Treatment of cannabis dependence using escitalopram in combination with cognitive-behavior therapy: a double-blind placebo-controlled study.

BACKGROUND: Cannabis is the most frequently used illegal substance in the United States and Europe. There is a dramatic increase in the demand for treatment for cannabis dependence. Cannabis users frequently have co-morbid mood symptoms, especially depression and anxiety, and regular cannabis users may self-medicate for such symptoms. OBJECTIVES: We report a double-blind, placebo-controlled treatment study, for the prevention of cannabis use in cannabis-dependent individuals. METHOD: Regular cannabis-dependent users (n = 52) were treated for 9 weeks with weekly cognitive-behavior and motivation-enhancement therapy sessions together with escitalopram 10 mg/day. Urine samples were collected to monitor delta-9 tetrahydrocannabinol (THC) during treatment and questionnaires were administered to assess anxiety and depression. RESULTS: We observed a high rate of dropout (50%) during the 9-week treatment program. Fifty-two patients were included in the intention-to-treat analysis. Of these, ten (19%) remained abstinent after 9 weeks of treatment as indicated by negative urine samples for THC. Escitalopram provided no advantage over placebo in either abstinence rates from cannabis or anxiety and depression scores during the withdrawal and abstinent periods. CONCLUSIONS: Escitalopram treatment does not provide an additional benefit either for achieving abstinence, or for the treatment of the cannabis withdrawal syndrome. Due to limitations of our study, namely, a high dropout rate and effects of low abstinence rates on measures of anxiety, depression and withdrawal, it is premature to conclude that selective serotonin reuptake inhibitors are not effective for treatment of the cannabis withdrawal syndrome.

Strategy for increasing detection rates of drug and alcohol abuse in paediatric emergency departments.

AIM: To determine whether implementation of criteria for performing a toxicology screen and increasing staff awareness improve detection of substance abuse among adolescents presenting to the emergency department. METHODS: Patients 12 to 18 years of age presenting to one of three emergency departments in Israel were included in a prospective cohort study. In the 'study' hospital, a set of criteria for urine toxicology screen and measurements of ethanol serum level were implemented. No specific interventions were implemented in the two other hospitals. The main outcome measure was the rate of substance abuse detection. RESULTS: The number of adolescents seen in the participating centres was 3200 at the study hospital, and 3493 and 2792 at the two other hospitals. High blood ethanol concentrations were found in 49 patients at the study hospital compared with 30 and 19 patients at the two other hospitals (p < 0.001). Illicit drugs were detected in 13, 4 and 1 patients, respectively (p = 0.002). CONCLUSIONS: Introducing structured guidelines for ordering toxicological screening increases the detection of alcohol and drug of abuse among adolescents presenting to paediatric emergency departments.

A study investigating the acute dose-response effects of 13 mg and 17 mg Delta 9- tetrahydrocannabinol on cognitive-motor skills, subjective and autonomic measures in regular users of marijuana.

Heavy use of marijuana is claimed to damage critical skills related to short-term memory, visual scanning and attention. Motor skills and driving safety may be compromised by the acute effects of marijuana. The aim of this study was to investigate the acute effects of 13 mg and 17 mg Delta 9-tetrahydrocannabinol (THC) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana. Fourteen regular users of marijuana were enrolled. Each subject was tested on two separate days. On each test day, subjects smoked two low-nicotine cigarettes, one with and the other without THC. Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day. The sequence of cigarette types was unknown to the subject. During smoking, heart rate and blood pressure were monitored, and the subjects performed a virtual reality maze task requiring attention and motor coordination, followed by 3 other cognitive tasks (Wisconsin Card Sorting Test (WCST), a "gambling" task and estimation of time and distance from an approaching car). After smoking a cigarette with 17 mg THC, regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC; this effect was not seen in patients after they smoked cigarettes with 13 mg THC. Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC. Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC, but not with 13 m THC. Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction, drug "effect" and drug "high". These findings imply that smoking of 17 mg THC results in impairment of cognitive-motor skills that could be important for coordinated movement and driving, whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana.

The effect of mianserin add-on, on the intensity of opioid withdrawal symptoms during detoxification program--a randomized, double blind, placebo controlled, prospective study.

