U Busto's research while affiliated with Centre for Addiction and Mental Health and other places

Publications (70)

Article
Full-text available
Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA...
Article
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The presentation of drug-associated cues has been shown to elicit craving and dopamine release in the striatum of drug-dependent individuals. Similarly, exposure to tobacco-associated cues induces craving and increases the propensity to relapse in tobacco- dependent smokers. However, whether exposure to tobacco-associated cues elicits dopamine rele...
Article
Full-text available
The association between cigarette smoking and depression has been well documented; however, little research has been done to elucidate the neurobiological substrates of this highly prevalent comorbidity. We used multiple linear regression analysis to evaluate the relationship between depression severity as assessed by the Hamilton Depression Rating...
Article
Following the introduction of mandatory Canadian folic acid flour fortification in mid-1997, the incidence of selected childhood cancers that declined in Ontario prior to and subsequent to this public policy initiative was examined. A population-based cohort study of all incident cases of childhood malignancy in Ontario between the years 1985 and 2...
Article
Variation in the activity of cytochrome P450 2D6 (CYP2D6) affects the pharmacokinetics and effectiveness of dextromethorphan (DM), because it controls the production of dextrorphan, an active metabolite, with higher affinity for the NMDA receptor than the parent compound. This study examined whether pharmacological inhibition of CYP2D6 activity wit...
Article
Bupropion is an efficacious non-nicotine medication for smoking cessation; however, its cessation-mediating mechanism is unclear. This randomized, placebo-controlled trial examined the effect of bupropion SR (300 mg/day for 6 weeks) on plasma cotinine and on the subjective effects of smoking in 24 current daily smokers who were not trying to quit o...
Article
The extent of concurrent use and abuse of benzodiazepines and alcohol in chronic alcoholics is not known. Prospective data collected on 216 consecutive outpatient referrals between 1 June and 31 July 1981 (age range, 16 to 70 years, 75 per cent men) showed that benzodiazepines were detected in the urine of 33 per cent of patients undergoing medical...
Article
Full-text available
We have identified CYP2C19 and CYP3A4 as the principal cytochrome P450s involved in the metabolism of flunitrazepam to its major metabolites desmethylflunitrazepam and 3-hydroxyflunitrazepam. Human CYP2C19 and CYP3A4 mediated the formation of desmethylflunitrazepam with Km values of 11.1 and 108 microM, respectively, and 3-hydroxyflunitrazepam with...
Article
Identifying determinants to pharmacotherapy response in alcoholics is difficult. We studied responses in 31 non-depressed alcoholics (aged 14 to 68 years, 64.5% males) receiving naltrexone (50 mg/day), citalopram (40mg/day) or placebo using fuzzy logic. Fuzzy logic models use a series of if-then rules to relate continuous input variables (e.g. depe...
Article
MDD patients display characteristic anhedonic symptoms whose brain mechanisms are unknown. In a between subject, double blind, placebo controlled study, a d-amphetamine (30mg p.o.) challenge was used to probe the brain reward system via the release of dopamine, an important neurotransmitter in reward mediation, in healthy volunteers (n=16) versus d...
Article
The elderly frequently use psychoactive drugs including alcohol (ethanol), benzodiazepines and opioid analgesics, which have a propensity to cause abuse and dependence. Theoretically, the changes in pharmacokinetics of these agents in the elderly may modify their abuse and dependence potential. In the elderly, blood alcohol concentrations following...
Article
The validity of the Geriatric Depression Scale (GDS) short form was assessed in a geriatric affective disorders outpatient clinic (N = 116). The GDS was highly correlated with the Montgomery Asberg Depression Rating Scale (MADRS), and with optimal cutoff scores of 5/6, demonstrated a sensitivity of 85% and a specificity of 74.0%. The GDS appears to...
Article
Clinical Pharmacology & Therapeutics (1996) 59, 211–211; doi: 10.1038/sj.clpt.1996.342
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Clinical Pharmacology & Therapeutics (1996) 59, 160–160; doi:10.1038/sj.clpt.1996.138
Article
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The authors' goal was to determine the clinical characteristics of persistent users of alprazolam or lorazepam who wished to discontinue their medication. Long-term users (daily use for more than 3 months) of alprazolam (N = 34) or lorazepam (N = 97) who entered an outpatient treatment program for discontinuation of benzodiazepines were carefully a...
