Sensory handedness is not reflected in cortical responses after basic nerve stimulation: a MEG study.

Motor dominance is well established, but sensory dominance is much less clear. We therefore studied the cortical evoked magnetic fields using magnetoencephalography (MEG) in a group of 20 healthy right handed subjects in order to examine whether standard electrical stimulation of the median and ulnar nerve demonstrated sensory lateralization. The global field power (GFP) curves, as an indication of cortical activation, did not depict sensory lateralization to the dominant left hemisphere. Comparison of the M20, M30, and M70 peak latencies and GFP values exhibited no statistical differences between the hemispheres, indicating no sensory hemispherical dominance at these latencies for each nerve. Field maps at these latencies presented a first and second polarity reversal for both median and ulnar stimulation. Spatial dipole position parameters did not reveal statistical left-right differences at the M20, M30 and M70 peaks for both nerves. Neither did the dipolar strengths at M20, M30 and M70 show a statistical left-right difference for both nerves. Finally, the Laterality Indices of the M20, M30 and M70 strengths did not indicate complete lateralization to one of the hemispheres. After electrical median and ulnar nerve stimulation no evidence was found for sensory hand dominance in brain responses of either hand, as measured by MEG. The results can provide a new assessment of patients with sensory dysfunctions or perceptual distortion when sensory dominance occurs way beyond the estimated norm.

Anesthetic block of pain-related cortical activity in patients with peripheral nerve injury measured by magnetoencephalography.

BACKGROUND: This study examined whether chronic neuropathic pain, modulated by a local anesthetic block, is associated with cortical magnetic field changes. METHODS: In a group of 20 patients with pain caused by unilateral traumatic peripheral nerve injury, a local block with lidocaine 1% was administered and the cortical effects were measured and compared with a control group. The global field power (GFP), describing distribution of cortical activation after median and ulnar nerve stimulation, was plotted and calculated. The effects on the affected hemisphere and the unaffected hemisphere (UH) before and after a block of the injured nerve were statistically evaluated. RESULTS: Major differences based on the GFP curves, at a component between 50 ms - 90 ms (M70), were found in patients: in the affected hemisphere the M70 GFP peak values were statistically significantly larger in comparison with the UH, and the GFP curves differed morphologically. Interestingly, the mean UH responses were reduced in comparison with the control group, a finding suggesting that the UH is also part of the cortical changes. At M70, the GFP curves and values in the affected hemisphere were modulated by a local block of the median or the ulnar nerve. The most likely location of cortical adaptation is in the primary somatosensory cortex. CONCLUSIONS: Cortical activation is enhanced in the affected hemisphere compared with the UH and is modulated by a local block. The UH in neuropathic pain changes as well. Evoked fields may offer an opportunity to monitor the effectiveness of treatments of neuropathic pain in humans.

Association of Serotonin Transporter (SERT) Polymorphisms with Opioid Dependence and Dimensional Aspects of Cocaine Use in a Caucasian Cohort of Opioid Users.

INTRODUCTION: A functional tandem repeat polymorphism in the promoter of the serotonin transporter (SERT) gene (SLC6A4) has been studied for association to neuropsychiatric conditions, including substance use disorders. Short (S) forms of this repeat result in reduced transcription, and presumably greater synaptic levels of serotonin, which are involved in opioid and cocaine-induced reward. Dual exposure to heroin and cocaine is a common pattern of poly-drug use and is associated with considerable morbidity. We hypothesize that SLC6A4 variants are associated with cocaine exposure in subjects with an opioid dependence diagnosis (OD), and also in non-dependent opioid users (NOD). Other single nucleotide polymorphisms (SNPs) of SLC6A4 may also be likewise associated. MATERIALS AND METHODS: This study determined whether variants of the SLC6A4 promoter repeats and two intronic SNPs, rs16965628 and rs2066713, are associated with categorical diagnoses of opioid dependence (DSM-IV criteria) and with dimensional aspects of cocaine use, in a Caucasian cohort (n=591). Three groups of subjects were examined: (1) 276 subjects with opioid dependence diagnosis (OD); (2) 163 subjects who had used opioids for non-medical reasons but never had an opioid dependence diagnosis (NOD); (3) 152 healthy controls (HC). RESULTS: Aside from high exposure to heroin in the OD group, relatively high exposure to cocaine was detected in both OD and NOD groups. The SERT repeat genotype (classified as "long-long" [LL] versus "short-long" plus "short-short" [SL+SS]) was not associated with categorical opioid dependence diagnoses. A nominally significant association was identified with the [SL+SS] genotype of SLC6A4 and cocaine KMSK scores ≥"cutpoint" for a cocaine dependence diagnosis (p=0.026). The [SL+SS] genotype was associated with more rapid cocaine escalation than the LL genotype. No significant associations of rs16965628 and rs2066713 SNPs were found overall. CONCLUSION: The functional SERT promoter tandem repeat genotype may be associated to heavy cocaine exposure and more rapid escalation of cocaine use, in persons with and without opioid dependence diagnosis.

