Kim Wolff

Ketamine - From medicine to misuse

This review describes the medical, research and recreational uses of ketamine, an anaesthetic derivative of phencyclidine that has dissociative, analgesic and psychedelic properties. Ketamine has a complex mechanism of action that is further complicated by stereoselectivity; however, antagonism of glutamate NDMA receptors is thought to underlie its analgesic, dissociative and neuroprotective effects. While ketamine use in medical and veterinary settings is well documented and has a good safety record, the increase in its unregulated use outside of such controlled environments is a cause for concern. The impact on higher centres in the brain, particularly altered perception of auditory, visual and painful stimuli, results in a general lack of responsive awareness that puts the recreational user at (often unrecognised) risk of personal harm. The perceptual and mood changes observed in those who have consumed ketamine are highly sensitive to age, dose, route of administration, previous experience and setting. At low doses, stimulant effects predominate and the effect of environmental conditions are significant; with higher doses, psychedelic effects predominate and the effect of the environment diminishes. The potential of ketamine as a novel clinical and research tool is matched by its abuse potential outside medical settings.

Imaging of Latent Fingerprints through the Detection of Drugs and Metabolites

Magnetic particles functionalised with anti-cotinine antibody have been used to image latent fingermarks through the detection of the cotinine antigen in the sweat deposited within the fingerprints of smokers. The antibody–magnetic particle conjugates are readily applied to latent fingerprints while excess reagents are removed through the use of a magnetic wand. The results have shown that drug metabolites, such as cotinine, can be detected and used to image the fingermark to establish the identity of an individual within 15 minutes.

Characterization of methadone overdose: clinical considerations and the scientific evidence.

Overdosing with methadone is a growing phenomenon in Britain and other countries due to the increase in prescription and the availability of this compound. Little is known of the circumstances surrounding methadone death due to some extent to the difficulty of defining drug-related death and also the difficulty of collecting clinical and biographical data in a predominantly illegal and marginal milieu. However, the evidence points to highest risk at night (to this end manifestations of its toxicity often go unrecognized) in those whose usual tolerance has been reduced and occurring some considerable time after ingestion. Further investigations are needed to elucidate fully the mechanism and spectrum of methadone overdose. Death from methadone is eminently preventable more so because of the long-term nature of the clinical sequelae. Indeed the key issue with methadone that sets it apart from other opioids is its potential for delayed toxicity. Consequently steps should be taken to disseminate the salient facts to all those who come into contact with the drug.

Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population

Despite the common use of MDMA (ecstasy) in the UK, the mechanism underlying associated potentially fatal cerebral oedema is unclear. We used a new experimental approach working directly with clubbers to perform a study on 30 (17 male) experienced clubbers (mean 6.6 years of clubbing). Pre and post-clubbing measurements were performed to compare plasma levels of pituitary hormones (vasopressin, oxytocin), plasma and urine osmolality, urinary pH, and plasma sodium and urea. Ecstasy consumption was con.rmed by using urinary drug screening preand post-clubbing. MDMA was detected in the urine samples of 17 subjects, three of which tested positive during pre-clubbing tests. Mean plasma vasopressin concentration increased in the MDMA group (1.28 ± 0.29 to 1.43 ± 0.41 pmol/l), but fell in other participants (1.23 ± 0.42 to 1.16 ± 0.0.34 pmol/l). Similarly, mean plasma oxytocin concentrations increased after ingestion of MDMA (2.02 ± 0.29 to 2.43 ± 0.24 pmol/l), but fell in the group that did not use MDMA (2.17 ± 0.36 pmol/l to 1.89 ± 0.37 pmol/l). There was a significant group by time interaction for plasma osmolality and plasma sodium (p= 0.001 and p= 0.003, respectively) and between change in urinary osmolality (p< 0.001) and MDMA use, with the pattern of change being consistent with the induction of inappropriate vasopressin secretion (also known as SIADH) by MDMA. This report demonstrates SIADH in ecstasy-using ‘clubbers’, which has important clinical implications.

Steady-state pharmacokinetics of methadone in opioid addicts

SummaryKinetic parameters were investigated in tolerant methadone maintenance patients. The disposition of methadone at steady-state was assessed on 8 occasions — in 5 opioid addicts prescribed wide ranging doses of methadone (10 mg to 60 mg per day) — providing unique pharmacokinetic data.Statistical analysis showed that the kinetics of oral methadone at steady-state were described using a single compartment model. Analysis of the plasma concentration-time curves gave estimates of the variance of methadone clearance and apparent volume of distribution, and indicate that methadone is rapidly absorbed (mean Ka, 1.7 h−1) with a detectable increase in the plasma drug concentration 15 to 30 min after dosing.The elimination of methadone from plasma was found to occur slowly (mean t1/2 26.8 h) beginning soon after the administration of the daily oral prescription. The apparent volume of distribution — assuming the oral bioavailability (f) of methadone to be 0.95 — was large (mean 6.71 · kg−1).The slow clearance of this drug from the body (mean 3.1 ml · min−1 · kg−1) confirms that daily dosing at steady-state is adequate to maintain effective plasma concentrations throughout the dosing interval.

