The Swiss heroin trials. Scientifically sound?

The objective of this article is to critique a study conducted by the Swiss Federal Office of Public Health to evaluate Switzerland's heroin maintenance project. Heroin abusers (N = 1,146) were enrolled in 18 research clinics. Subjects were recruited into three study arms--heroin, morphine, or methadone maintenance, but randomization was unsuccessful, and all received heroin. Medications were self-administered by injection on site. Patients were interviewed at intake and 6-month intervals up to 18 months. A review of the study revealed design weaknesses, including the absence of control groups, lack of corroboration of self-reports, failure to control for the influence of social services on outcome, and the absence of follow-up on those who left the trial prematurely. The program's ability to avert human immunodeficiency virus (HIV) transmission could not be fully evaluated because patients did not consistently submit to HIV testing. The Swiss trials of supervised heroin prescription trials do not withstand scientific scrutiny.

No association between D2 dopamine receptor (DRD2) alleles or haplotypes and cocaine dependence or severity of cocaine dependence in European- and African-Americans.

BACKGROUND: Association studies between marker alleles at the D2 dopamine receptor gene (DRD2) and various psychiatric illnesses have produced conflicting results. Reports of allelic associations were originally made with alcoholism, but were then extended to other psychiatric disorders; there has been a series of positive reports suggesting an association between DRD2 alleles and substance dependence in European-American (EA) subjects. METHODS: In an attempt to replicate the reported association between DRD2 alleles, substance dependence, and severity of substance dependence, we studied allele frequencies for three polymorphic DRD2 systems (TaqI "A," "B," and "D") in 96 EA and 77 African-American (AA) cocaine-dependent subjects, and 87 EA and 45 AA control subjects. To increase our power to detect such an association and to better understand any association detected, we also constructed three-locus haplotypes and compared haplotype frequencies. RESULTS: For both the EA and AA samples, there were no significant differences in allele frequency between substance-dependent and control subjects for any of the three DRD2 polymorphic systems studied. There were also no significant differences in haplotype frequency between substance-dependent and control subjects for either EA or AA subjects; and, finally, there were no significant differences in "A" or "B" system allele frequency by severity. There were, however, significant differences between EAs and AAs. CONCLUSIONS: Our data do not support an association between DRD2 alleles or haplotypes and cocaine dependence, in EA or AA subjects. Moreover, DRD2 alleles are not associated with severity of cocaine dependence in this sample.

Influence of retroactive disability payments on recipients' compliance with substance abuse treatment.

OBJECTIVE: This study examined whether substance abusers who received large retroactive payments from Social Security disability programs were more likely to terminate residential treatment precipitously than those who did not receive payments. METHODS: The records of 43 patients of a long-term residential treatment facility who received disability payments at some point during their treatment stay were blindly examined. Twenty-six of these patients received a large one-time retroactive payment representing money that accumulated during processing of the claims. To test the hypothesis that receipt of such a payment would lead to precipitous discharge, a survival regression model was used. A control group of nonrecipient patients was sampled at a comparable point in treatment. RESULTS: Subjects in the recipient group were significantly more likely to have unplanned discharges than those in the comparison group. CONCLUSIONS: These preliminary data suggest that large cash infusions can be disruptive to the course of treatment for substance abusers.

No association between D3 dopamine receptor (DRD3) alleles and cocaine dependence.

Cocaine is thought to act in the brain primarily by blocking dopamine re-uptake. The dopamine D3 receptor (genetic locus DRD3) is localized to brain regions that have been implicated in the reinforcing effects of a number of substances of abuse, including cocaine. The DRD3 coding region contains a polymorphism identifiable as a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). This polymorphism leads to an amino acid substitution at position 9 in the extracellular N-terminus of the D3 dopamine receptor. We examined alleles of the DRD3 gene in cocaine dependence using a genetic association strategy in samples of 62 white and 62 black cocaine-dependent individuals. Comparisons were made with local (Connecticut) control subjects for both groups, and with a larger sample of literature controls (for the white subjects) and a contrast group of schizophrenic patients (for the black subjects). No association was found between cocaine dependence and DRD3 alleles in either group (Bonferroni corrected). There was a significant difference in allele frequency between whites and blacks. These results are consistent with no role for genetic variation of the D3 dopamine receptor in susceptibility to cocaine dependence.

Tryptophan depletion and attenuation of cue-induced craving for cocaine.

OBJECTIVE: Although cocaine is a potent serotonin (5-HT) reuptake blocker, the role of 5-HT systems in cocaine craving and relapse in humans has been unclear. The authors evaluated whether acute reductions in central 5-HT synthesis modulated craving for cocaine in cocaine-dependent patients. METHOD: Twenty-five cocaine-dependent male inpatients were exposed to cocaine-craving cues while their 5-HT levels were lowered and during a placebo condition in a counterbalanced, double-blind design. 5-HT levels were reduced by rapidly lowering plasma levels of its precursor, tryptophan; tryptophan levels were reduced by stimulating protein synthesis with a large drink of amino acids devoid of tryptophan. During the placebo condition the patients drank an identical amino acid drink containing tryptophan. Craving was induced by exposing patients to cocaine paraphernalia and a videotape depicting drug use. Craving was assessed 7 hours after ingestion of the drink. Visual analog ratings of craving for cocaine were administered before and after cue exposure at each test session. RESULTS: Patients reported less desire for cocaine stimulated by cue exposure after drinking amino acids without tryptophan than they did after drinking placebo. The order that tryptophan depletion and placebo tests were performed influenced the impact of tryptophan depletion on cue-induced craving. CONCLUSIONS: Serotonergic systems modulate cue-induced craving for cocaine, a factor implicated in relapse to cocaine use.

