Introduction to the Special Issue on "Informing Longitudinal Studies on the Effects of Maternal Stress and Substance Use on Child Development: Planning for the HEALthy Brain and Child Development (HBCD) Study".

The HEALthy Brain and Child Development (HBCD) study will establish a large cohort of pregnant women from regions of the country significantly affected by the opioid crisis and follow them and their children for at least 10 years. Findings from this cohort will help researchers understand normative childhood brain development as well as the long-term impact of prenatal and postnatal opioid and other drug and environmental exposures. The study will collect data on pregnancy and fetal development; infant and early childhood structural and functional brain imaging; anthropometrics; medical history; family history; biospecimens; and social, emotional, and cognitive development. Knowledge gained from this research will be critical to help predict and prevent some of the known effects of prenatal and postnatal exposure to certain drugs or environmental exposures, including risk for future substance use, mental disorders, and other behavioral and developmental problems. In this special issue, a subset of investigators that received funding for planning grants for the HBCD study provide careful guidelines and frameworks for study design, recruitment and retention of vulnerable populations, culturally sensitive practices, and biospecimen and neurodevelopmental assessment recommendations gathered in feasibility studies that will help inform the full HBCD study planned to begin recruitment in 2022.

The conception of the ABCD study: From substance use to a broad NIH collaboration.

Adolescence is a time of dramatic changes in brain structure and function, and the adolescent brain is highly susceptible to being altered by experiences like substance use. However, there is much we have yet to learn about how these experiences influence brain development, how they promote or interfere with later health outcomes, or even what healthy brain development looks like. A large longitudinal study beginning in early adolescence could help us understand the normal variability in adolescent brain and cognitive development and tease apart the many factors that influence it. Recent advances in neuroimaging, informatics, and genetics technologies have made it feasible to conduct a study of sufficient size and scope to answer many outstanding questions. At the same time, several Institutes across the NIH recognized the value of collaborating in such a project because of its ability to address the role of biological, environmental, and behavioral factors like gender, pubertal hormones, sports participation, and social/economic disparities on brain development as well as their association with the emergence and progression of substance use and mental illness including suicide risk. Thus, the Adolescent Brain Cognitive Development study was created to answer the most pressing public health questions of our day.

Commentary: Navigating the complexities of marijuana.

Science needs to drive our thinking as we navigate a new legislative environment in which many Americans have access to marijuana for therapeutic or recreational use. With the responsibility to fund, conduct, and make use of the research on marijuana, and understand the impacts of new policies, comes the obligation of not thinking in simplistic, black-and-white terms about this substance. The drug's unique harms include neurodevelopmental impacts that may be long lasting or permanent, yet some evidence suggests the drug may benefit people with certain medical conditions (e.g., chronic pain). Marijuana use is also entangled with other substance use and should not be considered in isolation. Finally, policy options are not limited to the extremes of prohibition vs. full commercialization; a spectrum of intermediate options can and should be considered and evaluated as states create new policies around this drug.

Building smart cannabis policy from the science up.

Social attitudes and cultural norms around the issue of substance abuse are shifting rapidly around the world, leading to complex and unpredictable consequences. On the positive side, efforts to more intensely disseminate the scientific evidence for the many connections between chronic substance use and the emergence of measurable and discrete brain dysfunctions, has ushered in an evolving climate of acceptance and a new era of improved access to more effective interventions, at least in the United States. On the negative side, there has been a steady erosion in the public perception of the harms associated with the use of popular drugs, especially cannabis. This worrisome trend has sprouted at the convergence of several forces that have combined, more or less fortuitously, to effectively change long-standing policies away from prohibition and toward decriminalization or legalization. These forces include the outsized popularity of the cannabis plant among recreational users, the unflagging campaign by corporate lobbyists and patient advocates to mainstream its medicinal use, and the honest realization in some quarters of the deleterious impact of the drug war and its draconian cannabis laws, in particular, on society's most vulnerable populations. Updating drug policies is a desirable goal, and significant changes may indeed be warranted. However, there is a real concern when policy changes are hurriedly implemented without the required input from the medical, scientific, or policy research communities. Regardless of how well intentioned, such initiatives are bound to magnify the potential for unintended adverse consequences in the form of far ranging health and social costs. To minimize this risk, science must be front and center in this important policy debate. Here, we review the state of the science on cannabis and cannabinoid health effects, both adverse and therapeutic. We focus on the prevalence of use in different populations, the mechanisms by which cannabis exerts its effects (i.e., via the endocannabinoid system), and the double-edged potential of this system to inspire new medications, on one hand, and to cause short and long term harmful effects on the other. By providing knowledge of cannabis' broad ranging effects, we hope to enable better decision making regarding cannabis legislation and policy implementation.

