The single-cell opioid responses in the context of HIV (SCORCH) consortium.

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families and communities. One of the seminal challenges in treating and studying addiction in human populations is the high prevalence of co-morbid conditions, including an increased risk of contracting a human immunodeficiency virus (HIV) infection. Of the ~15 million people who inject drugs globally, 17% are persons with HIV. Conversely, HIV is a risk factor for SUD because chronic pain syndromes, often encountered in persons with HIV, can lead to an increased use of opioid pain medications that in turn can increase the risk for opioid addiction. We hypothesize that SUD and HIV exert shared effects on brain cell types, including adaptations related to neuroplasticity, neurodegeneration, and neuroinflammation. Basic research is needed to refine our understanding of these affected cell types and adaptations. Studying the effects of SUD in the context of HIV at the single-cell level represents a compelling strategy to understand the reciprocal interactions among both conditions, made feasible by the availability of large, extensively-phenotyped human brain tissue collections that have been amassed by the Neuro-HIV research community. In addition, sophisticated animal models that have been developed for both conditions provide a means to precisely evaluate specific exposures and stages of disease. We propose that single-cell genomics is a uniquely powerful technology to characterize the effects of SUD and HIV in the brain, integrating data from human cohorts and animal models. We have formed the Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium to carry out this strategy.

Δ9-Tetrahydrocannabinol does not upregulate an aversive dopamine receptor mechanism in adolescent brain unlike in adults.

Earlier age of cannabis usage poses higher risk of Cannabis Use Disorder and adverse consequences, such as addiction, anxiety, dysphoria, psychosis, largely attributed to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC) and altered dopaminergic function. As dopamine D1-D2 receptor heteromer activation causes anxiety and anhedonia, this signaling complex was postulated to contribute to THC-induced affective symptoms. To investigate this, we administered THC repeatedly to adolescent monkeys and adolescent or adult rats. Drug-naïve adolescent rat had lower striatal densities of D1-D2 heteromer compared to adult rat. Repeated administration of THC to adolescent rat or adolescent monkey did not alter D1-D2 heteromer expression in nucleus accumbens or dorsal striatum but upregulated it in adult rat. Behaviourally, THC-treated adult, but not adolescent rat manifested anxiety and anhedonia-like behaviour, with elevated composite negative emotionality scores that correlated with striatal D1-D2 density. THC modified downstream markers of D1-D2 activation in adult, but not adolescent striatum. THC administered with cannabidiol did not alter D1-D2 expression. In adult rat, co-administration of CB1 receptor (CB1R) inverse agonist with THC attenuated D1-D2 upregulation, implicating cannabinoids in the regulation of striatal D1-D2 heteromer expression. THC exposure revealed an adaptable age-specific, anxiogenic, anti-reward mechanism operant in adult striatum but deficient in adolescent rat and monkey striatum that may confer increased sensitivity to THC reward in adolescence while limiting its negative effects, thus promoting continued use and increasing vulnerability to long-term adverse cannabis effects.

Daily Δ9-Tetrahydrocannabinol and Withdrawal Increase Dopamine D1-D2 Receptor Heteromer to Mediate Anhedonia- and Anxiogenic-like Behavior Through a Dynorphin and Kappa Opioid Receptor Mechanism.

