Aversion Therapy Research Articles

PARADIGM TO TEST A DRUG-INDUCED AVERSION TO ETHANOL

The screening of new agents for aversive therapy of alcoholism requires a simple animal model. Animals trained to ingest ethanol solutions and subsequently administered a drug known to produce an aversion to ethanol in humans, do not readily make the association between the malaise induced by the aversive drug-ethanol reaction and the consumption of the same ethanol-containing solution that has been consumed previously without ill effects. An experimental paradigm is reported in which the malaise of the drug-ethanol reaction is quickly recognized by rats as derived from ethanol. Disulfiram was used as the model drug. Lewis rats were deprived of water for 18 h after which 6% (v/v) ethanol was offered as the only fluid. During the first hour of ethanol access, both controls (vehicle) and disulfiram (100 mg/kg)-treated animals consumed intoxicating amounts of ethanol (0.7-0.9 g ethanol/kg). Plasma acetaldehyde levels developed were 3-5 microM and 40-50 microM in the two groups respectively. After this time, disulfiram-treated animals virtually ceased consuming alcohol (90% inhibition), indicating that the disulfiram-ethanol reaction is associated with alcohol ingestion. Control animals continued consuming the alcohol solution for the additional 4-5 h tested. This model should be of value in the testing of new agents that reduce aldehyde dehydrogenase levels for prolonged periods for their potential as an aversive treatment in alcoholism.

Disulfiram Produces a Non-Carbon Disulfide-Dependent Schwannopathy in the Rat

Disulfiram is a dithiocarbamate drug used for alcohol aversion therapy that produces a distal sensorimotor peripheral neuropathy in certain individuals. Because carbon disulfide, a disulfiram metabolite, produces a peripheral neuropathy clinically similar to disulfiram, it has been postulated that disulfiram neuropathy results from CS2 release in vivo. The current study evaluated the morphological changes produced by disulfiram and the contribution of CS2-mediated protein cross-linking to disulfiram-induced neuropathy. Male Sprague-Dawley rats were administered 1% w/w disulfiram in their feed for 2, 4, 5, or 7 wk, and erythrocyte spectrin, hemoglobin, and neurofilament preparations were isolated and the extent of cross-linking assessed by SDS-PAGE, RP-HPLC, and Western blotting, respectively. Spinal cord and peripheral nerve sections were obtained from separate treated animals and assessed by light and electron microscopy. Significant protein cross-linking was only detected in neurofilament preparations obtained after 7 wk of exposure. Morphological changes were observed after 4 wk exposure and consisted of vacuoles within the Schwann cell cytoplasm and segmental demyelination. No neurofilamentous axonal swellings were detected and no significant changes were observed in the CNS. Because disulfiram neuropathy lacks both the morphological changes and intermolecular cross-linking characteristic of CS2, we conclude that disulfiram neuropathy is not mediated by the axonal toxicant CS2; instead, disulfiram appears to be a primary Schwann cell toxicant. Recognition of a diethylcarbamoyl adduct on globin and axonal proteins presents a novel putative neurotoxic mechanism for disulfiram.

Identification of the protein-drug adduct formed between aldehyde dehydrogenase and S-methyl-N,N-diethylthiocarbamoyl sulfoxide by on-line proteolytic digestion high performance liquid chromatography electrospray ionization mass spectrometry.

Disulfiram has been used clinically as an aversion therapy treatment for recovering alcoholics. One of its metabolites, S-methyl-N, N-diethylthiocarbamoyl sulfoxide (MeDTC-SO), is currently believed by some to be the active metabolite in vivo. We demonstrate in this report that MeDTC-SO is a potent irreversible inhibitor of recombinant rat liver mitochondrial aldehyde dehydrogenase (rlmALDH), the enzyme responsible for oxidizing acetaldehyde formed during ethanol metabolism. Recombinant rlmALDH was inhibited by MeDTC-SO after in vitro incubation with an IC(50) = 4.62 microM. The inhibition of rlmALDH was found to be accompanied by a concomitant increase of approximately 100 Da to the molecular mass of the native enzyme as determined by on-line high performance liquid chromatography (HPLC) electrospray ionization mass spectrometry (LC/MS), indicating that a covalent modification has occurred. To determine the site and structure of this covalent adduct, we developed a novel approach to characterize specific protein-drug interactions by linking a proteolytic enzyme digestion cartridge on-line with LC/MS. The on-line pepsin digestion LC/MS of MeDTC-SO-inhibited rlmALDH revealed an ion at MH(2)(2+) = 500.9, which was not present in the pepsin digestion of the non-inhibited enzyme. This peptide was tentatively attributed to the putative active site peptide (FNQGQC(301)C(302)C(303)) plus the adduct. This peptide was subjected to analysis by LC/MS/MS, which allowed us to determine that the covalent modification was associated with a single carbamoyl adduct at Cys-302, which has been shown to be the active site nucleophile of the enzyme.

