Impact of prospectively determined A118G polymorphism on treatment response to injectable naltrexone among methamphetamine-dependent patients: an open-label, pilot study.

OBJECTIVES: Methamphetamine (MA) addiction has no known effective pharmacotherapy. Small trials showed beneficial effects for oral naltrexone in amphetamine users. Trials in alcohol-dependent subjects showed better response in persons with the A118G single nucleotide polymorphism of the µ-opioid receptor. We conducted a pharmacogenetic trial of sustained release intramuscular naltrexone to examine the role of the A118G single nucleotide polymorphism in MA dependence. METHOD: All eligible A118G subjects screened were enrolled; an equal number of wild type (A118A) subjects were selected using modified urn randomization, balanced on sex and frequency of recent MA use. Enrolled subjects received a single 380 mg naltrexone injection and weekly psychotherapy for 4 weeks. Self-report of MA use and urine toxicology for MA was assessed twice weekly. Urine samples with less than 1000 ng/mL of MA were considered negative. RESULTS: Eleven A118G and 11 A118A subjects were enrolled. There were no significant differences between the groups in days of abstinence from MA use (11.5 vs 14.8, respectively, P = 0.51), the number of MA-negative urine samples (1.7 vs 1.8, respectively, P = 0.97), consecutive MA-negative urine samples (1.0 vs 1.5, respectively, P = 0.91), or the number of MA-negative urine samples before first relapse (0.9 vs 1.5, respectively, P = 0.86). CONCLUSIONS: Although A118G polymorphism has been shown to be associated with improved treatment response to naltrexone among alcoholics, whether this polymorphism impacts naltrexone treatment response among MA users is unclear at this time.

Developing biomarkers for methamphetamine addiction.

There are an estimated 11.7 million methamphetamine (MA) abusers in the United States and epidemics of MA addiction are occurring worldwide. In our human laboratory and outpatient clinical trials we use innovative methods to quantify the severity of MA addiction and test biomarkers that may predict response to therapy or risk of relapse. One potential biomarker of addiction is the quantity of abused drug intake. Qualitative urinalysis is used in clinical trials and during treatment but provides only a binary outcome measure of abuse. Using non-pharmacologic doses of deuterium labeled l-MA we have developed a continuous quantitative measure to estimate the bioavailable amount of MA addicts ingest. Brain Derived Neurotrophic Factor is a neurotrophin that encourages growth and differentiation of new neurons and synapses. Low BDNF levels are seen in many addictive disorders and BDNF is elevated in recovering MA addicts, suggesting BDNF may be a marker of MA addiction. We are investigating the effects of controlled doses of MA on BDNF levels and gene regulation and measuring BDNF in our clinical trials. We believe both patients and clinical researches will benefit from the addition of new, objective and quantifiable outcome measures that reflect disease severity and recovery from addiction.

A simple, novel method for assessing medication adherence: capsule photographs taken with cellular telephones.

OBJECTIVES: Medication nonadherence is an important factor in clinical practice and research methodology. Although many methods of measuring adherence have been investigated, there is as yet no "gold standard." We compared the usefulness and accuracy of a novel measure of adherence, photographs taken by cellular telephones with 2 incumbents: capsule count and the Medication Event Monitoring System (MEMS). METHOD: Twenty subjects participated in a clinical trial of the efficacy of modafinil for the treatment of methamphetamine dependence. Subjects were issued cell phones and medication in MEMS Cap equipped bottles and were instructed to take 1 capsule a day for 8 weeks, recording adherence with both systems. Pill counts were recorded at weekly inpatient visits. Subjects were paid for participation and for each capsule photograph and the returned medication bottle with MEMS Cap. RESULTS: Capsule count-indicated adherence (proportion of prescribed medication taken) was 94.9%. When compared with capsule count, the novel method was found to underestimate adherence, whereas MEMS overestimated adherence. By using the dosing time data collected, we determined that subjects who dosed at a consistent time daily were more likely to adhere to the prescribed regimen. We also detected discrepancies in the timestamps recorded by MEMS. CONCLUSIONS: Capsule photographs are a useful measure of adherence, allowing more accurate time measures and more frequent adherence assessment than MEMS or capsule count. Given the ubiquity of cellular telephone use, and the relative ease of this adherence measurement method, we believe it is a useful and cost-effective approach.

Lack of effect of sublingual salvinorin A, a naturally occurring kappa opioid, in humans: a placebo-controlled trial.

RATIONALE: Salvinorin A (SA) is a highly selective kappa opioid receptor agonist and the putative psychoactive compound in Salvia divinorum (SD), an increasingly abused hallucinogenic plant. OBJECTIVES: The objectives of this study were to characterize the physiological and subjective effects of SA versus placebo and measure drug and metabolite levels. METHODS: Sublingual SA doses up to 4 mg were administered in dimethyl sulfoxide/polyethylene glycol 400 solution to eight SD-experienced subjects using a placebo-controlled ascending-dose design. RESULTS: No dose of SA produced significantly greater physiological or subjective effects than placebo. Furthermore, effects did not resemble reported "typical" effects of smoked SD. SA was detectable in plasma and urine, but was, in most cases, below the reliable limit of quantification (0.5 ng/mL). CONCLUSIONS: Our results suggest that the sublingual bioavailability of SA is low. Higher doses, alternate formulations, or alternate routes of administration will be necessary to study the effects of SA in humans.