Background: Frequent cannabis use is associated with a higher risk of developing cannabis use disorder and other adverse consequences. However, rodent models studying the underlying mechanisms of the reinforcing and withdrawal effects of the primary constituent of cannabis, Δ9-tetrahydrocannabinol (THC), have been limited. Methods: This study investigated the effects of daily THC (1 mg/kg, intraperitoneal, 9 days) and spontaneous withdrawal (7 days) on hedonic and aversion-like behaviors in male rats. In parallel, underlying neuroadaptive changes in dopaminergic, opioidergic, and cannabinoid signaling in the nucleus accumbens were evaluated, along with a candidate peptide designed to reverse altered signaling. Results: Chronic THC administration induced anhedonic- and anxiogenic-like behaviors not attributable to altered locomotor activity. These effects persisted after drug cessation. In the nucleus accumbens, THC treatment and withdrawal catalyzed increased cannabinoid CB1 receptor activity without modifying receptor expression. Dopamine D1-D2 receptor heteromer expression rose steeply with THC, accompanied by increased calcium-linked signaling, activation of BDNF/TrkB (brain-derived neurotrophic factor/tropomyosin receptor kinase B) pathway, dynorphin expression, and kappa opioid receptor signaling. Disruption of the D1-D2 heteromer by an interfering peptide during withdrawal reversed the anxiogenic-like and anhedonic-like behaviors as well as the neurochemical changes. Conclusions: Chronic THC increases nucleus accumbens dopamine D1-D2 receptor heteromer expression and function, which results in increased dynorphin expression and kappa opioid receptor activation. These changes plausibly reduce dopamine release to trigger anxiogenic- and anhedonic-like behaviors after daily THC administration that persist for at least 7 days after drug cessation. These findings conceivably provide a therapeutic strategy to alleviate negative symptoms associated with cannabis use and withdrawal.

Endocannabinoid System and Exogenous Cannabinoids in Depression and Anxiety: A Review.

Background: There is a growing liberalization of cannabis-based preparations for medical and recreational use. In multiple instances, anxiety and depression are cited as either a primary or a secondary reason for the use of cannabinoids. Aim: The purpose of this review is to explore the association between depression or anxiety and the dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms. After a brief description of the constituents of cannabis, cannabinoid receptors and the endocannabinoid system, the most important evidence is presented for the involvement of cannabinoids in depression and anxiety both in human and from animal models of depression and anxiety. Finally, evidence is presented for the clinical use of cannabinoids to treat depression and anxiety. Conclusions: Although the common belief that cannabinoids, including cannabis, its main studied components-tetrahydrocannabinol (THC) and cannabidiol (CBD)-or other synthetic derivatives have been suggested to have a therapeutic role for certain mental health conditions, all recent systematic reviews that we report have concluded that the evidence that cannabinoids improve depressive and anxiety disorders is weak, of very-low-quality, and offers no guidance on the use of cannabinoids for mental health conditions within a regulatory framework. There is an urgent need for high-quality studies examining the effects of cannabinoids on mental disorders in general and depression/anxiety in particular, as well as the consequences of long-term use of these preparations due to possible risks such as addiction and even reversal of improvement.

Effects of daily Δ9-Tetrahydrocannabinol (THC) alone or combined with cannabidiol (CBD) on cognition-based behavior and activity in adolescent nonhuman primates.

BACKGROUND: Daily use of marijuana is rising in adolescents, along with consumption of high potency marijuana products (high % Δ-9-tetrahydrocannabinol or THC). These dual, related trends have opened gaps in understanding the long-term effects of daily consumption of a high dose of THC in adolescents and whether a therapeutic dose of cannabidiol (CBD) modulates THC effects. METHODS: Adolescent squirrel monkeys (Saimiri boliviensis) were treated daily for four months with vehicle (n = 4), a high THC dose (1 mg/kg i.m.; n = 4), or THC + CBD (1 mg/kg +3 mg/kg i.m.; n = 4), to investigate whether: (1) a daily high THC dose affects performance in tasks of cognition (repeated acquisition, discrimination reversal); (2) a daily high THC dose affects spontaneous behavior and day/night activity (3) tolerance develops to the behavioral effects of THC; (4) whether CBD modulates THC effects. RESULTS: THC impaired performance of adolescent monkeys in a cognitive test initially, but not performance on a task of cognitive flexibility. THC reduced motor activity and increased sedentary behavior, with tolerance developing after weeks of daily treatment. Co-administered with THC, CBD did not modulate THC effects on cognitive performance, activity or tolerance, but prevented THC-induced emesis on the first day of daily treatment. CONCLUSIONS: Daily high dosing with THC compromised performance on a task of cognition, and reduced activity in adolescent primates, with tolerance developing within weeks. Whether our observations are relevant to a broader range of cognitive tasks vital for daily function in human adolescents is uncertain.