Involuntary Hospitalization or Aversive Incarceration?

Back to table of contents Previous article Next article LetterFull AccessInvoluntary Hospitalization or Aversive Incarceration?Richard C. Christensen, M.D., M.A.Richard C. ChristensenSearch for more papers by this author, M.D., M.A.Published Online:1 May 2000https://doi.org/10.1176/appi.ps.51.5.676-bAboutSectionsView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: A 26-year-old man recently diagnosed as having schizophrenia was admitted to my ward at the state hospital. Obviously frightened and a little overwhelmed, he had spent the last two months within the narrow confines of a community-based crisis unit. During the initial evaluation, I asked what he understood about his commitment. Though I had heard it from more than one patient over the years, his response made me wince. "The doctor," he said, "told me this would teach me a lesson about the need to take my medications."Crisis units, community hospitals, and state institutions have traditionally served as receiving facilities for individuals involuntarily committed for psychiatric reasons. However, public institutions designed to facilitate healing are too commonly portrayed—by clinicians, no less—as places prepared to punish.On more occasions than I care to count, I have admitted patients to the state hospital whose understanding of the situation was that hospitalization was a form of aversive therapy. They believed they were being detained to be taught a lesson about the seriousness of their mental illness and the consequences of noncompliance. Sometimes these views were distorted by their psychoses and the absence of insight. Sadly, at other times their understanding was an accurate portrayal of the committing physician's intentions.When the referring psychiatrists were contacted, many of them readily expressed less than therapeutic motives for initiating the commitment process. "I finally called his bluff," one proclaimed, describing the crises-driven admissions of a borderline patient. Another, clearly exasperated with a dually diagnosed client, stated, "He needed to get the message that his behavior won't be tolerated." There was the one psychiatrist who simply admitted, "We really needed a break from him here at the [community mental health] center."I am not railing against the evils of involuntary psychiatric hospitalization. I have worked too long with homeless mentally ill people and others ravaged by brain disorders to argue against the need for hospitalizing those in desperate need of safety and treatment. Rather, my views on involuntary commitment have been shaped by years of serving as the receiving, rather than the referring, psychiatrist. I am the one who has to establish a new therapeutic alliance, work through the mistrust, and create a relationship with the individual before treatment can begin. Not infrequently, so much damage has been done before hospitalization that all future collaboration is seemingly doomed.Aversive incarceration, in the guise of involuntary hospitalization, may be the means to "teach a lesson" to our most difficult clients, but it will never foster the healing relationship our patients need. And we, patients and physicians alike, will suffer from that lost opportunity.Dr. Christensen is a senior psychiatrist at Northeast Florida State Hospital in MacClenny, Florida. FiguresReferencesCited byDetailsCited byNone Volume 51Issue 5 May 2000Pages 676-b-677 Metrics History Published online 1 May 2000 Published in print 1 May 2000

Disulfiram generates a stable N,N-diethylcarbamoyl adduct on Cys-125 of rat hemoglobin beta-chains in vivo.

