Adolescent religiousness and its influence on substance use: preliminary findings from the Mid-Atlantic School Age Twin Study.

Research has consistently shown that religiousness is associated with lower levels of alcohol and drug use, but little is known about the nature of adolescent religiousness or the mechanisms through which it influences problem behavior in this age group. This paper presents preliminary results from the Mid-Atlantic School Age Twin Study, a prospective, population-based study of 6-18-year-old twins and their mothers. Factor analysis of a scale developed to characterize adolescent religiousness, the Religious Attitudes and Practices Inventory (RAPI), revealed three factors: theism, religious/spiritual practices, and peer religiousness. Twin correlations and univariate behavior-genetic models for these factors and a measure of belief that drug use is sinful reveal in 357 twin pairs that common environmental factors significantly influence these traits, but a minor influence of genetic factors could not be discounted. Correlations between the multiple factors of adolescent religiousness and substance use, comorbid problem behavior, mood disorders, and selected risk factors for substance involvement are also presented. Structural equation modeling illustrates that specific religious beliefs about the sinfulness of drugs and level of peer religiousness mediate the relationship between theistic beliefs and religious/spiritual practices on substance use. Limitations and future analyses are discussed.     

Religion and depression: a review of the literature.

We reviewed data from approximately 80 published and unpublished studies that examined the association of religious affiliation or involvement with depressive symptoms or depressive disorder. In these studies, religion was measured as religious affiliation; general religious involvement; organizational religious involvement; prayer or private religious involvement; religious salience and motivation; or religious beliefs. People from some religious affiliations appear to have an elevated risk for depressive symptoms and depressive disorder, and people with no religious affiliation are at an elevated risk in comparison with people who are religiously affiliated. People with high levels of general religious involvement, organizational religious involvement, religious salience, and intrinsic religious motivation are at reduced risk for depressive symptoms and depressive disorders. Private religious activity and particular religious beliefs appear to bear no reliable relationship with depression. People with high levels of extrinsic religious motivation are at increased risk for depressive symptoms. Although these associations tend to be consistent, they are modest and are substantially reduced in multivariate research. Longitudinal research is sparse, but suggests that some forms of religious involvement might exert a protective effect against the incidence and persistence of depressive symptoms or disorders. The existing research is sufficient to encourage further investigation of the associations of religion with depressive symptoms and disorder. Religion should be measured with higher methodological standards than those that have been accepted in survey research to date.     

Prescribing of psychoactive drugs for chronically ill elderly patients.

The prescribing of psychoactive drugs for 1431 chronically ill elderly patients being assessed for long-term institutional or community care was surveyed. Psychoactive drugs had been prescribed for about one quarter of the patients; benzodiazepines were the most frequently prescribed group. Judging from the extensive prescribing of flurazepam and chloral hydrate, commonly used hypnotics, the main reason psychoactive drugs were prescribed was to provide night-time sedation. Antidepressants and drugs promoted as useful in improving cognitive function were infrequently prescribed. Commendable prescribing practices included the infrequent use of "cerebral vasodilators" and barbiturates. Questionable prescribing practices included the infrequent use of tricyclic antidepressants in severely depressed patients and the use of tranquilizers in patients described by their attending physician as markedly or extremely withdrawn.     

Screening the receptorome for plant-based psychoactive compounds

Throughout time, humans have used psychoactive plants and plant-derived products for spiritual, therapeutic and recreational purposes. Furthermore, the investigation of psychoactive plants such as Cannabis sativa (marijuana), Nicotiana tabacum (tobacco) and analogues of psychoactive plant derivatives such as lysergic acid diethylamide (LSD) have provided insight into our understanding of neurochemical processes and diseases of the CNS. Currently, many of these compounds are being used to treat a variety of diseases, such as depression and anxiety in the case of Piper methysticum Kava Kava (Martin et al., 2002; Singh and Singh, 2002). G-protein coupled receptors (GPCRs) are the most common molecular target for both psychoactive drugs and pharmaceuticals. The "receptorome" (that portion of the genome encoding ligand reception) encompasses more than 8% of the human genome (Roth et al., 2004) and as such provides a large number of possible targets for psychoactive drug interactions. A systematic, comprehensive study is necessary to identify novel active psychoactive plant-based compounds and the molecular targets of known compounds. Herein we describe the development of a high throughput system (HTS) to screen psychoactive compounds against the receptorome and present two examples (Salvia divinorum, the "magic mint" hallucinogen and Banisteriopsis caapi, the main component of Ayahuasca, a psychoactive beverage) where HTS enabled the identification of the molecular target of each compound.     