Dopamine D1-D2 receptor heteromer expression in key brain regions of rat and higher species: Upregulation in rat striatum after cocaine administration.

BACKGROUND: Dopamine receptors interact with other receptors to form heterooligomers. One such complex, the D1-D2 heteromer, demonstrated in cultured striatal neurons and rat striatum has been linked to drug addiction, Parkinson's disease, schizophrenia, depression and anhedonia. METHODS: D1-D2 heteromer expression was evaluated using in situ proximity ligation assay, in parallel with cellular colocalization of D1 and D2 mRNA using in situ hybridization in 19 different key rat brain regions. Expression in higher species and changes in rat striatum after repeated cocaine administration were evaluated. RESULTS: Differences in D1-D2 heteromer expression in striatal subregions are documented in higher species with nonhuman primate and human demonstrating higher density of heteromer-expressing neurons compared to rodents. All species had higher density of D1-D2 neurons in nucleus accumbens compared to dorsal striatum. Multiple other brain regions are identified where D1-D2 heteromer is expressed, prominently in cerebral cortical subregions including piriform, medial prefrontal, orbitofrontal and others; subcortical regions such as claustrum, amygdala and lateral habenula. Three categories of regions are identified: D1-D2 heteromer expressed despite little to no observed D1/D2 mRNA colocalization, likely representing heteromer on neuronal projections from other brain regions; D1-D2 heteromer originating locally with the density of neurons expressing heteromer matching neurons with colocalized D1/D2 mRNA; regions with both a local origin and targeted inputs projecting from other regions. Repeated cocaine administration significantly increased density of neurons expressing D1-D2 heteromer and D1/D2 mRNA colocalization in rat striatum, with changes in both direct and indirect pathway neurons. CONCLUSION: The dopamine D1-D2 heteromer is expressed in key brain cortical and subcortical regions of all species examined. Species differences in striatum revealed greater abundance in human>nonhuman-primate>rat>mouse, suggesting an evolutionary biologic role for the D1-D2 heteromer in higher CNS function. Its upregulation in rat striatum following cocaine points to regulatory significance with possible relevance for clinical disorders such as drug addiction. The dopamine D1-D2 receptor heteromer may represent a potential target for neuropsychiatric and neurodegenerative disorders, given its distribution in highly relevant brain regions.

Sex difference in dopamine D1-D2 receptor complex expression and signaling affects depression- and anxiety-like behaviors.

Depression and anxiety are more common among females than males and represent a leading cause of disease-related disability in women. Since the dopamine D1-D2 heteromer is involved in depression- and anxiety-like behavior, the possibility that the receptor complex may have a role in mediating sex differences in such behaviors and related biochemical signaling was explored.In non-human primate caudate nucleus and in rat striatum, females expressed higher density of D1-D2 heteromer complexes and a greater number of D1-D2 expressing neurons compared to males. In rat, the sex difference in D1-D2 expression levels occurred even though D1 receptor expression was lower in female than in male with no difference in D2 receptor expression. In behavioral tests, female rats showed faster latency to depressive-like behavior and a greater susceptibility to the pro-depressive and anxiogenic-like effects of D1-D2 heteromer activation by low doses of SKF 83959, all of which were ameliorated by the selective heteromer disrupting peptide, TAT-D1. The sex difference observed in the anxiety test correlated with differences in low-frequency delta and theta oscillations in the nucleus accumbens. Analysis of signaling pathways revealed that the sex difference in D1-D2 heteromer expression led to differences in basal and heteromer-stimulated activities of two important signaling pathways, BDNF/TrkB and Akt/GSK3/ß-catenin.These results suggest that the higher D1-D2 heteromer expression in female may significantly increase predisposition to depressive-like and anxiety-like behavior in female animals.