Tolerance to the prophylactic effects of carbamazepine and related mood stabilizers in the treatment of bipolar disorders.

Tolerance development after successful long-term treatment of bipolar disorder is under recognized, as are ways to prevent or show its occurrence or reverse it once it has occurred. We review the clinical literature which suggests that tolerance can develop to most treatment approaches in bipolar illness and present an animal model of tolerance development to anticonvulsant effects of carbamazepine or lamotrigine on amgydala-kindled seizures. In this model tolerance does not have a pharmacokinetic basis, but is contingent upon the drug being present in the brain at the time of amygdala stimulation. The occurrence of seizures in the absence of drug is sufficient to reverse tolerance and re-establish anticonvulsant efficacy. Based on the model, we hypothesize that some episode-induced compensatory adaptive changes in gene expression fail to occur in tolerant subjects and that episodes off medication re-induce these changes and renew drug effectiveness. Approaches that slow or reverse tolerance development in the animal model are reviewed so that they can be tested for their applicability in the clinic. Criteria for assessing tolerance development are offered in the hope that this will facilitate a more systemic literature about its prevalence, prevention, and reversal. Careful longitudinal monitoring of episode occurrence is essential to understanding tolerance development in the affective disorder and its treatment.

Gender effects on drug use, abuse, and dependence: a special analysis of results from the National Survey on Drug Use and Health.

BACKGROUND: Gender is increasingly being studied for risk and protective factors underlying substance abuse and addiction. OBJECTIVE: The aim of this study was to assess gender differences in rates of substance abuse and dependence among drug users. METHODS: A national population sample was examined, focusing on 2 age groups (youths, aged 12-17 years, and young adults, aged 18-25 years) and several commonly abused substances (alcohol, marijuana, and nonmedical prescription medication use). Combined annual data from the National Survey on Drug Use and Health (NSDUH), aggregated from 2002-2005, were used for gender comparisons of rates of substance use, as well as abuse and dependence, among users. RESULTS: Overall rates of substance use were significantly higher for males than for females (P < 0.01 for all substances except sedatives and tranquilizers); however, patterns of use, abuse, or dependence among users differed by age group and drug. Interestingly, patterns for youths differed from the overall population and from young adults. Girls exceeded boys in their use of alcohol (P < 0.01) and their nonmedical use of psychotherapeutics (ie, prescription-type pain relievers, stimulants, tranquilizers, sedatives) (P < 0.01); among users, girls were significantly more likely to be dependent on the latter (P < 0.01). Boys reported significantly greater use and abuse of and dependence on marijuana (P < 0.01). In the young adults, the proportion of female users reporting dependence on cocaine or psychotherapeutics was significantly higher than for male users (P < 0.01), who nonetheless reported significantly greater use of these drugs (P < 0.01). Among users, males generally exceeded females in meeting abuse criteria (P < 0.01 for marijuana among 12- to 17-year-olds and for alcohol, marijuana, and psychotherapeutics among 18- to 25-year-olds), with some exceptions mainly in the youngest cohort. CONCLUSIONS: In this national population sample of youths and young adults, these findings suggest that gender, age, and substance of abuse may all play a role in the observed patterns of drug use, abuse, and dependence. Understanding the reasons for these differences and continuing to evaluate these patterns over time could help in the development of targeted and more effective prevention and treatment interventions.

