic factors, degree of baseline atrophy, number of detoxifications, and comorbid medical , psychiatric , and SUDs including tobacco use disorder . The same factors as well as stress and stress response also modulate metabolic and functional brain injury and recovery in AUD. Finally, a critical determinant of brain injury is the age of onset of substance use, with substance-associated brain changes in adolescents being different both qualitatively and quantitatively from those in adults, as they likely interact with brain development. Studying the effects of substance use cessation in the developing brain is in its infancy, with the current Adolescent Brain Cognitive Development Study, a longitudinal, observational study of over 10,000 youth recruited throughout the United States, promising to address this issue. Given these many modulators of neurobiology in alcohol and SUDs, some of which are also risk factors for relapse , neurobiological and neurocognitive recovery with abstinence from alcohol and other substances is complex and not trivial to study and interpret in a meaningful way.One successful example of such development is the now much more widespread integration of smoking cessation into substance abuse treatment: tobacco use, a significant but modifiable health risk for both relapse and common psychiatric comorbidities in AUD, has a greater annual mortality than SUD and AUD combined, and we can ill afford to continue ignoring it in addiction treatment . It has been demonstrated that treating tobacco use effectively in those seeking treatment for their substance abuse may promote better long-term outcomes . But our efforts cannot end here, as newer forms of nicotine delivery also need to be considered carefully regarding their addictive and brain-altering potentials.

Despite the seemingly overwhelming complexities in studying brain function, morphometry, and recovery in human addiction, demonstrating specific neuroadaptations after detoxification, their time courses, and their dependence on critical modulators are important for several reasons: There might be an optimal window of opportunity for augmenting such intrinsic neurobiological repair processes via interventions such as plasticity-based cognitive remediation, magnetic/electrical stimulation, or pharmacotherapy; many neurocognitive deficits and/or their neurobiological correlates are not premorbid/risk factors of abuse, but rather consequences of abuse, and brain function and tissue integrity can improve with sustained abstinence; and relapse risk likely decreases over time with abstinence as brain neurobiology and functions recover from injury . Identifying the specific neurobiological mechanisms associated with such improvements, their mitigating factors, time courses, and trajectories can critically inform interventions aimed at facilitating brain repair and recovery processes, such as strengthening prefrontal neural connectivity or employing GABAergic therapy to improve inhibitory control. A recent opinion piece calls for “expanding and deepening the neuroscience of recovery from addiction” to improve addiction-focused clinical care and public policy. In that spirit, we hope that this chapter contributes to describing a critical part of the current state of addiction recovery research. Finally, it is noteworthy that all recovery research described in this chapter has been conducted in individuals having achieved complete abstinence from alcohol and other substances. Research has rarely examined psychological or physical functioning in moderation-focused treatment approaches . Given the increasing consideration of treatment outcome endpoints other than complete abstinence,outdoor cannabis grow future research will almost certainly be conducted to better understand the degree of neurobiological recovery associated with reduced substance use . Additional research might focus on recovery processes that go beyond the standard treatment durations of several months described here, to better understand neuropsychological and neurobiological factors associated with sustained recovery in later years when treated individuals remain at some degree of relapse risk. Electronic cigarette , or nicotine vape, use among youth and young adults has been increasing in the United States , a cause for concern due to potential nicotine addiction, increased risk for use of other tobacco products and drugs, and long-term health risks .