Δ-Tetrahydrocannabinol Increases Dopamine D1-D2 Receptor Heteromer and Elicits Phenotypic Reprogramming in Adult Primate Striatal Neurons.

Long-term cannabis users manifest deficits in dopaminergic functions, reflecting Δ9-tetrahydrocannabinol (THC)-induced neuroadaptive dysfunctional dopamine signaling, similar to those observed upon dopamine D1-D2 heteromer activation. The molecular mechanisms remain largely unknown. We show evolutionary and regional differences in D1-D2 heteromer abundance in mammalian striatum. Importantly, chronic THC increased the number of D1-D2 heteromer-expressing neurons, and the number of heteromers within individual neurons in adult monkey striatum. The majority of these neurons displayed a phenotype co-expressing the characteristic markers of both striatonigral and striatopallidal neurons. Furthermore, THC increased D1-D2-linked calcium signaling markers (pCaMKIIα, pThr75-DARPP-32, BDNF/pTrkB) and inhibited cyclic AMP signaling (pThr34-DARPP-32, pERK1/2, pS845-GluA1, pGSK3). Cannabidiol attenuated most but not all of these THC-induced neuroadaptations. Targeted pathway analyses linked these changes to neurological and psychological disorders. These data underline the importance of the D1-D2 receptor heteromer in cannabis use-related disorders, with THC-induced changes likely responsible for the reported adverse effects observed in heavy long-term users.

Improving Access to Evidence-Based Medical Treatment for Opioid Use Disorder: Strategies to Address Key Barriers within the Treatment System.

Even though evidence-based treatment for opioid use disorders (OUD) is effective, almost four in five Americans with OUD do not receive any form of treatment. The gap in access to evidence-based care, including treatment with medications for OUD, stems in part from barriers to change within the health care system. This paper includes nine key barriers that prevent access to evidence-based care, including stigma; inadequate clinical training; a dearth of addiction specialists; lack of integration of MOUD provision in practice; regulatory, statutory, and data sharing restrictions; and financial barriers. Action from a number of actors is urgently needed to address this crisis.

Associations of Parental Marijuana Use With Offspring Marijuana, Tobacco, and Alcohol Use and Opioid Misuse.