Validation of triage criteria for deciding which apparently inebriated persons require emergency department care.

OBJECTIVES: The sensitivity and specificity of consensus triage criteria for identifying which apparently inebriated patients could be triaged to care in a sobering centre were determined. Sensitivity and specificity for modifications to these criteria were also investigated. METHODS: Paramedics prospectively collected data on apparently inebriated persons en route to the emergency department (ED). 99 of these patients' ED charts were retrospectively reviewed to assess who actually required ED care. RESULTS: Of 99 subjects with both paramedic and ED chart data available, most were male (89%), homeless (57%) and found on the street (81%). Five were admitted and 13 others appeared to require ED care. Per consensus criteria, only 40 were eligible for triage to a sobering centre, but among those were five who appeared to require ED care (sensitivity 72%, 95% CI 47% to 90%; specificity 43%, 95% CI 32% to 55%). Paramedic opinion alone was specific (80%) but not very sensitive (39%). Lowering the pulse exclusion threshold from 130 to 83 would increase sensitivity to 100%, but decrease specificity to 22%. A simple post hoc rule excluding those with age >55 or pulse >83 from non-ED care had high sensitivity (94%) and fair specificity (61%). The consensus criteria's sensitivity and specificity varied (65-83% and 44-49%, respectively) depending on which ED services were considered optional (eg, psychiatric consultation, ECG, intravenous fluids, etc.). CONCLUSION: Most apparently inebriated individuals in this study did not require ED care, but prospective identification of these persons is difficult. A low exclusion cut-off for tachycardia may improve sensitivity.

Psychiatric comorbidity in methamphetamine dependence.

The primary aim of the present study was to assess the prevalence of psychiatric comorbidity in a large sample of methamphetamine (MA)-dependent subjects using a validated structured clinical interview, without limitation to sexual orientation or participation in a treatment program. The secondary aim was to assess whether the prevalence of psychiatric comorbidities varied by gender. Structured clinical interviews (SCIDs) were administered to 189 MA-dependent subjects and lifetime prevalence of DSM-IV diagnoses was assessed. Across the sample, 28.6% had primary psychotic disorders, 23.8% of which were substance-induced; 13.2% had MA-induced delusional disorders and 11.1% had MA-induced hallucinations. A substantial number of lifetime mood disorders were identified that were not substance-induced (32.3%), whereas 14.8% had mood disorders induced by substances, and 10.6% had mood disorders induced by amphetamines. Of all participants, 26.5% had anxiety disorders and 3.7% had a substance-induced anxiety disorder, all of which were induced by MA. Male subjects reported a higher percentage of MA-induced delusions compared to female abusers. Given the impact of MA psychosis and other drug-induced symptoms on hospitals and mental health services, the description and characterization of comorbid psychiatric symptoms associated with MA use is of paramount importance.

Methamphetamine and paranoia: the methamphetamine experience questionnaire.

Paranoia in methamphetamine (MA) users is not well characterized or understood. To investigate this phenomenon, we created the Methamphetamine Experience Questionnaire (MEQ), and tested its reliability and validity in assessing MA-induced paranoia. We administered the MEQ to 274 MA-dependent subjects. Of the total subjects, 45% (123) first experienced paranoia with MA use; 55% did not. Obtaining or using a weapon while paranoid was common (37% and 11% of subjects with MA-induced paranoia, respectively). Test-retest and inter-rater reliability for MA-induced paranoia showed substantial agreement (kappa = .77, p < .05 and kappa = .80, p < .05, respectively). First episodes of paranoia occurred more often with intravenous use of MA, and subsequent episodes at higher doses. There was modest correlation between paranoia on the MEQ and the Brief Symptom Inventory (BSI) paranoid ideation scale (rho = .27, p < .05). As expected, there was a poor correlation between paranoia on the MEQ and the BSI depression scale (rho = .14, p = .07). The MEQ provides useful information on drug use variables that contribute to paranoia commonly associated with MA use. (Am J Addict 2010;00:1-14).

Addiction to prescription opioids: characteristics of the emerging epidemic and treatment with buprenorphine.

Dependence on and abuse of prescription opioid drugs is now a major health problem, with initiation of prescription opioid abuse exceeding cocaine in young people. Coincident with the emergence of abuse and dependence on prescription opioids, there has been an increased emphasis on the treatment of pain. Pain is now the "5th vital sign" and physicians face disciplinary action for failure to adequately relieve pain. Thus, physicians are whipsawed between the imperative to treat pain with opioids and the fear of producing addiction in some patients. In this article, the authors characterize the emerging epidemic of prescription opioid abuse, discuss the utility of buprenorphine in the treatment of addiction to prescription opioids, and present illustrative case histories of successful treatment with buprenorphine.