The receptors for tetrahydrocannabinol, the active ingredient of marijuana, have been identified. A microsatellite polymorphism (AAT) n at the cannabinoid CB1 (brain) receptor gene (CNR1) consists of 9 alleles. Since the cannabinoid system is part of the reward pathway we examined the hypothesis that genetic variants of the CNR1 gene might be associated with susceptibility to alcohol or drug dependence. The study consisted of 92 subjects on an Addiction Treatment Unit (ATU) and 114 controls. All were non-Hispanic Caucasians. The ATU subjects were screened for all types of substance dependence using the Diagnostic Interview Schedule (DIS), and for a variety of substance abuse symptoms using the Addiction Severity Index (ASI). Since inspection of the distribution of alleles in controls vs IV drug use showed a decrease in the frequency of the 4 allele, and the Ͻ4 alleles were rare, the alleles were divided into two groups, Ͻ5 and Ն5, and three genotypes Ͻ5/Ͻ5, heterozygotes, and Ն5/Ն5. When all variables were subjected to factor analysis, factor 1 showed a clustering of drug dependence variables and factor 2 of alcohol dependence variables. By ANOVA only factor 1 showed significant differences by genotype consistent with a model where homozygosity for the Ն5 repeat alleles showed the greatest effect. The number of IV drugs used was significantly greater for those carrying the Ն5/Ն5 genotype than for other genotypes (P = 0.005). The association with specific types of drug dependence was greatest for cocaine, amphetamine, and cannabis dependence. The results are consistent with a role of cannabinoid receptors in the modulation of dopamine and cannabinoid reward pathways. Independent studies should be designed to further confirm the hypothesis that cannabinoid receptors may contribute to the susceptibility to drug abuse.

Prior studies have reported an association between the presence of the 7 repeat allele of the 48 bp repeat polymorphism of the third cytoplasmic loop of the dopamine D4 receptor gene (DRD4) and novelty seeking behaviors, attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), pathological gambling, and substance abuse. However, other studies have failed to replicate some of these observations. To determine whether we could replicate these associations we genotyped 737 individuals from four different groups of control subjects, and 707 index subjects from four different groups of impulsive, compulsive addictive behaviors including substance abuse, pathological gambling, TS, and ADHD. Chi-square analysis of those carrying the 7 allele versus non-7 allele carriers was not significant for any of the groups using a Bonferroni corrected alpha of.0125. However, chi-square analysis of those carrying any 5 to 8 allele versus noncarriers was significant for pathological gambling (p <.0001), ADHD (p

This paper presents a simple Bayesian approach to sample size determination in clinical trials. It is required that the trial should be large enough to ensure that the data collected will provide convincing evidence either that an experimental treatment is better than a control or that it fails to improve upon control by some clinically relevant difference. The method resembles standard frequentist formulations of the problem, and indeed in certain circumstances involving 'non-informative' prior information it leads to identical answers. In particular, unlike many Bayesian approaches to sample size determination, use is made of an alternative hypothesis that an experimental treatment is better than a control treatment by some specified magnitude. The approach is introduced in the context of testing whether a single stream of binary observations are consistent with a given success rate p(0). Next the case of comparing two independent streams of normally distributed responses is considered, first under the assumption that their common variance is known and then for unknown variance. Finally, the more general situation in which a large sample is to be collected and analysed according to the asymptotic properties of the score statistic is explored.

After having controlled for differences in body mass, V0(2max) did not differ between pure endurance sports (P > 0.05). Assuming that athletes' thigh muscle mass increases in proportion to body mass as observed in study 2, a similar disproportional increase in V0(2max) would be anticipated, providing a plausible explanation for the inflated mass exponent associated with V0(2max) identified in this and other studies.

In addition to neurotransmitters, hormones, acting through the blood stream, also play a role in behavior. To test the potential contribution of genetic variations in hormone receptors we have examined the association between the alleles of the dinucleotide repeat of the estrogen receptor 1 gene (ESR1) and the nine subscores and total score of the SCL-90 in a group of 179 adult males treated for substance abuse. Based on our prior hypothesis that the length of repeat polymorphisms may play a direct role in gene regulation, the alleles were divided into two groups, short (S) and long (L). ANOVA of the SS, LS, and LL genotypes showed a significant association at ␣ Յ0.05 for three of the SCL-90 scores: anxiety, phobic anxiety, and total symptoms. Of these the anxiety score remained significant at a Bonferroni corrected ␣ of Յ0.005. By regression analysis, the ESR1 gene accounted for 7% of the variance of the anxiety score (P Յ 0.0004). These results are consistent with a role of the ESR1 gene in human behavior. Since estrogen levels are much higher in women than men, this could account for the increased frequency of anxiety in women.Pert 1 (p 139) pointed out that the majority of neurons that release specific neurotransmitters or neuropeptides are not immediately adjacent to the neurons that carry the corresponding receptors. This suggests that many of the most important events in the brain may occur at a distance-as hormones. Estrogen exerts a profound effect on mood and memory through its action on monoamine and neuropeptide transmitter mechanisms in the brain. 2 We previously observed that the alleles of two trinucleotide repeat polymorphisms of the first exon of the androgen receptor gene (AR) are significantly associated with a range of disruptive behavioral disorders. 3 This led us to also examine the estrogen receptor gene (ESR1). Evidence that this gene plays a role in behavior in animals comes from studies showing that ESR1 knockout mice show aggressive behaviors. 4 While variants of the ESR1 gene have been implicated in osteoporosis and osteoarthritis, 5-7 there have been no prior studies of the role variants of the ESR1 in human behavior. To examine this we have genotyped 179 subjects with substance abuse at a highly polymorphic dinucleotide repeat of the ESR1 gene. 8 The SCL-90 9 was utilized as a screening test for depression, anxiety, and related disorders.The distribution of the 787 alleles of the ESR1 gene that we have genotyped in our laboratory, for this and other studies, is shown in Figure 1 There was no significant difference in the frequency of the S vs the L alleles in the three racial groups. Table 1 shows the results of ANOVA for the ATU subjects of all racial groups, for the nine sub-scores of the SCL-90 and the total SCL-90 score (number of nonzero scores). There was a progressive decrease in the mean anxiety score from the LL, to SL to SS groups (P Ͻ 0.002) (Figure 2). By linear ANOVA P = 0.0005. Two other scores were significant at P Յ 0.05, phobic anxiety and total symptoms, but did no...