Importance: Marijuana use is increasing among adults and often co-occurs with other substance use; therefore, it is important to examine whether parental marijuana use is associated with elevated risk of substance use among offspring living in the same household. Objective: To examine associations of parental marijuana use with offspring marijuana, tobacco, and alcohol use and opioid misuse. Design, Setting, and Participants: This cross-sectional study used survey data from the 2015 through 2018 National Surveys on Drug Use and Health (NSDUH), which provide nationally representative data on adolescents or young adults living with a parent (the mother or the father). Annual average percentages were based on survey sampling weights. Final analyses were conducted September 21 through 23, 2019. Exposures: Parental marijuana use status. Main Outcomes and Measures: Offspring self-reported use of marijuana, tobacco, or alcohol or misuse of opioids. Results: Survey respondents included 24 900 father-offspring or mother-offspring dyads sampled from the same household. Among mothers living with adolescent offspring, 8.2% (95% CI, 7.3%-9.2%) had past-year marijuana use, while 7.6% (95% CI, 6.2%-9.2%) of mothers living with young adult offspring had past-year marijuana use. Among fathers living with adolescent offspring, 9.6% (95% CI, 8.5%-10.8%) had past-year marijuana use, and 9.0% (95% CI, 7.4%-10.9%) of fathers living with young adult offspring had past-year marijuana use. Compared with adolescents whose mothers never used marijuana, adjusted relative risk (ARR) of past-year marijuana use was higher among those whose mothers had lifetime (without past-year) marijuana use (ARR, 1.3; 95% CI, 1.1-1.6; P = .007), less than 52 days of past-year marijuana use (ARR, 1.7; 95% CI, 1.1-2.7; P = .02), or 52 days or more of past-year marijuana use (ARR, 1.5; 95% CI, 1.1-2.2; P = .02). Compared with young adults whose mothers never used marijuana, adjusted risk of past-year marijuana use was higher among those whose mothers had lifetime (without past-year) marijuana use (ARR, 1.4; 95% CI, 1.1-1.7; P = .001), less than 52 days of past-year marijuana use (ARR, 1.5; 95% CI, 1.0-2.3; P = .049), or 52 days or more of past-year marijuana use (ARR, 1.8; 95% CI, 1.3-2.5; P = .002). Compared with adolescents whose fathers never used marijuana, adolescents whose fathers had less than 52 days of past-year marijuana use were more likely to use marijuana (ARR, 1.8; 95% CI, 1.2-2.7; P = .006). Compared with young adults whose fathers never used marijuana, young adults whose fathers had 52 days or more of past-year marijuana use were more likely to use marijuana (ARR, 2.1; 95% CI, 1.6-2.9; P < .001). Compared with their peers whose parents never used marijuana and after adjusting for covariates, the adjusted risk of past-year tobacco use was higher among adolescents whose mothers had lifetime marijuana use (ARR, 1.3; 95% CI, 1.0-1.6; P = .03), less than 52 days of past-year marijuana use (ARR, 1.5; 95% CI, 1.0-2.1; P = .04), or 52 days or more of past-year marijuana use (ARR, 1.6; 95% CI, 1.1-2.3; P = .03); adolescents whose fathers had lifetime marijuana use (ARR, 1.5; 95% CI, 1.1-1.9; P = .004) or 52 days or more of past-year marijuana use (ARR, 1.8; 95% CI, 1.2-2.7; P = .006); young adults whose mothers had lifetime marijuana use (ARR, 1.2; 95% CI, 1.0-1.4; P = .04); and young adults whose fathers had 52 days or more of past-year marijuana use (ARR, 1.4; 95% CI, 1.0-1.9; P = .046). Compared with their peers whose parents had no past marijuana use and after adjusting for covariates, risk of past-year alcohol use was higher among adolescents whose mothers had lifetime marijuana use (ARR, 1.2; 95% CI, 1.1-1.4; P = .004), less than 52 days of past-year marijuana use (ARR, 1.5; 95% CI, 1.2-1.9; P = .002), or 52 days or more of past-year marijuana use (ARR, 1.3; 95% CI, 1.0-1.7; P = .04). After adjusting for covariates, parental marijuana use was not associated with opioid misuse by offspring. Conclusions and Relevance: In this cross-sectional study, parental marijuana use was associated with increased risk of substance use among adolescent and young adult offspring living in the same household. Screening household members for substance use and counseling parents on risks posed by current and past marijuana use are warranted.

Psychiatry and the Opioid Overdose Crisis.

For the third year in a row, the Centers for Disease Control and Prevention reported an unprecedented decline in life expectancy for the United States, a decline attributable mainly to drug overdose deaths and suicides. Drug overdoses have continued to rise and are now estimated to account for 70,237 deaths in 2017. The root causes of the modern opioid crisis are complex and traceable to at least 30 factors. A prime driver has been the health care system. Pressure on medical practitioners to resort to opioids for managing chronic pain led to a nation awash with prescription opioids. In 2017, an unprecedented action was taken by President Donald J. Trump as he signed an executive order establishing the President's Commission on Combating Drug Addiction and the Opioid Crisis, tasked with producing guidance on reversing the crisis. The 56 recommendations of the President's Commission report were grounded in advanced strategies for prevention, treatment, rescue, recovery support, research, improved data analytics, and accountability. With a focus on the quality of treatment services and recovery homes, the report calls for implementing high standards of care for treatment. Specialists in addiction medicine and addiction psychiatry are best positioned to develop and implement high-quality care.