Disulfiram (DSF) is a drug used in aversion therapy to treat alcoholics and acts by inhibiting mitochondrial low-K(m) aldehyde dehydrogenase. Investigations into the mechanisms for in vivo inactivation suggest that the DSF metabolite S-methyl-N, N-diethylthiocarbamate sulfoxide reacts irreversibly with an active site Cys. This work aimed to determine if DSF generates monothiocarbamate adducts on cysteine residues in vivo by examining hemoglobin. Sprague-Dawley rats were treated with DSF po for 2, 4, and 6 weeks. Rats have four different globin beta-chains, of which three (beta-1-3) contain two cysteine residues each. MALDI-TOF MS analysis of two new globin species from DSF-treated rats collected by HPLC revealed increments of 99 Da above the mass of the unmodified chains (beta-2 and beta-3). In a separate experiment, the globin mixture was digested for 2 h with Glu-C and reanalyzed by MALDI-TOF MS. Results showed a peptide at m/z 2716.3 having a mass 99 Da higher than a known Cys-containing peptide. Subsequently, the Glu-C digest was analyzed using Q-TOF tandem MS, enabling observation of the +4 charge state of the peptide with m/z 2716.3. This peptide was fragmented to produce y-sequence ions that located the modification to Cys-125 (present on both beta-2 and beta-3). Cys-125 is the most reactive of two cysteine residues on these beta-chains. To confirm the structure of the modification, globin was hydrolyzed with 6 N HCl at 110 degrees C for 18 h. The adduct survived these conditions so that S-(N,N-diethylcarbamoyl)cysteine was detected in the hydrolysates of treated rats on the basis of comparison with the tandem MS spectrum of a standard. These results extend the findings of others obtained using glutathione conjugates and demonstrate the ability of DSF to covalently modify Cys residues of proteins in a manner consistent with the production of S-methyl-N, N-diethylthiocarbamate sulfoxide, or sulfone, intermediates.

Absolute bioavailability and absorption profile of cyanamide in man.

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral administration. Cyanamide plasma levels were determined by a sensitive HPLC assay, specific for cyanamide. After intravenous administration cyanamide displayed a disposition profile according to a two-compartmental open model. Elimination half-life and total plasma clearance values ranged from 42.2 to 61.3 min and from 0.0123 to 0.0190 L.kg-1.min-1, respectively. After oral administration of 0.3, 1.0, and 1.5 mg/kg x +/- SEM values of Cmax, tmax (median) and AUC were 0.18 +/- 0.03, 0.91 +/- 0.11, and 1.65 +/- 0.27 micrograms.ml-1; 13.5, 13.5, and 12 min; and 8.59 +/- 1.32, 45.39 +/- 1.62, and 77.86 +/- 17.49 micrograms.ml-1.min, respectively. Absorption was not complete and the oral bioavailability, 45.55 +/- 9.22, 70.12 +/- 4.73, and 80.78 +/- 8.19% for the 0.3, 1.0, and 1.5 mg/kg doses, respectively, increased with the dose administered. The models that consider a first-order absorption process alone (whether with a fixed or variable bioavailability value as a function of dose) or with loss of drug due to presystemic metabolism (with zero-order or Michaelis-Menten kinetics) were simultaneously fitted to plasma level data obtained following 1 mg/kg i.v. and 0.3, 1.0, and 1.5 mg/kg oral administrations. The model that best fit the data was that with a first-order absorption process plus a loss by presystemic metabolism with Michaelis-Menten kinetics, suggesting the presence of a saturable first-pass effect.

Treatment of an unusual case of masochism

Masochistic sexual activity is potentially dangerous, rarely reported voluntarily, and hard to treat. This article describes a masochist patient who received sexual gratification from being burnt or crushed. Antiandrogen medication, serotonin uptake inhibitor, and psychodynamic psychotherapy along with sexual education and social-skills training and aversive behavior therapy were all tried over a period of 9 months. The response was measured by effects of treatments on the frequency of erotic fantasies and masturbation. Antiandrogens and aversive behavior therapies may be the most effective treatments for such cases, at least in the short term, although the underlying social deficits and the need to reshape the sexual behavior ought to be addressed in the long term.

Carbon disulfide and N,N-diethyldithiocarbamate generate thiourea cross-links on erythrocyte spectrin in vivo.

