Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine.

The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20mg of cocaine on Day 1, and saline and 40mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20mg of cocaine on Day 6, and saline and 40mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8mg dose level discontinued, and five of 11 participants at the 0.2mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "any drug effect", "good effects", and "desire cocaine", but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population.

Ketamine is associated with lower urinary tract signs and symptoms.

BACKGROUND: Case reports and series indicate that ketamine, an anesthetic agent, causes lower urinary tract symptoms (LUTS). This study explored whether ketamine users were more likely to report LUTS compared to other substance users. METHODS: Participants were recruited through an online survey on erowid.org, a drug information website. A notice posted on the website invited substance users to participate in a web-based survey on "drug use and health". The notice did not mention ketamine, or other aspects of the research questions, to avoid participation bias. The anonymous survey collected demographics, drug use history, and history of LUTS (urinary frequency, urgency, incontinence, hematuria, and dysuria). RESULTS: Of 18,802 participants, 18.7% and 5.8% reported ever (lifetime) and recent (past-6-month) use of ketamine, respectively. Prevalence of LUTS among ever, recent, and never users of ketamine were 28%, 30%, and 24% respectively. Multivariate analysis showed significant associations between recent ketamine use and urinary symptoms. For each additional day of ketamine use in the last 180 days, the odds of developing urinary frequency, urgency, dysuria, and hematuria increased by 1.6%, 1.4%, 1.7%, and 1.9% respectively. One excess case of urinary frequency was reported per 17 recent users of ketamine. CONCLUSION: Compared to non-users, recent ketamine users had increased odds of LUTS. This is the first large-scale community-based study assessing the association of non-medical ketamine use with LUTS. Associations between ketamine and urological symptoms should be confirmed through longitudinal studies.

A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction.

Sixty treatment-seeking individuals with methamphetamine (MA) dependence entered a randomized, placebo-controlled, double-blind clinical trial of oral dextroamphetamine (d-AMP) as a replacement therapy for MA dependence. The subjects took 60 mg sustained-release d-AMP for 8 weeks, during which time they received eight 50-min sessions of individual psychotherapy. Adverse events and urine toxicology for MA were assessed two times a week. There were no serious adverse events. Urine samples containing <1,000 ng/ml of MA were classified as negative for MA. The MA-negative scores in the d-AMP group (3.1 ± SD 4.6) were no higher than those in the placebo group (3.3 ± SD 5.3; P > 0.05). However, withdrawal and craving scores were significantly lower in the d-AMP group (P < 0.05 for both). Although subjects taking d-AMP did not reduce their use of MA, the significant reductions observed in withdrawal and craving scores in this group support the need for further exploration of d-AMP as a pharmacologic intervention for MA dependence, possibly at higher doses.

Efficacy, safety, and ethics of cosmetic neurology far from settled.

In this issue, Larriviere and colleagues discuss the emerging use of drugs to enhance cognitive function. Several cautions they raise warrant amplification. People have tried to pharmacologically improve cognitive function for millennia, but Larriviere and colleagues postulate that new, more effective drugs will lead to the emergence of  "cosmetic neurology." The ethics of using drugs to improve performance, as opposed to treating disease or restoring normal function, are far from settled.

Craving predicts use during treatment for methamphetamine dependence: a prospective, repeated-measures, within-subject analysis.

Clinical lore dictates that craving drives the compulsive use of drugs and alcohol - the core feature of substance dependence. Yet limited research has yielded mixed results, suggesting that craving is neither necessary nor sufficient for continued use or relapse to addictive substances. To investigate the role of craving in compulsive methamphetamine use, 31 men and women in treatment for methamphetamine dependence were asked to indicate, once each week for 12 weeks, the severity of craving that they had experienced during the previous 24 h, using a 100-mm visual analog scale. In a prospective, repeated-measures, within-subject analysis, craving intensity significantly predicted methamphetamine use in the week immediately following each craving report. Craving remained a highly significant predictor in multivariate models controlling for pharmacological intervention, and for methamphetamine use during the prior week. Craving scores that preceded use were 2.7 times higher than scores that preceded abstinence. Risk of subsequent use was 2.5 times greater for scores in the upper half of the scale relative to scores in the lower half. The results obtained demonstrate that, while craving alone may be neither necessary nor sufficient to explain substance addiction, when measured prospectively in a carefully-designed study craving emerges as a salient predictive factor in continued methamphetamine use for patients in treatment for methamphetamine dependence.

Treatment-as-usual in the methamphetamine treatment project.