Pharmacological Research as a Key Component in Mitigating the Opioid Overdose Crisis.

The United States is experiencing an epidemic of opioid overdose deaths. Many of the recent fatalities are associated with illicitly manufactured fentanyl, which is being added to heroin and counterfeit pain pills. The crisis is further exacerbated by the emergence of an increasing number of novel synthetic opioids (NSOs), including various fentanyl analogs and non-fentanyl compounds that display potent agonist actions at the µ-opioid receptor. Importantly, most users are unaware of their exposure to fentanyl and NSOs. Stemming the tide of opioid-related fatalities will require a coordinated multidisciplinary response from policy makers, law enforcement personnel, first responders, treatment providers, family members, and scientists. To this end, basic research in pharmacology can contribute significantly to mitigating the crisis through efforts to characterize the biological effects of NSOs, discover more effective antidotes for overdose rescue, and develop safer medications for treating addiction and alleviating pain.

Drug use among youth: National survey data support a common liability of all drug use.

The prevalence of substance use disorders in adults is higher if substance use is initiated during adolescence, underscoring the importance of youth substance use prevention. We examined whether the use of one substance by adolescents is associated with increased risk for using any other substance, regardless of use sequences. In 2017 we examined data from 17,000 youth aged 12-17 who participated in the 2014 National Survey on Drug Use and Health, a sample of nationally representative data on substance use among the U.S. civilian, noninstitutionalized population aged 12 or older. Descriptive analyses and multivariable logistic regression models were applied. After controlling for age, sex, and race/ethnicity, compared with youth without past-month marijuana use, youth with past-month marijuana use were 8.9 times more likely to report past-month cigarette use, 5.6, 7.9 and 15.8 times more likely to report past-month alcohol use, binge use, or heavy use (respectively), and 9.9 times more likely to report past-month use of other illicit drugs. The prevalence of past-month use of cigarettes, marijuana, and other illicit drugs was significantly higher among past-month alcohol users compared with youth without past-month alcohol use, and increased as intensity of alcohol use rose. Among past-month cigarette smokers, the prevalence of marijuana, other illicit drugs, and alcohol use were each significantly higher than youth without past-month cigarette use. Youth marijuana use, cigarette smoking, or alcohol consumption is associated with other substance use. This finding has importance for youth prevention, supporting a message no use by youth of any substance.

The President's Commission on Combating Drug Addiction and the Opioid Crisis: Origins and Recommendations.

The United States has the ignominious distinction of leading the world in opioid prescribing,1 and in opioid-related overdose deaths. The Centers for Disease Control (CDC) estimates that over 40,000 people died of an opioid-related overdose, with fentanyl-related deaths exceeding those of heroin or prescription opioids.2 Opioid overdoses are now the leading cause of unintentional deaths in the US and of declining lifespan expectancies.3 With a worsening crisis, agencies of the US government and others produced an array of reports on the opioid crisis. Yet the death rate escalated further from 2010 to the present.

The Growing Problem of New Psychoactive Substances (NPS).

The term "new psychoactive substances" (NPS) can be defined as individual drugs in pure form or in complex preparations that are not scheduled under the Single Convention on Narcotic Drugs (1961) or the Convention on Psychotropic Substances (1971). NPS may be categorized by chemical structure, by psychoactive properties, by biological targets, or by source (plant, synthetic, or combined). The emergence of hundreds of NPS in the past decade is challenging for public health and drug policies globally. The novelty of NPS, their ambiguous legal status, ability to evade toxicological tests, swift adaptation to legal restrictions, global Internet marketing, and scant public knowledge of their adverse effects are among the key drivers of this twenty-first century phenomenon. Multi-disciplinary research in areas of biology, epidemiology, prevention, and web analytics are needed to develop effective responses in a domain capable of overwhelming current international conventions and national drug control policies. Ultimately, research-guided prevention education will fortify societies against this tidal wave.