BACKGROUND: Based on pre-clinical studies regarding the interaction of various antidepressant drugs with the opioid system, we designed a clinical study to be carried out in the 'in-patient detoxification unit' within a large community centre for treatment of drugs dependent people. We evaluated the effect of mianserin add-on, on the intensity of opioid withdrawal symptoms in opiate dependent subjects undergoing medication-supported physical detoxification and integrated psychosocial and psychotherapeutic intervention for the treatment of dependence. METHODS: Mianserin (or placebo) was added to the routine medication protocol, during the 3-week in-patient phase of detoxification in a prospective, randomized, double blind, placebo controlled study. Mianserin (or placebo) was continued after discharge and patients were followed up for 3 months in order to evaluate relapse rates. Opiate withdrawal symptoms were assessed during the first 10 days, while depression and anxiety were assessed throughout the 3 months of study. RESULTS: From day 2 onward, patients in the study group showed significantly lower withdrawal symptoms than the control group patients and reached this peak faster (study group 2.8 days, control group 3.2 days, p<0.001). However, drop out rates were higher in the study group throughout the study period and only 13% of the study group patients, compared to 30% of the control group patients reached the end point. CONCLUSION: Though adding mianserin to the medication treatment during detoxification of opiate-dependent persons attenuated significantly both the intensity and the duration of withdrawal symptoms, the overall drop out rate was negatively influenced in the study group compared to the control group and fewer patients completed the study. Further study is needed in order to establish the origin of the paradox of higher drop out rates in the presence of attenuated intensity and duration of opiate withdrawal symptoms in the study group, and the clinical implications that should be drown.

Mianserin and trazodone significantly attenuate the intensity of opioid withdrawal symptoms in mice.

The aims of this study were to evaluate the effects of trazodone and mianserin on opioid-withdrawal symptoms in morphine-dependent mice. We used a comparative study of the effect of each drug on withdrawal symptoms in one model of acutely high-dose morphine-dependent mice, and two models (high-dose and lu-dose) of chronically morphine-dependent mice at the Tel Aviv University Sackler School of Medicine's laboratory.Trazodone, mianserin or both were given to the morphine-dependent mice together with a high dose of naloxone. Intensity of withdrawal symptoms was evaluated by tail-flick assay latencies and three behavioural measurements (rearing, jumping and grooming) in each group. Trazodone and mianserin, each separately,significantly attenuated withdrawal symptoms in all three models. However, the combined treatment of trazodone together with mianserin was not superior to each drug alone. The combination of trazodone and mianserin has no additive value to each drug alone in the control of withdrawal symptoms in opiate-dependent mice undergoing detoxification. When used in clinical settings, caution is needed in order to prevent the unknown influence of opioid-like drugs in medication-assisted detoxification programmes if complete opiate detoxification is the aim.

Developmental outcome of school-age children born to mothers with heroin dependency: importance of environmental factors.

Development of children aged 5 to 12 years born to mothers with heroin dependency raised at home or adopted was studied in comparison with: (1) children with environmental deprivation alone (i.e. low parental socioeconomic status [SES] and evidence of neglect), (2) children born to fathers with heroin dependency fathers, and (3) control individuals of average SES. One hundred and sixty children (84 males and 76 females; average age at examination 8 years) were evaluated between 1998 and 1999. All were attending mainstream schools. All participants were examined by a paediatrician and a psychologist using standard neurological and psychological age-appropriate tests, as well as tests and questionnaires to assess learning ability and attention span. The Conners and Achenbach questionnaires and the Pollack Taper test were used to assess possible presence of attention-deficit-hyperactivity disorder (ADHD). Mothers were assessed for ADHD using Wender's questionnaire. Children born to parents with heroin dependency raised at home and those of low SES exhibited intellectual impairment both on verbal and performance skills. They also had impaired reading and arithmetic skills. Children born to mothers with heroin dependency but who were adopted at a young age had normal intellectual and learning abilities, except for some reduced function on the performance Wechsler Intelligence Scale for Children-Revised. We found a high rate of ADHD among all children born to parents with heroin dependency, including those adopted, as well as in children with low parental SES. The highest rate of ADHD was in children born to mothers with heroin dependency raised at home, being twice that observed in the other groups. Mothers of these groups of children also had a high rate of ADHD.

[Drug abuse among patients requiring psychiatric hospitalization].

We assessed the incidence of drug abuse among patients requiring psychiatric hospitalization, and characterized the population at risk. The data on drug abuse were obtained from self-reports and urine tests in 103 patients, aged 18-65, hospitalized in the Kfar Shaul Psychiatric Hospital (autumn 1998). There was close correspondence between the self-reports and the results obtained from urine tests. 1/3 admitted to having used illegal drugs and signs of drug abuse were found in about 1/4 of the urine tests. The most prevalent drugs were cannabis products (hashish and/or marijuana) and in 15 patients opiates. Drug users were younger than non-users. With regard to psychiatric symptomatology, fewer negative symptoms were recorded among cannabis abusers with schizophrenia, compared to schizophrenic patients with no history, past or present, of cannabis abuse. The present findings confirm the clinical impression that there has been an increase in drug abuse among mental patients, parallel to that found in society at large. Confirmatory surveys are necessary. Our findings clearly suggest that a change in attitude has occurred in Israel to what has been considered a marginal problem. Hospitalized mentally-ill patients, the younger in particular, should be considered at risk for drug abuse.

The developmental outcome of children born to heroin-dependent mothers, raised at home or adopted.