Article
Sertraline is an effective antidepressant acting as a selective serotonin reuptake inhibitor. The subjective and behavioral effects of sertraline were studied and compared with the effects of alprazolam and dextroamphetamine in a within-subject, randomized, double-blind study in 20 volunteers aged 18 to 46 years. These subjects were experienced but...
Article
To assess the pharmacologic effects and abuse liability of bretazenil, a partial benzodiazepine agonist, and compare them to the short-term effects of diazepam and alprazolam over a range of doses. This was a placebo, within-subject, randomized, double-blind study conducted in 28 male volunteers. They were experienced but nondependent users of cent...
Article
1. In microsomes prepared from three human livers, methadone competitively inhibited the O-demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty-two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing...
Article
Benzodiazepines are the most prescribed psychotropic drugs in the world. Comparative international data on benzodiazepine use, specifically among developed and developing countries, are unavailable. To determine the different patterns of benzodiazepine use in two representative countries, use of benzodiazepines in Chile (a developing country) and C...
Article
The present review discusses the available data on the kinetic properties of non-opiate abused drugs including psychomotor stimulants, hallucinogens and CNS-depressants. Some of the drugs of abuse reviewed here are illicit drugs (e.g. cannabis, cocaine), while others are effective pharmacological agents but have the potential to be abused (e.g. ben...
Article
The presence of protracted tinnitus after discontinuation of long-term therapeutic doses of diazepam (less than or equal to 30 mg/day) is described in three patients. In one of these patients, the association of the tinnitus appearance with the drug discontinuation was documented in a double-blind, randomized, crossover single case study. Objective...
Article
In a double-blind outpatient trial, long-term users of therapeutic doses of benzodiazepines seeking treatment were randomly assigned to either gradual tapering of their daily active dose (N = 23) or abrupt cessation of benzodiazepine intake (N = 19). The latter was achieved by substitution of placebo tablets for active benzodiazepines. All subjects...
Article
Individuals who were using therapeutic doses (approximately 15 mg diazepam or its equivalent daily) of a benzodiazepine persistently and wished to attempt to stop were recruited into a study offering a medically supported outpatient behavioral treatment with a goal of abstinence. All subjects received the same behavioral treatment that emphasized t...
Article
We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically...
Article
Drugs that produce physical dependence or have similar pharmacological profiles to highly abused drugs are unlikely to be considered acceptable for marketing. Thus, the prediction of abuse and dependence becomes an important issue in the development of new psychotropic drugs. Both pharmacokinetic and non-pharmacokinetic factors play an important ro...
Chapter
One of the most difficult problems in discussing drug abuse is definitional. Where benzodiazepines are concerned the definitional problems are particularly complex, since most of their use occurs within a legitimate medical/therapeutic context, and decisions must be made as to where appropriate therapy ends and abuse or misuse begins. Moreover, alt...
Article
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The clinical characteristics and management of patients who abuse high doses of benzodiazepines are not well described. In a prospective open study, 23 subjects who abused high doses of benzodiazepines were admitted for detoxification. Urine or blood test results confirmed benzodiazepine use in all but one subject and multiple drug use in eight (35...
Article
The extent of concurrent use and abuse of benzodiazepines and alcohol in alcoholics is not known. Prospective data collected on 216 consecutive outpatient referrals between 1 June and 31 July 1981 (age range, 16 to 70 years, 75 per cent men) showed that benzodiazepines were detected in the urine of 33 per cent of patients undergoing medical assessm...
Article
1 Liver disease can alter the disposition and clinical effects of drugs. However, even though altered drug disposition occurs, there is no clinical evidence relating it to an increased susceptibility to adverse drug reactions (ADRs). 2 An intensive prospective drug monitoring study of 2,582 hospitalized patients was conducted. The adverse drug reac...
Chapter
The assessment of adverse drug reactions* presents few unique methodologic issues not shared with determination of drug efficacy or trial methodology in general. For example, sample size is always an important consideration. However, drug trial protocols, drug trial methodology and published reports illustrate that assessment of drug efficacy (bene...