Genetic association between dopamine transporter protein alleles and cocaine-induced paranoia.

Paranoia in the context of cocaine abuse is common and potentially dangerous. Several lines of evidence suggest that this phenomenon may be related to function of the dopamine transporter protein (DAT). DAT is the site of presynaptic reuptake of dopamine, an event that terminates its synaptic activity. The gene coding for dopamine transporter protein (DAT1) contains a variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region that can be typed by the polymerase chain reaction (PCR) (Vandenbergh et al. 1992). Although this is not a coding region polymorphism, it is close to the coding region and could plausibly be in linkage disequilibrium with a mutation in the gene. Cocaine blocks the dopamine transporter and increases synaptic availability of dopamine. We examined DAT alleles in 58 white and 45 black cocaine users in order to test only two hypotheses: (1) Is there an allelic association between DAT and cocaine dependence? and (2) Is there an allelic association between DAT and cocaine-induced paranoia? We did not demonstrate an allelic association with cocaine dependence. However, within the white sample, DAT genotype was associated with cocaine-induced paranoia (allele frequency for allele 9 = .16 for those without paranoid experiences versus .35 for those with, chi 2 = 3.9 [2 x 2 table], p < .05). There was no significant difference for the same measure in the black sample. Certain DAT genotypes may therefore predispose to paranoia in the context of cocaine use in white populations. We caution that these results require independent replication.

Personality disorders and associated features in cocaine-dependent inpatients.

Previous research has shown a high prevalence of comorbid personality disorders among individuals seeking treatment for cocaine dependence. We studied axis II disorders (using the Structured Clinical Interview for DSM-III-R Personality Disorders [SCID-II]) in 50 patients admitted for inpatient rehabilitation. All patients met lifetime criteria for cocaine dependence and reported cocaine use during the month before admission. Seventy percent of patients met criteria for at least one axis II diagnosis; the mean number of axis II diagnoses among these patients was 2.54 (range, one to six). The most common axis II diagnosis was borderline (34% of all patients), followed by antisocial and narcissistic (each 28%), avoidant and paranoid (each 22%), obsessive-compulsive (16%), and dependent (10%). To evaluate the relationship between comorbid personality pathology, substance abuse, and other psychiatric symptomatology, patients were divided into two groups based on whether they received an axis II disorder diagnosis. The groups did not differ on substance abuse variables. However, there were significant group differences on a measure of psychosis proneness and in the number of comorbid depressive and anxiety disorder diagnoses. These results are consistent with other studies of personality disorders in substance abuse patients, and suggest that it may be clinically useful to characterize cocaine-dependent patients with respect to comorbid axis II disorders.

Reducing obstacles to affiliation with alcoholics anonymous among veterans with PTSD and alcoholism.

Alcohol use is prevalent among Vietnam veterans who suffer from chronic combat-related posttraumatic stress disorder (PTSD). Although Alcoholics Anonymous (AA) is the mainstay of ambulatory alcoholism treatment, adherence to particular components of the AA philosophy may prove especially challenging for alcoholic Vietnam veterans with PTSD. The authors describe elements of AA's philosophy, such as "surrendering" to a "higher power," making amends to persons one has harmed, and sharing one's story publicly, that may be difficult for the Vietnam veteran with PTSD. The authors suggest that an important factor in the successful affiliation of these patients with AA is their capacity to separate their alcohol-related problems and treatment from their PTSD symptoms and treatment and to accommodate dual identities as both an alcoholic and a traumatized soldier. Preparing such patients for AA by reframing some of the 12 steps is recommended.

Language therapy for schizophrenic patients with persistent 'voices'.

One of us has hypothesised that the 'voices' of schizophrenic patients reflect altered preconscious planning of discourse that can produce involuntary 'inner speech' as well as incoherent overt speech. Some schizophrenic patients reporting voices do not, however, have disorganised speech. We hypothesise that these 'counterexample' patients compensate for impairments of discourse planning by reducing language complexity and relying on highly rehearsed topics. A 'language therapy' designed to challenge and enhance novel discourse planning was administered to four such patients; three had significant albeit temporary reductions in the severity of their voices. These clinical findings provide further evidence that alterations of discourse planning may underlie hallucinated voices.

Should protracted withdrawal from drugs be included in DSM-IV?

OBJECTIVE: The authors reviewed both clinical data and selected laboratory research related to withdrawal from alcohol, opiates, and stimulants in order to draw a conclusion about whether the phenomenon of protracted withdrawal exists and should be included in DSM-IV. METHOD: Studies were located through computerized searches and reference sections of published articles. RESULTS: Symptoms extending beyond the period of acute withdrawal in alcohol and opiate dependence have been fairly consistently described; this is not the case with cocaine. Nevertheless, protracted alcohol and opiate withdrawal has not been conclusively demonstrated because of the failure of studies to do multiple time point sampling, to use standardized instruments and control groups, and to re-administer the substance in an attempt to suppress withdrawal symptoms. Further, the concept of protracted withdrawal itself is ambiguously defined. This confounds interpretation of the literature and precludes derivation of a unified concept of the term, which would be necessary for adding the diagnosis to DSM-IV. CONCLUSIONS: There is insufficient documentation to justify inclusion of protracted withdrawal in DSM-IV because of methodologic limitations of the studies and lack of consensus definition of the term itself. An outline for conceptualizing protracted withdrawal is offered in which the symptoms can be seen as: 1) a global post-use syndrome, 2) attenuated physiologic rebound, 3) toxic residuals, 4) expression of preexisting symptoms unmasked by cessation of use. Future efforts to identify signs and symptoms of protracted withdrawal should carefully define the parameters of the syndrome.