Drugs of abuse and the aging brain.

Substance abuse among older adults has received little attention in the past, presumably because this population has traditionally accounted for only a small percentage of the drug abuse problem in the United States. The aging of the baby boomer generation (born 1946-1964), however, will soon swell the ranks of older adults and dramatically alter the demography of American society. Several observations suggest that this expansion will likely be accompanied by a precipitous increase in the abuse of drugs, including prescription medications and illicit substances, among older adults. While it is now evident that the brain changes continuously across life, how drugs of abuse interact with these age-related changes remains unclear. The dynamic nature of brain function, however, suggests that substance abuse during older age may augment the risks and require unique considerations for diagnosis and treatment. In addition to describing current and projected prevalence estimates of substance abuse among older adults, the present review discusses how aging affects brain systems involved in drug abuse, and explores the potential impact of drug abuse on the aging brain. Future directions for substance abuse research among older adults will also be considered.

Convergences in course of illness and treatments of the epilepsies and recurrent affective disorders.

The failure to achieve and maintain remission is a critical problem for a high percentage of patients with epilepsy and the primary affective disorders. Early illness onset and delayed initiation of treatment may contribute to primary treatment resistance or that associated with loss of efficacy (tolerance phenomenon). Neurobiological data and principles drawn from the amygdala kinding model of seizure progression are reviewed for their heuristic value in conceptualizing molecular mechanisms of illness progression and its prevention with pharmacological agents in the epilepsies and, indirectly, the recurrent affective disorders. Caveats in the use of this model and convergences and divergences in its predictive validity for seizures and affective disorders are noted.

Emerging issues in gender and ethnic differences in substance abuse and treatment.

The emerging understanding of gender differences among ethnic minorities in the rates, etiology, course, and treatment of substance abuse and common comorbid mental health disorders has significant scientific and practical implications. Growing recognition of these differences and their implications for treatment and policy decisions has highlighted research gaps and the need for more thoughtful application of the knowledge gained from existing research findings. In this brief review, we outline some of the unique aspects of substance abuse and comorbid mental health problems for women, as well as for women of various ethnic/cultural groups, including specific barriers to obtaining and remaining in treatment. Research challenges to improving limited knowledge about the rates, course, and treatment of substance abuse disorders among ethnic minority women are highlighted.

Coadministration of gabapentin or MK-801 with lamotrigine slows tolerance to its anticonvulsant effects on kindled seizures.

The development of tolerance to therapeutic effects of antiepileptic drugs can be a problem in the treatment of epilepsy, bipolar disorder, and pain syndromes. In the present study, acute treatment with the new antiepileptic drug lamotrigine (LTG, 15 mg/kg) markedly suppressed seizure stage and seizure duration in amygdala-kindled rats; but this antiseizure effect was rapidly lost following 4-8 days of repeated treatment. When gabapentin (GBP, 20 mg/kg) was coadministered with LTG, the ability of LTG to suppress seizure stage, seizure duration, and after-discharge (AD) duration was markedly extended. In addition, GBP coadministration with LTG decreased the number of animals that developed LTG-related running fits (Stage 6 seizures) and lengthened the number of days required to develop running fits or complete tolerance. Neither acute nor repeated treatment with MK-801 (0.3 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, had effects on kindled seizures. However, cotreatment with MK-801 markedly extended the anticonvulsant effects of LTG on the three seizure indices and reduced running fits. These data indicate that cotreatment with either GBP or MK-801 slows tolerance development to the anticonvulsant effects of LTG on kindled seizures. Therapeutic implications of the present study remain to be explored.

Psychological complexity: barriers to its integration into the neurobiology of major psychiatric disorders.