CS2, a known neurotoxicant, is used in the viscose production of rayon and is also a decomposition product of N, N-diethyldithiocarbamate, a metabolic product of the drug disulfiram used in alcohol aversion therapy. Previous in vitro investigations have demonstrated the ability of CS2 to cross-link proteins through thiourea, dithiocarbamate ester, and disulfide structures. Although in vivo studies have supported protein cross-linking as both a mechanism of neurotoxicity and a potential biomarker of effect, the chemical structures responsible for CS2-mediated protein cross-linking in vivo have not been elucidated. In the present study, the structure of one type of stable protein cross-link produced on erythrocyte spectrin by CS2 in vivo is determined. Rats were exposed to 50, 500, and 800 ppm CS2 for 13 weeks by inhalation or to 3 mmol/kg N,N-diethyldithiocarbamate administered orally on alternating days for 8 weeks. Erythrocyte spectrin preparations from control and exposed rats were hydrolyzed using 6 N HCl and separated by size-exclusion chromatography. The fraction that coeluted with the synthetic deuterated lysine-lysine thiourea internal standard was derivatized with 3-[4'-[(N,N,N-trimethylamino)ethylene]phenyl] 2-isothiocyanate and analyzed by liquid chromatography tandem mass spectrometry using selected reaction monitoring detection. Lysine-lysine thiourea was detected in spectrin preparations obtained from CS2-treated rats at 500 and 800 ppm and N, N-diethyldithiocarbamate-treated rats, but not from controls. These results establish that CS2-mediated protein cross-linking occurs in vivo through the generation of Lys-Lys thiourea and that diethyldithiocarbamate can, through in vivo release of CS2, produce the same cross-linking structure. This observation supports the utility of cross-linking of peripheral proteins as a specific dosimeter of internal exposure for CS2 and provides a mechanistic explanation to account for the high-molecular-weight neurofilament protein species isolated from rats exposed to CS2 or N, N-diethyldithiocarbamate.

Inhibition of Recombinant Human Mitochondrial Aldehyde Dehydrogenase by Two Intermediate Metabolites of Disulfiram

Disulfiram is used in aversion therapy for alcoholism. S-Methyl- N, N-diethylthiocarbamate (MeDTC) sulfoxide, a potent inhibitor of the target enzyme mitochondrial aldehyde dehydrogenase (ALDH2), is thought to be the principal active metabolite of disulfiram in vivo. We examined the effects on recombinant human ALDH2 of two intermediate metabolites of disulfiram, S-methyl- N, N-diethyldithiocarbamate (MeDDC) sulfoxide and MeDDC sulfine. MeDDC sulfoxide was a potent inhibitor of ALDH2 with an ic 50 of 2.2 ± 0.5 μM (mean ± SD, N = 4) after preincubation with enzyme for 30 min. MeDDC sulfine was a relatively weak inhibitor of ALDH2 under the same conditions with an ic 50 value of 62 ± 14 μM. The inhibition of ALDH2 by both compounds was irreversible and did not require the cofactor NAD. The latter finding demonstrates that inactivation of ALDH2 is independent of the dehydrogenase activity of the enzyme. GSH blocked almost completely the inhibition by 20 μM of MeDDC sulfoxide and greatly diminished the inhibition by 200 μM of MeDDC sulfine. Inactivation by MeDDC sulfoxide was time dependent. MeDTC sulfoxide was a more potent inhibitor of recombinant human ALDH2 ( ic 50 = 1.4 ± 0.3 μM after preincubation for 15 min) than either of the intermediate metabolites, and its inhibition was unaffected by GSH. Our results suggest that these newer intermediate metabolites of disulfiram, especially the more potent MeDTC sulfoxide, have the potential to inhibit the target enzyme ALDH2 in patients receiving disulfiram. However, until the significance of the interactions of the inhibitors with GSH is more fully understood, the contribution of MeDDC sulfine and MeDDC sulfoxide to the pharmacological effects of disulfiram in vivo is uncertain.

Management of Alcohol Dependence after Detoxification

Alcohol dependence is a major health problem associated with substantial social and healthcare costs. Until recently, the only available management options for maintaining abstinence in alcohol-dependent patients after detoxification were psychosocial/behavioural therapies (including self-help groups) and aversive therapies such as disulfiram. Although these approaches can reduce alcohol intake, their efficacy is limited and aversive therapy is associated with potentially serious adverse events and poor patient compliance.