Evidence has also shown a wide array of short-term adverse experiences attributed to ecigarette use . E-cigarette, or Vaping, Product Use-Associated Lung Injury , a uniquely severe adverse experience, garnered significant public attention in the summer of 2019 when a case series of patients presenting with pulmonary illness associated with e-cigarette use was reported and an increasing number of hospitalizations occurred across the United States . Hospitalization admissions for EVALI peaked in September 2019 and declined through the end of that year. By the end of January 2020, 2,668 hospitalized EVALI cases were reported to the U.S. Centers for Disease Control and Prevention . Sixty-eight EVALI deaths have also been confirmed in the United States as of February 2020 . Tetrahydro cannabinol -containing products were highly associated with EVALI cases, with 82% of hospitalized patients using any THC containing vaping product, though 14% of hospitalized cases reported using only nicotine-containing products . Previous research suggests that among smokers, discontinuation of ecigarettes was attributed to factors related to product characteristics such as taste, not adequately resembling the smoking experience, or cost . Among former and never smoker young adults, however, feeling that e-cigarettes were bad for one’s health was shown to be a major reason for discontinuation of e-cigarettes, but being made sick from trying e-cigarettes was not . This suggests that adverse symptoms and health concerns may operate as distinct constructs among young adult former e-cigarette users. The possible distinction made between adverse symptoms and health concerns suggests that a more nuanced understanding of how young adult e-cigarette users process and respond to information about e-cigarette harm is needed. In the context of the EVALI outbreak and its impact on young adult e-cigarette users, it is unclear how the news and information about the disease affected current and future e-cigarette use attitudes and behavior. Hence, this study conducted an in-depth qualitative assessment of young adult e-cigarettes users’ understanding of and response to the EVALI outbreak. In Fall 2019, college students who use tobacco products on-campus were recruited from two four-year public universities in Southern California to participate in focus group discussions as part of a larger study on compliance with tobacco-free policies. Two marketing firms managed recruitment of participants and project logistics for focus groups which were held at off-campus facilities. One marketing firm was assigned to each university and utilized panels of potential participants, social media outreach, on-campus recruiting, and participant referral to recruit participants. In addition, research staff passed out study flyers to individuals observed smoking or vaping on-campus referring potential participants to marketing firms for study recruitment. Inclusion criteria for the larger study were: age 18 or older; student at one of the two universities; and self-reported use of a tobacco product on university property. Inclusion criteria of participants were verified by the market research companies and included participants furnishing university identification cards prior to assignment to focus groups held in October and November 2019. As this analysis focused on young adult populations, we excluded responses from participants older than 29 years of age and not being a current e-cigarette user. Upon arrival at the focus group facility, a study alias, informed consent materials, and a demographic and tobacco use questionnaire were given to each participant. Informed consent forms and demographic questionnaires could be completed prior to focus groups in the facility lobby, or after entering the focus group room if participants had questions. Free and informed consent was obtained from all participants. Seven mixed-gender focus groups were held, 3 with students from University 1 and 4 with students from University 2, with participants assigned to groups based on reported tobacco products used on campus. Groups had an average of 7.85 participants and average duration of 78.7 min . Focus groups were facilitated by the first author and followed a semi-structured protocol. Open ended questions regarding EVALI were “Can you describe to me when you first heard about EVALI and what your reaction was?” and “How did the news [about EVALI] affect your tobacco or ecigarette use?” with follow-up probes used to extract details about individual experiences, beliefs, and attitudes. Students who completed the focus group were given a $125 incentive for participation. Focus groups were recorded and verbatim transcripts were provided by the market research firms. The study protocol was approved by the Institutional Review Board at California State University, Fullerton . In 2020, focus group transcripts were reviewed for accuracy by research assistants then imported into and analyzed using Atlas.ti 8 qualitative data analysis software . The principal investigator developed an initial coding scheme based on the focus group discussion protocol and emergent themes from a close reading of a subset of two transcripts. Two research assistants coded a subset of focus group transcripts using the initial coding scheme and added new codes as needed.

A study of the disparate prosecution of drug possession across California in 2010 is illustrative, and the case to which we will return: charging policies and decisions were influenced by community and judicial attitudes toward the crime and the political and philosophical beliefs of district attorneys and charging deputies . Studies of the use of prosecutorial discretion to mitigate or maximize penalties in the context of three strikes laws have also found that more politically conservative environments tend to be more punitive, and counties with a high case flow relative to the budget for prosecution have lower average sentence severities . Prosecutors and judges may appropriately use discretion to align a punishment with the characteristics of a case and the local community’s priorities for law enforcement. However, unequal application of the law to equivalent cases calls into question the integrity and equity of the law, and can undermine public trust in law enforcement . For example, after controlling for case characteristics, third strike sentences in California were disproportionately imposed upon black defendants, with the largest gaps evident for offenses that could be charged as felonies or misdemeanors at the prosecutor’s discretion . These geographic differences may stabilize or exacerbate social and health inequalities. Community principles of proportionality that inform prosecution policies and practices may differ even within a county, and represent those of wealthier suburban populations with political power and the ability to prioritize crime reduction without bearing the costs of punishment . Those costs are high. Criminal records, particularly felony convictions, create a broad range of legal and social barriers that persist long after time is served. Restrictions range from the loss of voting rights, parental rights,mobile grow systems public benefits that support health and education, employment and occupational licensing, and housing – creating conditions that can in turn impact mental and physical health .