The Methamphetamine Treatment Project is a multisite trial that compares the effectiveness of eight models of outpatient treatment for methamphetamine dependence to that of the Matrix model. These eight "treatment-as-usual" models represent diverse approaches developed in a variety of settings to serve markedly different populations. The theoretical foundations of these treatments are described as well as the settings in which they are delivered. To facilitate comparisons, details are presented with respect to frequency of group and individual sessions, duration of treatment, therapist qualifications, and access to ancillary services. The populations served by these programs vary with respect to race and ethnicity. Most programs serve primarily non-Hispanic Caucasians, but some programs serve significant proportions of Hispanics, Asians, Pacific Islanders, and Native Americans. Usual route of administration of methamphetamine also varies by site, with snorting, smoking, and injecting each reported as the most common route of administration at one or more sites. The Minnesota model and cognitive-behavioral approaches are most commonly used in these programs, although contingency management and psychodynamic approaches are also represented. The intensive phase of treatment ranges between four and 24 weeks; the number of hours per week of client contact varies between one and 13. This trial will provide the opportunity to test the effectiveness of a wide range of treatments currently in use in community settings.

Abuse and therapeutic potential of gamma-hydroxybutyric acid.

Gamma-hydroxbutyric acid is a compound found in mammalian brain that is structurally related to the neurotransmitters gamma-aminobutyric acid and glutamic acid. Gamma-hydroxybutyric acid effects dopaminergic systems in the brain and may be a neurotransmitter. Gamma-hydroxybutyric acid was first reported as a drug of abuse in 1990 and continues to be abused by bodybuilders, participants of "rave" dance parties, and polydrug abusers. Physical dependence can develop after prolonged, high-dose use, and overdoses have been widely reported. Its use in sexual assaults as a "date rape" drug and availability on the internet have recently emerged. Gamma-hydroxybutyric acid has established efficacy as an anesthetic agent, and preliminary evidence supports its utility in the treatment of alcohol dependence, opiate dependence, and narcolepsy.

Abuse potential of dronabinol (Marinol).

Dronabinol is an oral form of delta-9-tetrahydrocannabinol indicated for treatment of anorexia associated with weight loss in individuals with AIDS, and nausea and vomiting associated with cancer chemotherapy. The authors reviewed the literature and conducted surveys and interviews among addiction medicine specialists, oncologists, researchers in cancer and HIV treatment, and law enforcement personnel to determine the abuse liability of dronabinol. There is no evidence of abuse or diversion of dronabinol. Available prescription tracking data indicates that use remains within the therapeutic dosage range over time. Healthcare professionals have detected no indication of "scrip-chasing" or "doctor-shopping" among the patients for whom they have prescribed dronabinol. Cannabis-dependent populations, such as those treated in our Clinic and seen by the addiction medicine specialists we interviewed, have demonstrated no interest in abuse of dronabinol. There is no street market for dronabinol, and no evidence of any diversion of dronabinol for sale as a street drug. Furthermore, dronabinol does not provide effects that are considered desirable in a drug of abuse. The onset of action is slow and gradual, it is at most only weakly reinforcing, and the overwhelming majority of reports of users indicate that its effects are dysphoric and unappealing. This profile of effects gives dronabinol a very low abuse potential.

Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence.

Gamma-hydroxybutyrate (GHB) is a compound found in mammalian brain which meets many criteria of a neurotransmitter. GHB has been investigated as a tool for inducing absence (petit mal) seizures, for use as an anesthetic, and for treatment of narcolepsy, alcohol dependence and opiate dependence. Since 1990 GHB has been abused in the United States for euphoric, sedative and anabolic effects. Coma and seizures have been reported following abuse of GHB, but dependence liability has received little attention. The neuropharmacology, potential therapeutic uses and acute adverse effects of GHB are reviewed, followed by a case series of eight people using GHB. Adverse effects of GHB may include prolonged abuse, seizure activity and a withdrawal syndrome. This withdrawal syndrome includes insomnia, anxiety and tremor; withdrawal symptoms resolve in 3-12 days. GHB has the potential to cause a significant incidence of abuse and adverse effects. Prolonged use of high doses may lead to a withdrawal syndrome, which resolves without sequelae. Educational efforts should address the narrow therapeutic index, possible physical dependence and dangers of combining GHB with other drugs of abuse.

Ritanserin in the treatment of alcohol dependence--a multi-center clinical trial. Ritanserin Study Group.