Multiplexed Detection of Metabolites of Narcotic Drugs from a Single Latent Fingermark

An immunoassay based technique is used for the detection of psychoactive substances in the sweat deposited within fingermarks of a narcotic drug user. Magnetic particles functionalized with antimorphine and antibenzoylecgonine antibodies were used for the detection of a metabolite of heroin (morphine) and a metabolite of cocaine (benzoylecgonine), respectively. The drug metabolites were detected individually as well as simultaneously from a single fingermark. The images of the fingermarks obtained using brightfield and fluorescence microscopy were of high evidential quality with resolution to enable identification of an individual in addition to providing information on drug usage.

Cannabis use in patients with multiple sclerosis

Introduction Little is known about the extent and patterns of cannabis use in people with multiple sclerosis (MS). Methods MS patients attending neurology outpatient clinics at two hospitals in London and one in Kent, UK completed a questionnaire. Results Questionnaires were completed by 254/337 (75%) MS patients. Forty-three per cent had used cannabis at some stage (ever users). Of these, 68% (75/110) had used cannabis to alleviate symptoms of MS (MS-related cannabis use). Forty-six (18%) had used cannabis in the last month (current users), of whom 12% (31/254) had used it for symptom relief. Being married or having a long-term partner, tobacco smokers and increasing disability were independent risk factors for MS-related cannabis use. Compared to patients who could walk unaided, cannabis use was more likely in those who were chair-bound (adjusted OR 2.47; 1.10-5.56) or only able to walk with an aid (adjusted OR 1.56; 0.90- 3.60). Pain and spasms were common reasons for cannabis use. Seventy-one per cent of individuals who had never used cannabis said they would try the drug if it were available on prescription. Conclusion A large proportion of MS patients had tried cannabis for symptom control, however current use was small. A subgroup with greater disability appears to derive some symptomatic benefit.

Route of drug use and its implications for drug effect, risk of dependence and health consequences

Route of administration has a profound, but often overlooked, influence on the actual experience of the drug use itself, on the risk of resulting development of dependence, and on the nature of the harms to which drug users are exposing themselves. These three areas are reviewed. The influence of route of administration on drug effect is considered first with regard to overall effectiveness of absorption, and also with regard to speed of onset of effect. The implications for risk of dependence cover animal and human laboratory studies of reinforcement schedules, epidemiological studies, the attitudes of drug users themselves to the different routes of possible drug use and associated dependence risk and the postulated influences on progression to dependence. Finally, the relationship between route of drug use and health sequelae is explored for the three most widely used routes of administration of illicit drugs-snorting, smoking and injecting.

Benzodiazepine misuse by drug addicts.

Using a high-performance liquid chromatography method, we measured seven commonly prescribed benzodiazepines (chlordiazepoxide, nitrazepam, nordiazepam, oxazepam, lorazepam, temazepam and diazepam) in 100 urine samples obtained from patients attending the Leeds Addiction Unit. All of the urines selected for investigation were positive for benzodiazepines using an EMIT (Enzyme Immunoassay) screen. Forty-four of the urines contained a range of benzodiazepines, none of which had been prescribed. Nitrazepam was detected most frequently (61 urine samples), but had not been prescribed to any of the patients in this study. Chlordiazepoxide was detected in 49 urine samples, although it had been prescribed to only five patients. Temazepam was detected in 28 urine samples. Fourteen patients providing 21 urine samples had been prescribed temazepam for treatment. However, temazepam was detected in only 14 of these samples. Multiple benzodiazepine abuse was evident from the high rate of detection of unrelated benzodiazepines.

The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level-Dependent Resting State Functional Connectivity

Background The compound 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine releaser that produces an acute euphoria in most individuals. Methods In a double-blind, placebo-controlled, balanced-order study, MDMA was orally administered to 25 physically and mentally healthy individuals. Arterial spin labeling and seed-based resting state functional connectivity (RSFC) were used to produce spatial maps displaying changes in cerebral blood flow (CBF) and RSFC after MDMA administration. Participants underwent two arterial spin labeling and two blood oxygen level–dependent scans in a 90-minute scan session; MDMA and placebo study days were separated by 1 week. Results Marked increases in positive mood were produced by MDMA. Decreased CBF only was observed after MDMA, and this was localized to the right medial temporal lobe (MTL), thalamus, inferior visual cortex, and the somatosensory cortex. Decreased CBF in the right amygdala and hippocampus correlated with ratings of the intensity of global subjective effects of MDMA. The RSFC results complemented the CBF results, with decreases in RSFC between midline cortical regions, the medial prefrontal cortex, and MTL regions, and increases between the amygdala and hippocampus. There were trend-level correlations between these effects and ratings of intense and positive subjective effects. Conclusions The MTLs appear to be specifically implicated in the mechanism of action of MDMA, but further work is required to elucidate how the drug’s characteristic subjective effects arise from its modulation of spontaneous brain activity.