Expanding course goals beyond disciplinary boundaries: physiology education in an undergraduate course on psychoactive drugs

The topic of psychoactive drugs is one of inherent interest to college students. We used this insight to design and implement a multidisciplinary undergraduate course with psychoactive drugs as the central theme. The Medical Science of Psychoactive Drugs examines the biological mechanisms underlying all major effects of psychoactive drugs, including the effects on the brain and other organs and tissues. Physiological principles, molecular mechanisms, and genetic factors involved in drug-induced therapeutic and adverse effects are emphasized. The course is open to undergraduate students at all levels and carries no prerequisites, and enrollment is limited to approximately 50 students. Major teaching modes include lecture, short homework papers on topics related to the previous class meeting, small-group discussions at several points during each class, and whole class discussions. Because of the diversity of students' knowledge of basic science, we employ a variety of methods designed to help students grasp the necessary scientific concepts. Our methods are intended to be inquiry based and highly interactive. Our goals are 1) to foster the development of an organized knowledge base about psychoactive drugs that will have practical applicability in the daily lives of the students; 2) to promote the rational application of this knowledge in thinking about current medical, social, legal, and ethical issues involving psychoactive drugs; and 3) to cultivate science literacy, critical thinking, and communication skills among students.     

Synthetic cannabinoids and potential reproductive consequences

Increases in emergency room visits due to abuse of designer drugs, popularly known by the street names “K2” and “Spice,” are a cause for social, judicial, and clinical concerns. The psychoactive components in these herbal drugs mainly consist of different synthetic cannabinoids, and users of these street drugs are primarily within the age group of 12 to 20 years old. The abusive use of synthetic cannabinoids results in anxiety, nausea, vomiting, tachycardia, elevated blood pressure, tremors, seizures, hallucinations, and paranoid behavior, but the effects of maternal use of synthetic cannabinoids during pregnancy are ambiguous due to limited studies in humans and a relative short history of the drugs. In this review, we discuss the known and potential adverse effects of synthetic cannabinoids on human pregnancy using knowledge gathered from studies in mice and limited studies in humans. In mice, multiple sites and stages of pregnancy are potential targets of synthetic cannabinoids, including preimplantation embryo development, oviductal embryo transport, implantation, placentation, and parturition. It is anticipated that maternal use of synthetic cannabinoids would result in severely compromised female fertility and pregnancy outcome.     

The treatment of perinatal addiction. Identification,intervention, and advocacy.

Women of reproductive age who use and abuse psychoactive drugs and alcohol present a special challenge to primary care physicians. There are compelling medical reasons for identifying and intervening with pregnant women who are addicted or have alcoholism. The teratogenicity of all drugs of abuse and alcohol, the risk of infection with the acquired immunodeficiency syndrome (AIDS), and the potential for full recovery of a pregnant woman from addiction are some of the reasons that identification and intervention in the problem are indicated. Whether encountered in the clinic setting or in private practice, chemically dependent pregnant or postpartum women are usually responsive to appropriate physician interventions that include a detailed and caring confrontation- and advocacy-oriented support. Complex legal and ethical issues surround perinatal addiction including the role of toxicologic screening, reports to child welfare services, issues in noncompliance, and interdisciplinary case management.     

A twin study of personality and illicit drug use and abuse/dependence.