Four hundred and twenty-three alcohol dependent subjects were enrolled into a 12-week randomized, double-blind, placebo-controlled study to determine the safety and efficacy of the 5-HT2 receptor antagonist, ritanserin (2.5 mg/day or 5 mg/day), in reducing alcohol intake and craving. All subjects received 1 week of single-blind placebo prior to randomization into the 11-week double-blind phase. Additionally, all subjects received weekly individual sessions of manual-guided cognitive-behavioral therapy. Comparing the single-blind period with endpoint, there was approximately a 23% reduction in drinks/day; 34% fall in the total number of drinking days/week; 22% decrease in drinks/drinking day; and a 37% diminution in alcohol craving for all treatment groups. All treatment groups experienced a beneficial clinical outcome as assessed by the Clinical Global Impression Scale. There was, however, no significant difference between treatment groups on any of these measures of alcohol drinking, craving, or clinical outcome. Subjects were of relatively high social functioning at baseline, and this did not change significantly during treatment. Treatment groups did not differ significantly on either medication compliance or reported adverse events. Ritanserin treatment was associated with a dose-related prolongation of subjects' QTc interval recording on the electrocardiogram. These results suggest that alcohol dependent subjects can show marked clinical improvement within a structured alcohol treatment program. These findings do not support an important role for ritanserin in the treatment of alcohol dependence.

A controlled trial of imipramine for the treatment of methamphetamine dependence.

At the Drug Detoxification Program of the Haight Ashbury Free Clinics, we conducted a randomized clinical trial of imipramine in the treatment of methamphetamine dependence. The purposes of the trial were to test the efficacy of imipramine as a treatment for methamphetamine dependence and to establish the feasibility of conducting a controlled clinical trial at the Clinic. Thirty-two subjects were randomly assigned to receive either 10 or 150 mg/day of imiprine for 180 days. Imipramine 10 mg/day was the control. Subjects received intensive counseling. Retention in treatment was significantly longer for subjects who were treated with 150 mg of imipramine compared to control (median days: 33.0 vs. 10.5). There were no consistent differences in percent of urine samples positive for methamphetamine, Beck Depression Inventory scores, or craving. Determination of the full extent of imipramine's utility in the treatment of methamphetamine dependence awaits a larger trial.

A historically controlled trial of tyrosine for cocaine dependence.

Cocaine dependence continues to be a major public health problem and efforts to develop pharmacotherapies have been disappointing. Chronic cocaine use is believed to cause catecholamine depletion and similarities exist between cocaine withdrawal and major depression. Tyrosine is the dietary precursor to catecholamines and has yielded positive results in small trials of its antidepressant efficacy. Tyrosine 2 g every 8 hours was administered on an open-label basis to 49 cocaine-dependent individuals, as an adjunct to intensive out-patient drug abuse counseling. Retention in treatment at 90 days was compared to data from a control group of 80 subjects who had received 10 mg of imipramine per day in an earlier trial. Median retention was 17 days in both groups. No side effects were reported by the subjects receiving tyrosine. These results do not support the utility of tyrosine in the treatment of cocaine dependence.

Abuse of flunitrazepam (Rohypnol) and other benzodiazepines in Austin and south Texas.

Flunitrazepam (Rohypnol) is a benzodiazepine sedative-hypnotic that has generated significant media attention in the United States because of its abuse and its association with "date rape." A field investigation was conducted in south Texas to ascertain the nature and consequences of the abuse of flunitrazepam. In semistructured interviews, 66 subjects identified as flunitrazepam users were asked about their use of alcohol and other drugs and their sexual behaviors. Many subjects identified the drugs they had used as "roches" and gave descriptions of tablets of other benzodiazepines that were not consistent with flunitrazepam. Almost all subjects used other drugs, primarily alcohol and marijuana. Adverse consequences included amnesia, discoordination, automobile accidents, sexual assault, and respiratory depression or arrest. A significant proportion of the subjects reported that continued use was unappealing to them. The abuse of sedative-hypnotics in southeast Texas involves several benzodiazepines and is not limited to flunitrazepam.

Imipramine for the treatment of cocaine and methamphetamine dependence.

At the Drug Detoxification, Rehabilitation, and Aftercare Program of the Haight-Ashbury Free Clinics, we conducted a double-blind, controlled, randomized clinical trial of imipramine in the treatment of cocaine and methamphetamine abusers. The purpose of the trial was to test the efficacy of imipramine as a treatment for stimulant dependence and to establish the feasibility of conducting a controlled clinical trial at the clinic under conditions that approximated usual clinical practice. Subjects were randomly assigned to receive either 10 or 150 mg/day of imipramine. Imipramine 10 mg/day was the control condition. Subjects could receive study medication for up to 180 days. One-hundred eighty-three subjects participated in the study: 151 were cocaine dependent and 32 were methamphetamine dependent. In addition to receiving study medication, all subjects were assigned to intensive drug abuse counseling, which included an HIV education component. Using an intention-to-treat analysis, we found that retention in treatment was significantly longer for subjects who were treated with 150 mg of imipramine compared to control. However, we found no consistent differences between the two groups of subjects in Beck Depression Inventory scores, stimulant craving, self-report of time since last use of stimulants, or percent of urinalyses positive for stimulants. The feasibility of conducting a controlled, randomized clinical trial of medication for treatment of drug abuse was established for this community clinic setting.