Article
Ethanol and benzodiazepines interact both pharmacokinetically and pharmacodynamically. However, the importance of these effects has been exaggerated. Kinetically, acute doses of ethanol impair the disposition of benzodiazepines that are metabolized by demethylation or hydroxylation, but not those that undergo glucuronide conjugation. On the other h...
Article
Ethanol and benzodiazepines interact both phar-macokinetically and pharmacodynamically. However, the importance of these effects has been exaggerated. Kinetically, acute doses of ethanol impair the disposition of benzodiazepines that are metabolized by demethylation or hydroxylation, but not those that undergo glucuronide conjugation. On the other...
Article
1 A simple valid and reliable method for estimating the probability of adverse drug reactions (adverse drug reactions probability scale, APS) has been recently described (Naranjo et al., 1981a). 2 The results using APS were compared to those obtained with another more detailed algorithm (adverse reactions scoring system, ASS) described by Kramer et...
Article
1. The discovery of an adverse drug reaction (ADR) depends on: the relative frequencies of the drug-related and non-drug events; the mechanism of drug-induced toxicity; the number of patients exposed to the drug; and the methods used for detecting toxicity. Clinical trials are usually short-term studies conducted in a few hundred patients before ma...
Article
In a prospective study of 3546 patients with drug overdose and abuse, females outnumbered males in overdose 2:1 while males predominated in drug abuse 2:1. Half of drug abuse patients and 28% of overdose patients were under 21 years of age. In overdose the highest incidence rates were at ages 19–20 for both males and females (800 and 512 per 100,00...
Article
Full-text available
The estimation of the probability that a drug caused an adverse clinical event is usually based on clinical judgment. Lack of a method for establishing causality generates large between-raters and within-raters variability in assessment. Using the conventional categories and definitions of definite, probable, possible, and doubtful adverse drug rea...
Article
From 3,548 drug overdose or abuse cases presenting at 21 Metropolitan Toronto hospitals' Emergency departments, data concerning demographic and medical characteristics, investigative and management procedures, drug analysis services, and disposition of patients were collected. Of the 3,548 cases, 2,723 (77%) were acute overdose and 816 (23%) were d...
Article
Persons admitted to hospital emergency rooms for treatment of drug misuse with concomitant alcohol use were generally found to be heavy drinkers.
Article
In a prospective study of drug overdose patients admitted to emergency rooms of 21 Toronto hospitals, 39% said they had taken a benzodiazepine. Benzodiazepines were used more frequently by females than males and by suburban than core hospital patients. Patients who overdosed on benzodiazepines were admitted to the hospital less frequently and arriv...
Article
Sex-related variations in the clinical effects of drugs may be observed. In an intensive prospective drug surveillance study of 1920 patients hospitalized at the Department of Medicine of the J. J. Aguirre Hospital in Santiago, Chile, the frequency of adverse drug reactions (ADR) was significantly higher in females than in males (p < 0.0005). Women...
Article
Furosemide is frequently used for ascites and causes adverse reactions (AR). In an intensive prospective drug monitoring study of 1,920 patients, 172 (8.9%) had cirrhosis of the liver and received furosemide. Mean age was 53 years, and 66.3% were male; and 87% had alcoholic cirrhosis. Eighty-eight (51.2%) had 221 events that by consensus of the mon...
Article
Impaired liver function may increase susceptibility to drug toxicity. In a prospective drug surveillance study of 1280 patients the frequency of adverse drug reactions (ADR) was higher in 333 patients with clinical and/or histopathological evidence of liver cirrhosis than in 188 with other liver diseases (p<0.01) and than in 759 without liver disea...
Article
The frequency and types of adverse reactions (ARs) occurring in hospitalized patients receiving furosemide were surveyed prospectively in a four-year study at the Jose Joaquin Aquirre Hospital in Santiago, Chile. A team of clinical pharmacists and clinical pharmacologists monitored 533 patients receiving furosemide and recorded patient characterist...

Citations

... Busto et al. report that benzodiazepine withdrawal symptoms 'disappeared over a four-week period'. 12 Patients were randomized to placebo or diazepam, meaning one group quit benzodiazepines abruptly while the other was tapered over 6 weeks. Patients were followed over the course of a year. ...