Associations between the risk of criminal justice exposure and place of residence present the possibility that collateral consequences will be unequally distributed and exacerbate inequalities by race and location . Considering the significance of criminal history for the severity of punishment for subsequent offenses, including eligibility to receive drug diversion rather than a felony conviction and incarceration, the effects of living in a punitive location are likely to compound over time. Geographic differences in conviction rates also have implications for costs. Punitive charging and sentencing decisions are made by counties but costs are passed on to the state; a felony conviction can receive a sentence to state prison, while county jails and probation supervise those with misdemeanors . In essence, the decisions of more punitive counties to impose higher rates of imprisonment are subsidized by less punitive counties .Drug law enforcement has been especially susceptible to differential justice by geography in California. Prior to the passage of Prop 47 in 2014, possession of a controlled substance and possession of concentrated cannabis were classified as “wobbler” offenses, which are charged as felonies by default, but provide prosecutors with the discretion to reduce them to misdemeanors. This discretion was introduced through a penal code amendment 17 in 1969 to reduce caseloads at overburdened superior courts responsible for hearing felony cases, by allowing lesser felonies to be adjudicated as misdemeanors in municipal courts at the prosecutor’s discretion . Research conducted in 2010 found the proportion of arrests for possession of a controlled substance that were charged as felonies varied across California counties from 25 to 100 percent . Even after controlling for case characteristics and criminal history, county of residence was a strong predictor of felony filings following arrest . California law does not dictate how wobblers should be prosecuted, nor does it define the quantity of drug that differentiates possession from sale, the latter of which is always a felony. Charging policies are established by district attorneys and differ across counties; the study found that some simply charged all possession cases as felonies, and others considered the quantity of the drug, prior criminal record, and concurrent charges. The extant research has found that Prop 47 led to fewer arrests, bookings, and custody time on average for Prop 47 offenses , and identified county variation in changes in arrests and jail populations following passage . However, how Prop 47 impacted geographic disparities in the severity of case dispositions has not been investigated. While the reclassification of drug possession offenses to misdemeanors may have reduced county variation in felony convictions for drug possession, felony convictions for concurrent offenses or for drug offenses that remained felonies may have increased in more punitive counties, potentially offsetting a reduction in geographic disparities.

This study will assess the effect of Prop 47 on county variation in felony convictions in two ways. First, we will test whether there was a change in county variation in the probability of a felony conviction for those arrested for drug possession. Within this group, we will examine whether there was an increase in felony convictions for concurrent offenses, which would suggest mitigation of Prop 47’s effects. Second, we will assess the change in felony conviction probability for individuals arrested for non-Prop 47 felony drug offenses, such as sale and transport, which may also result in Prop 47 convictions. California law does not specify the amount of drug that differentiates sale from possession, and those arrested for sale might have their charges reduced to possession. If this group of defendants continues to have charges reduced to possession, which is now a misdemeanor, we would see a reduction in their felony convictions.For example, the practice of reducing sale to possession during plea bargaining could decline in these counties, potentially increasing cross-county variation in felony convictions following these arrests. We extracted criminal records from the California Department of Justice’s Automated Criminal History System , which records all arrests and corresponding convictions and sentences within California. The analysis includes all Prop 47 arrests , or non-Prop 47 felony drug arrests, for which the arrest or first court event was within one year prior to or post Prop 47 passage. Arrests including both Prop 47 and non-Prop 47 felony drug offenses concurrently were classified as non-Prop 47 felony drug. Non-Prop 47 felony drug included an extensive list of offenses, the most common of which were possession of a controlled substance for sale , transport of a controlled substance , possession of marijuana for sale , transport of narcotics , possession of narcotics for sale , and transport of marijuana .