Nocturnal Headbanging as a Settling Habit: The Behavioural Treatment of a 4-Year-Old Boy

A healthy 4-year-old boy of normal intelligence demonstrating nocturnal head-banging was treated successfully using behavioural methods. The behaviour was conceptualized as an atypical settling habit which was maintaining a disturbed sleep pattern. The intervention consisted of mild aversion therapy combined with a reward programme. The importance of stress as a factor in maintaining this problem is highlighted. Parental confidence was essential to the outcome of this intervention.

Inhibition of human mitochondrial aldehyde dehydrogenase by the disulfiram metabolite S-methyl- N, N-diethylthiocarbamoyl sulfoxide : Structural characterization of the enzyme adduct by HPLC-tandem mass spectrometry

S-Methyl- N, N-diethylthiocarbamoyl sulfoxide (MeDTC-SO) is a known metabolite of the aversion therapy drug disulfiram (DSF). MeDTC-SO is also a potent inhibitor of human mitochondrial aldehyde dehydrogenase (hmALDH) with an ic 50 of 1.5 μM. Inhibition of the enzyme by MeDTC-SO resulted in the addition of ~100 Da to the molecular mass of the intact protein, as determined by on-line HPLC-electrospray ionization MS (LC-MS). Dialysis of the inhibited protein did not reverse the inhibition, and the molecular mass of 54,533 Da (± 0.01%) remained unchanged, indicating that a covalent modification of the protein had occurred. Proteolytic digestion of hmALDH under basic conditions using trypsin at pH 7.8 revealed that the adduct was base labile. However, treating the adducted protein with endopeptidase-Glu-C at pH 3.7 produced a peptide adduct at MH + = 4924, tentatively attributable to a carbamoylated peptide. This peptide contains three adjacent cysteines, one of which has been implicated as a key amino acid in the highly conserved active site region of ALDH. A pepsin digestion of hmALDH carried out at pH 3.7 and subsequent LC-MS analysis revealed an ion at MH + = 501.5, corresponding to the carbamoylated peptide FNQGQC 1C 2C 3. This peptide contains the same adjacent active site cysteines. This latter peptide was subjected to LC-MS/MS, which enabled us to determine that the site of carbamoylation was at Cys 2. The MS/MS product ion data also confirmed the presence of a carbamoyl group as the adduct species.

Aversive smoking for smoking cessation.

Aversion therapy pairs the pleasurable stimulus of smoking a cigarette with some unpleasant stimulus. The objective is to extinguish the urge to smoke. This review has two aims. First, to determine the efficacy of rapid smoking and other aversive methods in helping smokers stop smoking. Second, to determine whether there is a dose-response effect on smoking cessation at different levels of aversive stimulation. We searched the Cochrane Tobacco Addiction Group trials register for studies which evaluated any technique of aversive smoking. Randomised trials which compared aversion treatments with 'inactive' procedures or which compared aversion treatments of different intensity for smoking cessation. Trials must have reported follow-up of least 6 months from beginning of treatment. We extracted data in duplicate on the study population, the type of aversion treatment, the outcome measure, method of randomisation and completeness of follow-up. The outcome measure was abstinence from smoking at maximum follow-up, using the strictest measure reported by the authors. Subjects lost to follow-up were regarded as smokers. Where appropriate, we performed meta-analysis using a fixed effects model. Twenty four trials met the inclusion criteria. Ten included rapid smoking and ten used other aversion methods. Ten trials included two or more conditions allowing assessment of a dose-response to aversive stimulation. The odds ratio for abstinence following rapid smoking compared to control was 2.08 (95% confidence interval 1.39 to 3.12). Several factors suggest that this finding should be interpreted cautiously. A funnel plot of included studies was asymmetric, due to the relative absence of small studies with negative results. Most trials had a number of serious methodological problems likely to lead to spurious positive results. The only trial using biochemical validation of all self reported cessation gave a non significant result. Other aversion methods were not shown to be effective (odds ratio 1.19, 95% confidence interval 0.77 to 1.83). There was a borderline dose-response to the level of aversive stimulation (odds ratio 1.66, 95% confidence interval 1.00 to 2.78). The existing studies provide insufficient evidence to determine the efficacy of rapid smoking, or whether there is a dose-response to aversive stimulation. Milder versions of aversive smoking seem to lack specific efficacy. Rapid smoking is an unproven method with sufficient indications of promise to warrant evaluation using modern rigorous methodology.