... Psychotropic drugs comprise one of the most commonly prescribed categories of drugs in industrialised countries. Over the past twenty years, the widespread use of these types of drugs and specifically the potential for abuse and dependency of benzodiazepines have become an area of concern for scholars in a variety of fields (Cappell et al 1986). In assessing the issue of psychotropics on an international scale, medical experts have suggested that if the character of psychotropic drug use is to be understood and indeed effective health and social policies are to be developed, the abuse potential and dependency liability of these drugs be thoroughly investigated (Idanpaa-Heikkila et al 1987, Medawar 1992. ...
... Because 88% of benzodiazepine users report the additional consumption of alcohol and 28% indicate intentional combined use (Ilomäki et al., 2013), it is important to clarify the potential impact of their combination for road safety. Past reviews in this area have taken a broader approach to investigating the pharmacodynamic interaction between alcohol and benzodiazepines (Moody, 2012;Sellers & Busto, 1982). Thus, rather than reiterate these conclusions, this review aims to provide an updated and concise synthesis of the available experimental research that has examined the effect of the combination of alcohol and benzodiazepines on neurocognitive domains implicated in driving performance. ...
... ADEs cause-effect relationship was evaluated using the Naranjo's algorithm. 11 Briefly, this questionnaire is one of the more commonly used algorithms for determining the likelihood of whether an adverse drug reaction is actually due to the drug rather than the result of other factors. Probability is assigned via a score termed definite, probable, possible or doubtful, avoiding data omissions or inaccuracy among evaluators. ...
... and projection regions express several nAChR subtypes on dopaminergic, GABAergic, and glutamatergic neurons 63,64 . Ultimately, administration of nicotine increases dopamine levels through increased dopaminergic neuron firing in striatal and extrastriatal areas (such as the ventral pallidum) 65 (fig. 6). ...
... The potent dopamine D 2 /D 3 receptor agonist (+)-PHNO ((+)-4-propyl-3,4,4a,5,6,10bhexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol, molecular weight 247.33 g/mol) can cause nausea, vomiting and orthostatic hypotension, at doses of 0.25 mg three times a day (Weiner et al. 1989). In initial clinical studies using the radiotracer (+)-[ 11 C]PHNO, participants commonly experienced nausea (Willeit et al. 2006(Willeit et al. , 2008Chiuccariello et al. 2013). Houle and co-workers subsequently recommended a dose below 0.029 µg/kg for (+)-[ 11 C]PHNO, and therefore a maximum administered dose of 2.03 µg for a 70 kg participant, which is even lower than for [ 11 C]carfentanil (Blecha et al. 2017). ...
... In addition to these online assessments, we evaluated memory performance offline, at baseline and at 1 month after intervention. We also determined general cognitive function, quantified using the Montreal Cognitive Assessment (MoCA) 30 , and depression symptoms, assessed using the Geriatric Depression Scale (GDS) 31 , at baseline. Experiment 2 served as a control to test the frequency specificity of the effects in Experiment 1. ...
... Consequently, people with cirrhosis are at greater risk of experiencing adverse drug reactions compared to those with non-cirrhotic liver disease. 39 This is especially the case for patients with complications like ascites, hepatic encephalopathy, jaundice and variceal bleeding who are at higher risk of pharmacodynamic interactions. ...
... A growing body of neuroimaging research has been examining the neural correlates of cigarette smoking as well as externalizing and internalizing behaviors. The insula and anterior cingulate cortex (ACC), two key nodes of the salience network, have been implicated in cigarette smoking and craving [19][20][21] . Positively correlated with individual variation in nicotine addiction severity, insula and ACC responses to smoking vs. neutral cues distinguished smokers who relapsed from those who maintained abstinence [22] . ...
... Among them, 17 studies plus the NARECHEM-ST case-control study (Doganis et al., unpublished data) provided information on the study variables as shown in Table 3. Among these, information for maternal vitamins, iron and/or folic acid supplementation, alcohol consumption or smoking during pregnancy was available in six [18,19,[32][33][34][35], four [36][37][38][39] and 13 [14,34,[36][37][38][39][40][41][42][43][44][45][46] studies, respectively. Of the remaining studies, regarding the individual risk factor meta-analysis for alcohol, five eligible studies were excluded because: in four the requested estimates were not provided by the authors [12,14,47,48] and in one there was partial overlapping [49]. ...