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A substantial body of evidence supports a role for serotonin in modulating alcohol intake, which suggests that this neurotransmitter represents a promising target for pharmacotherapy development for alcohol use disorders. Dexfenfluramine. a serotonin releaser and reuptake inhibitor, decreases alcohol self-administration by rats. Its greater potency and several mechanisms of action suggest it should be more effective in treating alcohol dependence than drugs that only inhibit serotonin reuptake.We conducted an 11 week, randomized, double-blind trial that compared oral placebo and dexfenfluramine 7.5, 15, 22.5, and 30 mg bid in 136 alcohol-dependent patients. A brief behavioral intervention was offered concurrently.The majority of subjects were male (72%), and the age of the group was 44 +/- 1 years (mean +/- SD). Both placebo- and drug-treated groups significantly reduced alcohol consumption compared with baseline (a 55% decrease in mean drinks per day; p0.01), but there were no significant differences between drug and placebo groups or dose effects for most outcome measures.Our results with dexfenfluramine are further evidence that serotonergic medications on their own do not significantly reduce alcohol consumption in alcohol-dependent individuals. Combination pharmacotherapy with agents that act on different receptors or neurotransmitter systems (e.g., naltrexone plus dexfenfluramine) may be one way to enhance serotonergic effects on drinking behavior and should be considered in future medication development clinical trials.

Substantial progress in the treatment of mental disorders over the past 40 years can be ascribed to the development of psychotropic medications for anxiety, sedation, depression, and psychosis. However, from a public health perspective, alcohol abuse and dependence have an even larger social, health, and economic impact than these other disorders.

Concern has been raised that the barbiturate component of barbiturate-containing analgesics constitutes a public and individual health problem because of information from literature before 1966 concerning preclinical and clinical abuse liability, and the dependence risk of barbiturates. The safety of barbiturates alone and in combination in analgesics was reviewed. In addition, information from manufacturers of combination products were evaluated. A meta-analysis was not possible because of the paucity of formal clinical trials. Even though barbiturates have a narrow margin of safety and substantial abuse potential, there is no evidence that barbiturate-containing analgesics without codeine represent a public health or social problem because of their abuse potential. However, proper studies to confirm this theory have not been performed. In the absence of better data concerning efficacy and lack of dependence potential, barbiturate-containing analgesics are not first-line medications for the initiation of treatment for pain. Codeine-containing combination analgesics have the potential to be a more important public health problem than those with only barbiturate in the combination.

Preceding chapters have reviewed progress made in the understanding of the basic mechanisms of action of alcohol and preclinical evidence suggesting the involvement of a number of neurotransmitter and neuropeptide systems in the modulation of ethanol1 self-administration, dependence, and tolerance. The aim of this chapter is to integrate some of these experimental findings with the clinical manifestations of alcohol abuse and dependence and to discuss their application to the development of pharmacotherapies for treatment of these disorders. It is impossible to review all the important research developments of the past several years, and we will therefore focus on those areas with direct and current relevance to the management of alcoholism. In particular, self-administration studies and their pharmacologic manipulation will be emphasized.

The incidence of nonmedical use of alprazolam is very low relative to its widespread legitimate medical use; in fact, given the millions of patients who have received this medication, the incidence is remarkably small. In particular, among patients with anxiety disorders, dependence does not appear to be a clinically important problem. Alprazolam abuse and dependence represent only a small fraction of the large and serious nonmedical use problem in the United States, and when they occur, are among individuals who abuse other drugs. For example, a serious problem of alprazolam abuse may exist among patients in methadone maintenance treatment. A similar problem exists with diazepam. Alcohol abusers and alcohol-dependent individuals are another group among whom concern about benzodiazepine and alprazolam abuse exists. However, more and better information about the extent and nature of this use is needed. Many patients with alcohol or drug abuse also have anxiety disorders for whom effective pharmacotherapy may be needed. In the interim, caution but not prohibition to use should prevail in prescribing alprazolam to such patients. To the extent that nonmedical alprazolam use exists, evidence suggests that the vast majority of such use is the consequence of the inappropriate prescribing of the medication by a small number of physicians. One way to reduce the inappropriate use of benzodiazepines in methadone programs is to drug test the methadone-maintenance patients and to link positive urine tests to contingency-management strategies. The available data provide some support to the idea that alprazolam and diazepam have more abuse liability than other benzodiazepines.

The widespread use of benzodiazepines remains a source of concern to the medical profession and the general public, especially as newer compounds come on the market. Our goal was to characterize long-term alprazolam users in the community and to determine whether such use represented abuse or behavioural dependence. We conducted three community surveys to learn about the natural history of long-term alprazolam use. Current long-term alprazolam users (those using the drug for 3 months or longer) were recruited on three separate occasions 1 year apart by identical newspaper advertisements in the metropolitan Toronto area. All respondents were mailed a questionnaire with a stamped, addressed return envelope. Our data from 312 respondents show that: (1) the majority of patients have a substantial history of prior medication use for symptom control (65%), (2) dose escalation is not a characteristic of long-term use, (3) patients change their initial pattern of regular use to one of symptom control only when required, (4) most physicians do not discuss discontinuation of the drug with their patients, (5) patients frequently try to stop their drug use (with a median of 2 attempts) and often report symptoms upon discontinuation, and (6) patients perceive a need for medication use and indicate that alprazolam is effective (75%). We conclude that some patients persistently use alprazolam but that this use does not represent abuse or behavioral dependence.