Although personality measures such as neuroticism (N), extraversion (E) and novelty-seeking (NS) are associated with the use and abuse/dependence of illicit drugs, little is known about the degree to which these associations are due to genetic or environmental factors. The goal of this analysis was to estimate the extent of genetic and environmental overlap between three dimensions of personality (N, E and NS) and illicit psychoactive substance use and abuse/dependence. Using data from adult male and female twins from the Mid-Atlantic Twin Registry, we used the structural equation modeling package Mx to perform bivariate Cholesky decompositions for personality measures of N, E and NS, individually with cannabis, cocaine, sedatives, stimulants and hallucinogens. This was done separately for use and for a polychotomous diagnosis of abuse and/or dependence. Sex differences were tested. The phenotypic relationship between personality and use and abuse/dependence of illicit drugs were moderate and most of the covariance was explained by genetic factors. Sexes could be equated for N and E but not for NS. For NS, use and abuse/dependence of illicit drugs showed greater phenotypic and genetic overlap in males than females. Of the personality measures, NS and illicit drug use and abuse/dependence were most closely related. NS was most closely related to cannabis use while N showed significant genetic overlap with sedative use. NS in males appears to be a good indicator of risk for cannabis use. This result may be useful for candidate gene studies.     

Off-target effects of psychoactive drugs revealed by genome-wide assays in yeast

To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 compounds that inhibited wild-type yeast growth and were thus selected for genome-wide fitness profiling. Many of these drugs had a propensity to affect multiple cellular functions. The sensitivity profiles of half of the analyzed drugs were enriched for core cellular processes such as secretion, protein folding, RNA processing, and chromatin structure. Interestingly, fluoxetine (Prozac) interfered with establishment of cell polarity, cyproheptadine (Periactin) targeted essential genes with chromatin-remodeling roles, while paroxetine (Paxil) interfered with essential RNA metabolism genes, suggesting potential secondary drug targets. We also found that the more recently developed atypical antipsychotic clozapine (Clozaril) had no fewer off-target effects in yeast than the typical antipsychotics haloperidol (Haldol) and pimozide (Orap). Our results suggest that model organism pharmacogenetic studies provide a rational foundation for understanding the off-target effects of clinically important psychoactive agents and suggest a rational means both for devising compound derivatives with fewer side effects and for tailoring drug treatment to individual patient genotypes.     

Novel psychoactive substances of interest for psychiatry

Novel psychoactive substances include synthetic cannabinoids, cathinone derivatives, psychedelic phenethylamines, novel stimulants, synthetic opioids, tryptamine derivatives, phencyclidine‐like dissociatives, piperazines, GABA‐A/B receptor agonists, a range of prescribed medications, psychoactive plants/herbs, and a large series of performance and image enhancing drugs. Users are typically attracted by these substances due to their intense psychoactive effects and likely lack of detection in routine drug screenings. This paper aims at providing psychiatrists with updated knowledge of the clinical pharmacology and psychopathological consequences of the use of these substances. Indeed, these drugs act on a range of neurotransmitter pathways/receptors whose imbalance has been associated with psychopathological conditions, including dopamine, cannabinoid CB1, GABA‐A/B, 5‐HT2A, glutamate, and k opioid receptors. An overall approach in terms of clinical management is briefly discussed.     

The diffusion of new genetic tests for predicting disease.

This paper examines the pathways by which new genetic tests will become available to the public. In view of the scarcity of genetic specialists, the pathway is likely to involve primary care physicians. Other pathways entail state-mandated testing, community-based programs, or testing by laboratories without much involvement of primary care physicians. When testing does become available the "destination" will be either family-centered testing or population-oriented screening. The deterrent to screening will not be the inability to detect disease-causing mutations but the costs and attitudes of providers and the public. When tests are provided primarily to provide information about risks to future children, some people will oppose screening on religious or moral grounds. When there are no inexpensive treatments, some will fear that insurance companies and employers will use tests to deny them health care coverage. Some may not want to know their risks for disorders about which little can be done. For common, multifactorial disorders, genetic tests will have low predictive value. Because of these problems, the decision to be tested, regardless of the destination, requires that "testees" be fully informed and consent to testing. When acceptance rates are low, screening is less likely to be cost-effective; family-centered testing becomes the default destination.     

