Keith Flower

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.

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.

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).

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.

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.

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 &mgr;-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.

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.

The Effects of 6β-Naltrexol, a Putative Neutral Opioid Antagonist, in Opioid-Dependent Subjects: A Proof-of-Concept Trial

Potential complications of prescription opioid use include abuse and constipation. 6β-Naltrexol (6βNTX), a neutral opioid antagonist, may alleviate these complications when co-formulated with μ-opioid analgesics. In a double-blind ascending dose study, four subjects on methadone maintenance received 6βNTX (0.05, 0.15, 0.50 and 1.0 mg). 6βNTX was generally well tolerated; three of four subjects reported willingness to take higher doses. Increased gastrointestinal activity was evidenced by decreased oral-cecal transit time and prompt laxation at higher doses.