In the present investigation we were interested to study the possible role of in-utero exposure to heroin and of the home environmental in the etiology of long-term developmental problems in children born to heroin-dependent parents in comparison to matched controls. The children were examined at .5-6 years of age by a developmental pediatrician and a developmental psychologist using, for the children up to 2.5 years of age, the Bayley Developmental Scales, and for children aged 3-6 years the McCarthy Scales for Children's Abilities. We examined 83 children born to heroin-dependent mothers, and compared the results to those of 76 children born to heroin-dependent fathers and to three control groups; 50 children with environmental deprivation, 50 normal children from families of moderate or high socioeconomic class, without environmental deprivation, and 80 healthy children from kindergartens in Jerusalem. There were five children (6.0%) with significant neurological damage among the children born to heroin-dependent mothers and six (7.9%) children among those born to heroin-dependent fathers. The children born to heroin-dependent mothers had a lower birth weight and a lower head circumference at examination when compared to controls. The children born to heroin-dependent parents also had a high incidence of hyperactivity, inattention, and behavioral problems. The lowest DQ or IQ among the children with cognitive levels above 70 was found in the children with environmental deprivation, next was the DQ or IQ of children born to heroin-dependent fathers, then the DQ or IQ of the children born to heroin-dependent mothers. When the children born to heroin-dependent mothers were divided to those that were adopted at a very young age and to those raised at home, the adopted children were found to function similarly to the controls while those not adopted functioned significantly lower. Our results show that the developmental delay and behavioral disorders observed among children born to drug-dependent parents raised at home may primarily result from severe environmental deprivation and the fact that one or both parents are addicted. The specific role of the in-utero heroin exposure in the determination of the developmental outcome of these children (if they do not have significant neurological damage), seems to be less important in comparison to the home environment.

Electro-encephalography spectral analysis of heroin addicts compared with abstainers and normal controls.

UNLABELLED: Previous studies have shown that opiates slow the EEG and, in high doses, reduce the threshold of seizure activity. The present work looks at computerized EEG analyses (in the Fast Fourier Transform-FFT-method) of heroin addicts, recent abstainers and normal controls, with the aim of comparison and delineation of group characteristics. Examinations of 60 taped EEG recordings were performed: 20 subjects were current heroin users, 20 were recent abstainers and 20 were normal controls. Statistical analysis was performed for the relative frequency of wave bands. To amplify the known findings of slowing in heroin users, specific ratios were calculated: the alpha ratio (namely, the 8.0-9.5 Hz to 9.5-12.0 Hz ratio) and the delta to low alpha ratio. The specificity and sensitivity of the FFT method were evaluated through the use of discriminant analysis. The EEG was also recorded on conventional paper and evaluated by a neurologist. RESULTS: The addicts had a higher alpha ratio. The abstainers had a slowing of their alpha waves, a high incidence of delta waves and a delta to low alpha ratio that was relatively high. As a function of time from the beginning of abstinence, this ratio decreased. Abstainers for more than 80 days and controls had identical EEGs. The FFT method had 50% sensitivity for the addicts and 70% for the abstainers, while the specificity was 55%. In contrast, the neurologist's reading of the EEG had a very low sensitivity (25% for the addicts, 30% for the abstainers and 20% for the controls) and a 70% specificity.

Characterization of a triple opioid system in the human neuroblastoma NMB cell line.

The human neuroblastoma NMB cell line was found to contain the three types of opioid receptors (60% delta 25% kappa and 15% mu). The opioid receptors were negatively coupled to adenylyl-cyclase. Maximal reduction in cAMP content was achieved by selectively activating single receptor types, indicating the co-presence of the various opioid receptors in the same cells. The opioid receptors in NMB cells were up-regulated following prolonged exposure to the opioid antagonist naloxone and down-regulated following chronic treatment with the opioid agonist etorphine. Down-regulation was time-, dose- and temperature-dependent and was inhibited by colchicine and sodium azide. The NMB culture is presented as an excellent experimental model for studying the selective activation and regulation of the different opioid receptor types when they are co-expressed in the same neuron, as well as for studying interactions between the various opioid receptors.

The efficacy of naltrexone in preventing reabuse of heroin after detoxification.

The efficacy of Naltrexone in preventing reabuse of heroin among heroin addicts in Israel was studied in a double-blind, controlled design. Naltrexone (or placebo) treatment was given as part of a general treatment plan that continued for 12 weeks. Thirty-two addicts who successfully completed a detoxification program and met research criteria, were included in the study. Fifty milligrams of Naltrexone were taken orally three times a week (25 mg twice a week for the first 2 weeks). The follow-up procedure included an interview, urine tests, and screening for possible adverse effects. In addition, social and psychological parameters were evaluated. Fewer heroin-positive urine tests were found the Naltrexone group than in the placebo group. Throughout the entire study, the number of drug-free patients in the Naltrexone group was higher than in the placebo group. The Naltrexone group showed a significant improvement in most psychological parameters as compared with the placebo group. No differences were found in compliance or ratio of adverse effects between the Naltrexone and placebo groups. The concept "heroin abuse load" based on daily heroin consumption and duration of addiction enabled us to predict which addicts would complete the treatment program. The results suggest that heroin addicts in Israel may benefit from treatment with Naltrexone.