Six- and Twelve-Month Abstinence Rates in Inpatient Alcoholics Treated with Either Faradic Aversion or Chemical Aversion Compared with Matched Inpatients

Two hundred forty-nine patients who were treated for alcoholism in an inpatient multimodal treatment program that included aversion therapy were matched post hoc on 17 baseline variables with patients from a national treatment outcome registry. The latter patients received inpatient treatment that emphasized individual and group counseling as the primary therapeutic elements but did not include aversion therapy for alcohol. Six- and 12-month abstinence rates from alcohol and all mood-altering chemicals are reported. The patients treated with aversion therapy for alcohol had higher alcohol abstinence rates at 6 and 12 months (p <0.01). The abstinence rates from all mood-altering chemicals were higher in the aversion group at 6 months (p <0.05) but not at 12 months. These comparisons pooled faradic aversion and chemical aversion results. In order to determine whether or not the faradic aversion gave comparable results to the chemical aversion, the two groups were separately analyzed. No significant differences in outcome were found. In fact, the faradic aversion group showed a slight (nonsignificant) increase in abstinence rate.

Inhibition of aldehyde dehydrogenase by disulfiram and its metabolite methyl diethylthiocarbamoyl-sulfoxide

Disulfiram (DSF) is presently the only available drug used in the aversion therapy of recovering alcoholics. It acts by inhibiting aldehyde dehydrogenase (ALDH), leading to high blood levels of acetaldehyde. The in vitro inhibition of ALDH by DSF and its metabolites was systematically studied by combined enzyme inhibition assay with direct molecular weight determination of the same sample using electrospray ionizationmass spectrometry (ESI-MS). Enzyme activity was measured after incubating yeast ALDH (yALDH) with excess concentrations of DSF, methyl diethyldithiocarbamate (MeDDC) and methyl diethylthiocarbamoyl-sulfoxide (MeDTC-SO) and then subjected to analysis by ESI-MS. Addition of DSF resulted in complete enzyme inhibition; however, ESI-MS analysis demonstrated no discernible shift in molecular weight, indicating that no intermolecular adduct was formed with the protein. Treatment of yALDH with MeDTC-SO also completely abolished yALDH activity with a concomitant increase of +≈100 Da in the molecular mass of the enzyme. This indicated formation of a covalent carbamoyl protein adduct. Furthermore, the effects of dithiothreitol (DTT) were examined on samples of inhibited protein in vitro. At pH 7.5, DTT completely reversed inhibition after DSF treatment. yALDH inhibited by MeDTC-SO could not be recovered by DTT at pH 7.5, but at pH 9 the enzymic activity was fully restored and a mass loss of-100 Da was noted. This observations are consistent with mechanisms where inhibition of yALDH by DSF in vitro involves oxidation of the active site, whereas MeDTCSO forms a covalent adduct with the protein in vitro resulting in cessation of enzyme activity.

Taxonomy of high‐risk situations for alcohol relapse: evolution and development of a

The purpose of this paper is to provide an historical overview of the development of the taxonomy of high‐risk situations for relapse in patients receiving abstinence‐based treatment for alcoholism. Research conducted during the 1970s on determinants of relapse is briefly reviewed, beginning with a preliminary analysis of relapse patterns in alcoholics treated with aversion therapy. Theoretical foundations underlying the development of the taxonomy are then discussed with an emphasis on social‐learning theory and its implications for cognitive‐behavioral interventions for relapse prevention. Findings supporting the efficacy of coping‐skills training for high‐risk relapse situations, based on a prospective treatment outcome study for inpatient alcoholics, are also presented in support of the clinical validity of the relapse model. The paper concludes with a description of the refined and extended taxonomy of high‐risk situations and the associated cognitive‐behavioral model of relapse described in the Marlatt &amp; Gordon (1985) text on relapse prevention.

