Marta Mas

Pharmacology of MDMA in Humans

MDMA given at recreational doses (range tested 50 to 150 mg) to healthy volunteers, produced mydriasis and marked increases in systolic and diastolic blood pressure, heart rate, and pupillary diameter. MDMA induced changes on oral temperature. The time course of this observation was biphasic, as a slight decrease at 1 h and a slight increase at 2 and 4 h were observed. MDMA induced a slight dose‐dependent impairment on psychomotor performance. MDMA produced a marked rise in plasma cortisol and prolactin concentrations. The elimination half‐life of MDMA was about 8‐9 h. Drug concentrations increased, and a parallel increase in physiologic and hormonal measures was observed. Both peak concentrations and peak effects were obtained between 1 and 2 h and decreased to baseline values 4‐6 h after drug administration.

Quantification of 3,4-methylenedioxymetamphetamine and its metabolites in plasma and urine by gas chromatography with nitrogen-phosphorus detection.

A gas chromatographic method with nitrogen-phosphorus detection involving a solid-liquid extraction phase was developed and validated for the simultaneous quantification of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) in plasma. A modification of this method was validated for the analysis of MDMA, MDA, 4-hydroxy-3-methoxymethamphetamine (HMMA) and, 4-hydroxy-3-methoxyamphetamine (HMA) in urine. Under the analytical conditions described, the limits of detection in plasma and urine were less than 1.6 microg/l and 47 microg/l, respectively, for all the compounds studied. Good linearity was observed in the concentration range evaluated in plasma (5-400 microg/l) and urine (100-2000 microg/l) for all compounds tested. The recoveries obtained from plasma were 85.1% and 91.6% for MDMA and MDA, respectively. Urine recoveries were higher than 90% for MDMA and MDA, 74% for HMMA, and 64% for HMA. Methods have been successfully used in the assessment of plasma and urine concentrations of MDMA and its main metabolites in samples from clinical studies in healthy volunteers.

Abuse liability of flunitrazepam among methadone-maintained patients

Abstract Abuse liability and acute subjective and psychomotor effects of flunitrazepam were assessed in ten methadone-maintained males with history of benzodiazepine and alcohol use, who voluntarily participated in a double-blind, controlled, cross-over, randomized clinical trial. There were six experimental sessions in which a single oral dose of flunitrazepam 1, 2, and 4 mg; triazolam 0.5 and 0.75 mg; and placebo was given. Evaluations included physiological measures; psychomotor performance tasks (simple reaction time, Digit Symbol Substitution Test, balance task, Maddox-wing device); and self-administered subjective effects questionnaires [Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS), a series of visual analog scales (VAS)]. All drugs but flunitrazepam 1 mg caused an impairment of psychomotor tasks. Effects were more evident with the highest doses of both drugs. Only flunitrazepam 4 mg produced a significant decrease in balance time. Triazolam 0.75 mg induced increases in sedation measured by ARCI-PCAG, depression in POMS, and VAS-drowsiness scores. Flunitrazepam 4 mg caused euphoria-related effects as measured by increases in ARCI-MBG and “high” scores in the VAS. Our findings of flunitrazepam-induced euphoria in methadone-maintained subjects together with epidemiological evidence of flunitrazepam abuse by opioid dependents, suggest that it may be included in the group of benzodiazepines with a relatively high abuse potential.

Modulation of rate of onset and intensity of drug effects reduces abuse potential in healthy males

Low, medium, and high doses of flunitrazepam were tested in three independent randomized, double-blind, balanced cross-over, placebo-controlled trials to study the influence of rate of onset of effects and dose administered on its acute effects. Three groups of 12 healthy male volunteers received six oral doses of placebo or flunitrazepam in slow and fast onset conditions as follows: six capsules of 0.16 mg (slow) and a single capsule of 0.8 mg (fast) in the low dose trial; six 0.25 mg (slow) and a single 1.25 mg (fast) capsules for medium dose; and six 0.4 mg (slow) and a single 2 mg (fast) capsule for high dose. At each dose level, slow or fast increasing flunitrazepam plasma concentrations lead to similar peak levels, but induced differential subjective and behavioral effects. In addition to objective and subjective sedation, flunitrazepam induced some pleasurable feelings, which were more intense in the fast than in the slow conditions. At the highest dose, unpleasant sedative effects surmounted positive effects, while at the lowest dose pleasurable effects were of low intensity. At the medium dose, the balance between pleasurable and unpleasant feelings resulted in euphorigenic effects, which were evident in the fast condition but were blunted in the slow condition.

Quantification of amphetamine plasma concentrations by gas chromatography coupled to mass spectrometry

We developed a fast and sensitive method for identification and quantification of plasma concentrations of amphetamine using gas chromatography with mass spectrometry detection (GC-MS). Amphetamine-d8 served as internal standard. The method involves a single extraction procedure and an easy treatment of the samples that allowed no losses during the evaporation process. Derivatisation of amphetamine with N-methyl-bis(trifluoroacetamide), a potent acylating agent, provides many advantages to the method compared with common derivatisation reactions usually used for amphetamines. The limits of detection and quantification following this method were 0.43 and 1.42 ng/ml, respectively. The assay has been successfully employed in the quantification of amphetamine in plasma samples from healthy volunteers at four different doses.

Comment: Use and Abuse of Flunitrazepam

TO THE EDITOR: We read with interest the case report by Mallet and Kuyumjian (Ann Pharmacother 1998;32:201-3), who described a case of indomethacin-induced behavioral changes in a 92-year-old man with Alzheimer’s disease. Although it has been suggested that this is a rare adverse effect of indomethacin therapy, our experience and that of others suggest that it is not a rare event, but rather that it is unreported.1 Indeed, it is well known that adverse drug reactions tend to be underreported for a variety of reasons.2 We agree that drug-induced psychosis may be unrecognized by some clinicians, possibly leading to inappropriate treatment of psychosis as a primary event. The literature contains various examples of potentially unrecognized drug-induced toxicity that are subsequently treated as a primary disorder. For example, Avorn et al.3 reported an increased incidence of levodopa therapy following metoclopramide use in a case–control study of Medicaid enrollees aged 65 years and older. In this study, metoclopramide users were three times more likely to begin use of a levodopa-containing medication than were nonusers of metoclopramide. However, we believe that the author’s warning, “Healthcare providers should be aware that patients with dementia receiving indomethacin may be at risk of developing severe behavior problems along with gastrointestinal and renal adverse effects,” may be far too conservative regarding the use of indomethacin in the older population. Indeed, Beers4 published criteria for determining potentially inappropriate medication prescribing for the elderly that were published in revised format in 1997. These criteria were carefully developed by using a thorough literature review of medication use in the older population, and consensus methods with established expertise in clinical pharmacology, clinical pharmacy, geriatric medicine, pharmacoepidemiology, and psychopharmacology. These guidelines clearly state that indomethacin should not be used in the older population, as it “...produces the most central nervous system side effects....” Furthermore, indomethacin provides no clinical advantage over more easily tolerated agents such as ibuprofen, which could also be used to treat acute inflammatory arthropathies. Despite the fact that the use of indomethacin in the older population should be avoided, it remains a commonly prescribed antiinflammatory drug. In Nova Scotia, indomethacin was the third most commonly used antiinflammatory drug among patients aged 65 years and older from April 1, 1993, through March 31, 1994. If more clinicians are aware of such guidelines for appropriate medication use in older patients, perhaps drug-induced toxicity, which is an important and preventable cause of morbidity in this population, can be reduced.