In the authors' experience interactions between clinical and laboratory research have been greatly mutually facilitatory in the understanding and development of new treatments for the major mental illnesses. Examples in the literature are also highlighted to show how cross-disciplinary studies are important in understanding the subtle interactions of genetic and environmental mechanisms in psychiatric illness. Yet, the results of some current science policies encouraging project focus and superspecialization can lead to the separation of clinical and basic investigators, which threatens the integration of psychological complexity into the neurobiology of psychiatry at both a molecular and behavioral level. This paper endorses renewed effort toward the multidisciplinary team approach under the leadership of a physician-scientist in order to better integrate many fields of study critical to ameliorating the effects of psychiatric illness.

The benzodiazepine partial inverse agonist Ro15-4513 alters anticonvulsant and lethal effects of carbamazepine in amygdala-kindled rats.

Ro15-4513 (ethyl-8-azido-5,6-dihydro-5methyl-6-oxo-4H-imidazo-[1,5-a]-1,4-benzodiazepine-3-carboxylate), a benzodiazepine partial inverse agonist of the GABA(A) receptor, is known to protect against alcohol toxicities. The present study was designed to determine the role of Ro15-4513 in preventing anticonvulsant, toxic, and lethal effects of carbamazepine (CBZ) in amygdala-kindled rats. Acute treatment with CBZ (25 mg/kg, i.p.) produced anticonvulsant effects in fully kindled rats characterized by a significant decrease in afterdischarge and seizure duration and stage. Repeated administration of this high dose of CBZ induced sedation and high (56%) lethality. The anticonvulsant and sedative effects of CBZ were strikingly suppressed by pretreatment with Ro15-4513 (2.5 and 5 mg/kg, i.p.), and there was no mortality in animals co-administrated with Ro15-4513 during the entire experimental period. These results indicate that Ro15-4513 protects against CBZ-induced sedation and lethality, while suppressing the anticonvulsant effects of CBZ, suggesting a role for the GABA(A) receptor in CBZ efficacy and side effects. The potential clinical implications for CBZ-induced toxicity and overdose remain to be explored.

Perspectives on the Mechanism of Action of Electroconvulsive Therapy: Anticonvulsant, Peptidergic, c-fos Proto-oncogene Effects.

Although the mechanism of action of electroconvulsive therapy (ECT) in affective illness has remained elusive, it is hoped that the consideration of mechanisms underlying the anticonvulsant efficacy of ECT will provide new insights into its biochemical and neuroanatomical substrates. In the amygdala-kindling model, electroconvulsive seizures (ECS) inhibit both the development and completed phases of kindled seizure evolution, and therefore, ECS is a more potent anticonvulsant modality than carbamazepine, which inhibits only completed kindled seizures. Carbamazepine is increasingly recognized for its acute and prophylactic efficacy in bipolar affective illness. Thus, comparing and contrasting effects of ECS and carbamazepine may provide insights into overlapping mechanisms of anticonvulsant and psychotropic action. Anticonvulsant effects of ECS have been most closely linked to endogenous opiate substances, perhaps acting on delta-opiate receptors, but a wide variety of other neurotransmitter and peptidergic effects are also potential candidates. Electroconvulsive seizures in mice activate the proto-oncogene c-fos in many discrete areas of brain, including a variety of limbic sites, the ventromedial nucleus of the hypothalamus, and the cerebellum. As such, c-fos induction may provide both an anatomical map of areas potentially activated by ECS and a potential mechanism for initiating a sequence of events that may be important to the mechanism of action of ECT. Although the anticonvulsant effects of ECT may ultimately prove to be separable from those mediating its therapeutic effects in affective illness, seizures and anticonvulsant effects provide easily measurable endpoints for preclinical and clinical studies. Given this clarity of effect, potential anticonvulsant mechanisms can rapidly be identified, enabling direct testing of whether or not these same mechanisms are also critical to the therapeutic effects of ECT in affective illness.