Metabolism and Pharmacokinetics of Selective Serotonin Reuptake Inhibitors

1. Five drugs with the predominant pharmacologic effect of inhibiting the neuronal reuptake of serotonin are available worldwide for clinical use. This class of psychoactive drugs, known as selective serotonin reuptake inhibitors (SSRIs), is comprised of fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram.2. The SSRIs appear to share similar pharmacodynamic properties which translate to efficacy in the treatment of depression and anxiety syndromes. The drugs are differentiated by their pharmacokinetic properties with regard to stereochemistry, metabolism, inhibition of cytochrome enzymes, and participation in drug–drug interactions. Studies focusing on the relationship of plasma drug concentration to therapeutic and adverse effects have not confirmed the value of plasma concentration monitoring.3. This review summarizes the metabolism and relevant pharmacokinetic properties of the SSRIs.     

In vitro P-glycoprotein affinity for atypical and conventional antipsychotics

The transmembrane transporter P-glycoprotein (P-gp) is an ATP-dependent efflux pump for a wide range of drugs. P-gp potentially limits access to brain tissue of psychoactive substrates, but little is known about its specificity for antipsychotics. The objective of this study was to assess the affinity of some atypical antipsychotic drugs in vitro for P-gp as indicative of their potential as P-gp substrates in vivo. The activity of P-gp towards four atypical and two conventional antipsychotics and a proven substrate, verapamil, was examined by their P-gp ATPase activity, a putative measure of P-gp affinity. The Michaelis-Menten equation was fitted to the data. The rank order of the ratio V(max) / K(m) was: verapamil (2.6) > quetiapine (1.7) > risperidone (1.4) > olanzapine (0.8) > chlorpromzaine (0.7) > haloperidol (0.3) = clozapine (0.3). The atypical antipsychotics quetiapine and risperidone were relatively good P-gp substrates, although their affinities were not as high as verapamil. Olanzapine showed intermediate affinity and clozapine showed the least affinity of the drugs studied. These results suggest that P-gp is likely to influence the access to the brain of all of the atypical antipsychotics studied to various degrees. In vivo studies are needed to confirm these findings.     

Drogues anciennes, drogues nouvelles, pratiques actuelles (1re partie)

Ever since homo sapiens let go of the hand of the ape to descend from the trees, endowed with a large frontal brain allowing projection and self-reference in the dry savannah, humans left, finally erect, the shaded quiet of those fruit trees for a scary world full of danger and unknowns. From that point on, people invented gods, myths, language, and war and would search in magical plants for ways to relieve suffering and anxiety, ways of escaping the enclosing world, or, by contrast, find the courage to confront it. For millennia, drugs have been the objects of sacred, magical, and therapeutic knowledge. The entirety of medical psychopharmacology is based on the same foundations as this “primitive” psychopharmacology and the technological and scientific revolution of the 19th century, which made it possible to isolate active ingredients and synthesize new molecules, facilitating the emergence of specific means of consumption, increased by the planetary-scale circulation of people, objects, and information. This mass consumption and trafficking, and the profits they generate, create major public health challenges for modern societies, as well as serious sociopolitical and economic problems. In terms of evolution, pure psychoactive drugs and the direct means of administering them are recent phenomena and pathogenic in that they short-circuit adaptive processes by acting directly on the circuits of the primitive brain, which controls emotions and basic survival behaviour. In this way, psychoactive multiple drugs seem to translate into an evolution toward the true chemical regulation of existence. In this first section, we will discuss tranquilizers and psychostimulants, true “analogue” drugs that act as volume controls for wakefulness andmood. Often strongly addictive, they raise widely recognised social, medical and psychological issues, secondary to addiction and its consequences.     

Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite

Cytochrome P450 (P450) is a super-family of drug metabolizing enzymes. P450 enzymes have dual function; they can metabolize drugs to pharmacologically inactive metabolites facilitating their excretion or biotransform them to pharmacologically active metabolites which may have longer half-life than the parent drug. The variable pharmacological response to psychoactive drugs typically seen in population groups is often not accountable by considering dissimilarities in hepatic metabolism. Metabolism in brain specific nuclei may play a role in pharmacological modulation of drugs acting on the CNS and help explain some of the diverse response to these drugs seen in patient population. P450 enzymes are also present in brain where drug metabolism can take place and modify therapeutic action of drugs at the site of action. We have earlier demonstrated an intrinsic difference in the biotransformation of alprazolam (ALP) in brain and liver, relatively more alpha-hydroxy alprazolam (alpha-OHALP) is formed in brain as compared to liver. In the present study we show that recombinant CYP3A43 metabolizes ALP to both alpha-OHALP and 4-hydroxy alprazolam (4-OHALP) while CYP3A4 metabolizes ALP predominantly to its inactive metabolite, 4-OHALP. The expression of CYP3A43 mRNA in human brain samples correlates with formation of relatively higher levels of alpha-OH ALP indicating that individuals who express higher levels of CYP3A43 in the brain would generate larger amounts of alpha-OHALP. Further, the expression of CYP3A43 was relatively higher in brain as compared to liver across different ethnic populations. Since CYP3A enzymes play a prominent role in the metabolism of drugs, the higher expression of CYP3A43 would generate metabolite profile of drugs differentially in human brain and thus impact the pharmacodynamics of psychoactive drugs at the site of action.     

Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids

Cannabinoids and related drugs generate profound behavioral effects (such as analgesic effects) through activating CNR1 (cannabinoid receptor 1 [brain]). However, repeated cannabinoid administration triggers lysosomal degradation of the receptor and rapid development of drug tolerance, limiting the medical use of marijuana in chronic diseases. The pathogenic mechanisms of cannabinoid tolerance are not fully understood, and little is known about its prevention. Here we show that a protein involved in macroautophagy/autophagy (a conserved lysosomal degradation pathway), BECN2 (beclin 2), mediates cannabinoid tolerance by preventing CNR1 recycling and resensitization after prolonged agonist exposure, and deletion of Becn2 rescues CNR1 activity in mouse brain and conveys resistance to analgesic tolerance to chronic cannabinoids. To target BECN2 therapeutically, we established a competitive recruitment model of BECN2 and identified novel synthetic, natural or physiological stimuli of autophagy that sequester BECN2 from its binding with GPRASP1, a receptor protein for CNR1 degradation. Co-administration of these autophagy inducers effectively restores the level and signaling of brain CNR1 and protects mice from developing tolerance to repeated cannabinoid usage. Overall, our findings demonstrate the functional link among autophagy, receptor signaling and animal behavior regulated by psychoactive drugs, and develop a new strategy to prevent tolerance and improve medical efficacy of cannabinoids by modulating the BECN2 interactome and autophagy activity.     

云南高黎贡山怒族对植物传统利用的初步研究

采用民族生物学和文化人类学等方法,广泛调查和研究了云南西北部高黎贡山地区怒族对植物的传统利用形式。结果表明：怒族对植物的传统利用主要表现在食用、药用、观赏、宗教祟拜和文化利用等方面。讨论了怒族的传统文化在当地植物多样性利用和管理中的作用和意义,并探讨了在植物多样性管理中传统管理和现代管理之间的关系以及在我国利用文化多样性进行自然生态环境保护的可能性、必要性和可行性。此外,面对优秀的传统文化知识和文化多样性逐渐消失的现实,作者建议加以拯救和广泛的研究。     

Benzodiazepine drugs in general medical patients.

Data from a hospital-based drug surveillance programme were used to determine how often benzodiazepine drugs were used in general medical wards. Benzodiazepines were the drugs most commonly used as hypnotics and were given to 32% of these patients. Concomitant use of more than one benzodiazepine drug or of benzodiazepines with other psychoactive drugs was common and often irrational. A series of double-blind patient-preference studies comparing various benzodiazepines and a benzodiazepine with an antihistamine showed that for short-term hypnotic effect there were no differences between three common benzodiazepines but elderly patients preferred benzodiazepines to the antihistamine, which produced more undesired effects. These results suggest that currently diazepam is the hypnotic of choice for medical ward inpatients.