Taxonomy of high-risk situations for alcohol relapse: evolution and development of a cognitive-behavioral model

The purpose of this paper is to provide an historical overview of the development of the taxonomy of high-risk situations for relapse in patients receiving abstinence-based treatment for alcoholism. Research conducted during the 1970s on determinants of relapse is briefly reviewed, beginning with a preliminary analysis of relapse patterns in alcoholics treated with aversion therapy. Theoretical foundations underlying the development of the taxonomy are then discussed with an emphasis on social-learning theory and its implications for cognitive-behavioral interventions for relapse prevention. Findings supporting the efficacy of coping-skills training for high-risk relapse situations, based on a prospective treatment outcome study for inpatient alcoholics, are also presented in support of the clinical validity of the relapse model. The paper concludes with a description of the refined and extended taxonomy of high-risk situations and the associated cognitive-behavioral model of relapse described in the Marlatt & Gordon (1985) text on relapse prevention.

Platelet Function in Alcoholics Treated with Disulfiram

Disulfiram is usually used in alcoholics as aversion therapy. It binds to various enzymes and pro teins in blood and in tissues. In particular, it inhibits the thromboxane synthetase in human platelets and, for this reason, it has been surmised that disulfiram has a possible effect on platelet function. So far, disulfiram failed to confirm this hypothesis in healthy volunteers. However, it appears able to decrease the threshold collagen concen tration for platelet aggregation. Our aim was to evaluate the effect of disulfiram on the platelet function of alco holics. In this study, 24 alcoholics, divided in group A (12 abstinent patients with disulfiram 200 mg/day), group B (12 abstinent patients without treatment), and 17 normal controls, are reported. Different tests were performed at time 0 (acute alcohol intoxication), time 2, and time 15 after the beginning of abstinence. A significant increase was observed in bleeding time (BT) of group B and in platelet count of both groups. No modification was seen in prothrombin time. In group A, a significant increase of platelet aggregation under adenosine diphosphate (ADP; 2 μ M) stimulus was observed. Whereas no difference was seen in platelet 5-hydroxytryptamine (5-HT), serum 5-HT increased significantly at time 15 in group A. We con clude that the increase in serum 5-HT was probably due to the inhibition of monoamine oxidase (MAO) promoted by disulfiram, followed by an activation of MAO induced by disulfiram.

Inhibition of and interaction with human recombinant mitochondrial aldehyde dehydrogenase by methyl diethylthiocarbamate sulfoxide.

Disulfiram is used as aversion therapy in the treatment of alcoholism. Following the administration of disulfiram there is a decrease in the activity of hepatic aldehyde dehydrogenase. A consequence of this effect is the accumulation of acetaldehyde subsequent to ethanol ingestion. The increase in levels of acetaldehyde produce flushing, nausea, vomiting, and tachycardia which is referred to as the disulfiram-ethanol reaction (Hald, et al., 1948; Kitson, 1977). In vivo disulfiram is rapidly reduced to N,N-diethylthiocarbamate (DDC) and it is therefore felt that the intact drug is not responsible for the inhibition of aldehyde dehydrogenase (ALDH) (Cobby, et al., 1977). An active metabolite of disulfiram is felt to be responsible for the inhibition. One such candidate is methyl diethylthiocar-bamate sulfoxide (MeDTC-sulfoxide) (Hart and Faiman, 1992). This compound has been shown to be an inhibitor of rat mitochondrial ALDH and has been detected in the plasma of rats given disulfiram (Hart and Faiman, 1992). Since the mitochondrial isoform of ALDH is felt to be important in the metabolism of acetaldehyde derived from ethanol metabolism (Svanas and Weiner, 1985), we examined the effect of MeDTC-sulfoxide upon the activity of human ALDH. We further investigated the interaction of the inhibitor with this enzyme by mass spectrometry.

Clinical interventions by psychologists with lesbians and gay men.

A questionnaire that assesses methods of intervention with, and attitudes toward, lesbians and gay men was completed by 139 clinical psychologists. None claimed to use aversion techniques to change sexual orientation. Eleven percent reported use of alternative methods (e.g., psychoanalytic techniques) to change sexual orientation, whereas 5.8% supported the use of aversion therapy for this purpose. Viewing homosexuality as "unacceptable" predicted both the use of alternative therapies and support of aversion therapy to change sexual orientation.