Though arrests were also made for offenses such as obtaining prescriptions by fraud, cultivating marijuana, or possession while armed, for simplicity, we will hereafter refer to non-Prop 47 felony drug offenses as sale/transport since these make up the vast majority of arrests. The dataset is organized in “cycles,” each of which holds a collection of related events, including the initial arrest and all subsequent court actions associated with the arrest. Some arrests were coded as having dispositions in a separate arrest cycle,cannabis grow supplies and could not be linked with their disposition in the available deidentified dataset. We therefore imposed the assumption that the arrest cycle that contained the missing disposition for these arrests was that which contained the next chronological case disposition. A total of 6.1% of Prop 47 drug arrests and 4.4% of non-Prop 47 felony drug arrests were reassigned based on this rule. After reclassifying concurrent Prop 47 drug and non-Prop 47 felony drug arrests, a total of 327,719 Prop 47 drug arrests and 123,726 non-Prop 47 felony drug arrests occurred during the two-year analytic period. Of the Prop 47 arrests, we excluded .02% due to missing county, and .01% due to missing gender. We also dropped Sierra and Alpine Counties, which made only 14 and 2 Prop 47 arrests during the analytic period, respectively. Of non-Prop 47 felony drug arrests, we excluded .07% due to missing county, and .02% due to missing gender. We again dropped Sierra and Alpine Counties, which made five and two arrests of this type, respectively. The remaining sample included 327,610 Prop 47 arrests, ranging from 53 to 65,341 across counties , and 123,599 non-Prop 47 felony drug arrests, ranging from 54 to 24,973 across counties . Separately for Prop 47 arrests and non-Prop 47 felony drug arrests, we determined whether the event resulted in a felony conviction for any offense associated with the arrest. We used any felony conviction as our primary outcome, because prosecutors have the discretion to consolidate arrest charges into an individual filing, or to alter offenses to negotiate a plea, and the charges prosecutors file may have been affected by Prop 47. For example, it is possible that prosecutors were more likely to file felony charges for non-Prop 47 offenses after passage, to counteract the drop in felonies due to reduced classification of Prop 47 offenses. By defining the outcome as any felony conviction, we attempted to account for possible changes in specific charges filed, and capture the severity of the overall case disposition following the arrest. Arrests with no disposition were assumed not to have been prosecuted. If Prop 47 shifted law enforcement practices, some individuals arrested during the pre-Prop 47 period might not have been arrested had they committed their crimes during the post-Prop 47 period. To assess the plausibility of such compositional changes in the populations arrested, we first compared pre- and post-policy groups on demographic characteristics, concurrent charges, and criminal histories, separately for Prop 47 offenses and non-Prop 47 felony drug offenses. Pearson’s chi-squared tests were used for categorical variables and Wilcoxon rank-sum tests for skewed continuous variables.

In the presence of compositional changes, we cannot estimate the effects of Prop 47 on arrest outcomes for individuals who would only have been arrested under pre-Prop 47 conditions, because a comparable group is not represented in the post-Prop 47 period. Furthermore, estimating the effect of reclassification on individuals unlikely to be arrested under the new laws would be of little value. Therefore, propensity score matching was used to assess the effect of the “treatment on the treated,” comparing arrest outcomes only among individuals who were likely to be arrested regardless of the reclassification of offenses. Each individual who was arrested after Prop 47 was matched with an individual who was approximately as likely, given their covariates, to have been arrested after Prop 47 was adopted, but was in fact arrested pre-Prop 47. We generated propensity scores using a logit model predicting the log odds that an arrest occurred during the post-Prop 47 vs. pre-Prop 47 period. Predictors included all available demographic variables, and concurrent arrest and criminal history variables likely to affect the arrest disposition. These consisted of age, gender, race/ethnicity; county and calendar month of arrest; any concurrent arrest, separately for felony or misdemeanor classifications: property, violent, sex, weapons, and other; whether the arrest included a probation or parole violation; number of prior arrests; prior arrest for a Prop 47 drug offense ; a measure of the severity of conviction history ; dummies for types of prior felony convictions, including drug, property, violent, sex, weapons, and other; any prior prison sentence and any prior jail sentence. For sale/transport arrests, we also include whether there was a concurrent Prop 47 drug offense. To accommodate non-linearities in age and the number of prior arrests, we use restricted cubic splines with five knots at equally spaced percentiles of each variable’s distribution. Propensity scores were estimated separately for arrests for Prop 47 and sale/transport offenses.Using within-county one-to-one matching without replacement, post-Prop 47 arrestees were matched on the logit of their propensity score to pre-Prop 47 arrestees, within a maximum of 0.2 of the standard deviations of the logit of the propensity score . For Prop 47 drug arrests, 5.6% of the post-Prop 47 group was dropped due to insufficient matches. For sale/transport arrests, 7.8% of the postProp 47 group was dropped. Covariate balance across propensity-score matched treatment and control groups was checked to assess the adequacy of the propensity score models. Standardized mean differences in all covariates were less than 5% in both samples. For each arrest category, we used a set of mixed logit models to examine the variance in county probabilities of felony conviction pre- and post-Prop 47 among propensity score matched samples. First, we specified the model to include county-specific random intercepts and random coefficients for the policy effect with an unstructured covariance structure. This generated an estimate of the covariance of pre-Prop 47 mean felony conviction probability with Prop 47 effects on conviction probability, which would indicate whether counties with higher pre-Prop 47 means declined to a greater degree, thus reducing variance in the outcome. Second, models were specified such that counties had separate random intercepts for pre- and post-Prop 47 periods, which generated an estimate of the variance in county probability of felony conviction in each period.