The pharmacologic effects of lorazepam (2 mg), buspirone (20 mg, 10 mg), secobarbital (100 mg), and placebo were compared in 15 male, experienced, intermittent nontherapeutic drug users. All drugs produced a "drug effect," however, buspirone 20 mg was significantly less liked than were lorazepam, secobarbital, or buspirone 10 mg (p less than .05) but not placebo. Lorazepam was liked better than were other drugs only at 1 hour and only compared with buspirone 20 and placebo. Compared with other drugs, lorazepam drug effects were greater and resulted in more prolonged impairment of a motor tracking task, standing steadiness, and memory. Buspirone 20 mg significantly impaired memory at 1 hour compared with placebo. Subjects were more likely to identify buspirone as unfamiliar. Because buspirone 20 mg was less liked than were other drugs, dose escalation as part of drug abuse is not likely to occur. Lorazepam also was not particularly liked and was not different from placebo on most subjective abuse-relevant measures.

The authors review both the preclinical and the clinical evidence for a role of serotonin (5-HT) systems in the regulation of drug-taking behavior. Animal studies show that pharmacologic treatments that enhance 5-HT function, notably selective reuptake inhibitors, reduce the self-administration of a variety of substances of abuse, including ethanol and cocaine. These treatments also tend to suppress consummatory behavior in general. In contrast to the broad spectrum of suppression following 5-HT enhancement, selective antagonists at the 5-HT3 receptor subtype have been reported to reduce ethanol but not cocaine or food intake. Although essentially limited to alcohol abusers, clinical studies seem to support the preclinical findings that a number of 5-HT reuptake inhibitors decrease interest in and intake of alcohol in mild-moderate ethanol-dependent individuals. Furthermore, other serotonergic drugs may show utility in the treatment of alcohol abuse. Another way in which serotonergic medications can be used in treating substance abuse is by the treatment of comorbid psychoactive illness for which such drugs are already known to be effective, e.g., depression and anxiety disorders.

Background NMDA receptor antagonists are currently being developed for the treatment of several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and neuropathic pain conditions. Some high affinity NMDA receptor antagonists (e.g. phencyclidine and ketamine) have dissociative properties and are established agents of abuse. Other NMDA receptor antagonists such as memantine, amantadine or dextromethorphan do not exhibit significant potential for abuse. Therefore based on the pre-clinical and/or clinical pharmacological profiles, a clinical abuse potential evaluation may be required for a new NMDA receptor antagonist or a new formulation of an existing NMDA receptor antagonist. Positive (abused) control drugs such as ketamine are required in the conduct of human abuse liability studies. Most published studies have evaluated intravenous ketamine as a comparator drug. Purpose The present study was designed to assess the subjective effects of oral ketamine. Methods Twenty-nine healthy, experienced recreational drug users were given d-amphetamine (d-AMP) 20 mg p.o. in a single-blinded within-day qualifying day in which they could receive three doses of placebo and one dose of d-AMP. Sixteen subjects reliably reported liking d-AMP and 11 subjects (9 males, 2 females) entered a single-blind controlled dose escalating study in which they received ketamine 65 mg, 100 mg or 150 mg (intravenous formulation dissolved in juice) or placebo-juice orally. Subjective and physiologic measures were evaluated for up to 8 hours post-drug administration. Results Graded dose related effects and differences from placebo were reported across a wide range of abuse measures (e.g. VAS feeling high, VAS liking, subjective price value, Cole ARCI euphoria). Pharmacologic effect characteristics of the class (e.g. floating, confusion) were also found. Ketamine 65 mg was readily distinguished from placebo on most measures. Doses of 150 mg were well tolerated in the 4 subjects who received this dose. Conclusions These pharmacological data suggest that oral doses of ketamine (60 -150 mg) can be used as positive controls for studies for NMDA receptor antagonist mediated effects. Clinical Pharmacology & Therapeutics (2004) 75, P72–P72; doi: 10.1016/j.clpt.2003.11.271

The distribution of basic drugs in blood differs qualitatively from that of acidic drugs. The binding of racemic, d-methadone, and l-methadone to human plasma and isolated protein fractions was studied by equilibrium dialysis at 37°. In plasma samples from 29 healthy subjects free fraction of dl-methadone was (x% ± SD) 10.62 ± 1.43. There were significant variations among subjects (p < 0.001). The free fraction of the d-isomer was 9.24 ± 1.61% and of the l-isomer, 12.44 ± 1.53%. Plasma albumin concentration and degree of binding do not correlate, but in normal hypoalbuminemic subjects the free fraction of dl-methadone correlates negatively with the concentration of α1-acid glycoprotein (α1-AGP), an acute-phase reactant protein. Percentage dl-methadone bound to purified human serum albumin (HSA) (4.1 gm/dl) was 36.60% (x ± SD). Isolated α1-AGP bound dl-methadone more avidly. As the α1-AGP increased from 0.05 to 2.0 gm/l, free fraction fell from 92.40% to 8.80%. Addition of α1-AGP (0.05 to 2.0 gm/l) to a physiologic concentration of purified HSA or to whole plasma progressively increased methadone binding. In eight monozygotic twin pairs, within-pair differences in binding of dl-methadone were less than in eight dizygotic twin pairs. Less than 20% of naloxone, codeine, morphine, heroin, pentazocine, and diphenoxylate bound to α1-AGP. Elevations of α1-AGP that occur in a variety of diseases may alter the kinetic and pharmacologic activity of methadone. Clinical Pharmacology and Therapeutics (1981) 29, 211–217; doi:10.1038/clpt.1981.34