Further evidence for the association of GAL, GALR1 and NPY1R variants with opioid dependence.

Aim: Heroin addiction is a chronic, relapsing disease that has genetic and environmental, including drug-induced, contributions. Stress influences the development of addictions. This study was conducted to determine if variants in stress-related genes are associated with opioid dependence (OD). Patients & methods: One hundred and twenty variants in 26 genes were analyzed in 597 Dutch subjects. Patients included 281 OD in methadone maintenance with or without heroin-assisted treatment and 316 controls. Results: Twelve SNPs in seven genes showed a nominally significant association with OD. Experiment-wise significant associations (p < 0.05) were found for three SNP pairs, through an interaction effect: NPY1R/GAL rs4691910/rs1893679, NPY1R/GAL rs4691910/rs3136541 and GALR1/GAL rs9807208/rs3136541. Conclusion: This study lends more evidence to previous reports of association of stress-related variants with heroin dependence.

VMAT2 gene (SLC18A2) variants associated with a greater risk for developing opioid dependence.

Aim: To determine if selected serotonergic and noradrenergic gene variants are associated with heroin addiction. Subjects & methods: A total of 126 variants in 19 genes in subjects with Dutch European ancestry from The Netherlands. Subjects included 281 opioid-dependent volunteers in methadone maintenance or heroin-assisted treatment, 163 opioid-exposed but not opioid-dependent volunteers who have been using illicit opioids but never became opioid-dependent and 153 healthy controls. Results: Nominal associations were indicated for 20 variants in six genes including an experiment-wise significant association from the combined effect of three SLC18A2 SNPs (rs363332, rs363334 and rs363338) with heroin dependence (pfinal = 0.047). Conclusion: Further studies are warranted to confirm and elucidate the role of these variants in the vulnerability to opioid addiction.

Association of variants of prodynorphin promoter 68-bp repeats in caucasians with opioid dependence diagnosis: Effect on age trajectory of heroin use.

The dynorphin/kappa opioid receptor (Dyn/KOR) system is involved in reward processing and dysphoria/anhedonia. Exposure to mu-opioid receptor agonists such as heroin increases expression of the prodynorphin gene (PDYN) in the brain. In this study in a Caucasian cohort, we examined the association of the functional PDYN 68-bp repeat polymorphism with opioid use disorders. In this case-control study, 554 subjects with Caucasian ancestry (142 healthy controls, 153 opioid-exposed, but never opioid dependent, NOD, and 259 with an opioid dependence diagnosis, OD) were examined for association of the PDYN 68-bp repeats with the diagnosis of opioid dependence (DSM-IV criteria), with a dimensional measure of heroin exposure (KMSK scale), and age trajectory parameters of heroin use (age of heroin first use, and age of onset of heaviest use). The PDYN 68-bp repeat genotype (classified as: "short-short" [SS], "long-long" [LL], and "short-long" [SL], based on the number of repeats) was not associated with categorical opioid dependence diagnoses. However, the LL genotype was associated with later age of first heroin use than the SS + SL genotype (19 versus 18 years; p < 0.01). This was also confirmed by a significant positive correlation between the number of repeats and the age of first use of heroin, in volunteers with OD (Spearman r = 0.16; p = 0.01). This suggests that the functional PDYN 68-bp repeat genotype is associated with the age of first use of heroin in Caucasians diagnosed with opioid dependence.

Assessment of cognitive brain function in ecstasy users and contributions of other drugs of abuse: results from an FMRI study.

Heavy ecstasy use has been associated with neurocognitive deficits in various behavioral and brain imaging studies. However, this association is not conclusive owing to the unavoidable confounding factor of polysubstance use. The present study, as part of the Netherlands XTC Toxicity study, investigated specific effects of ecstasy on working memory, attention, and associative memory, using functional magnetic resonance imaging (fMRI). A large sample (n=71) was carefully composed based on variation in the amount and type of drugs that were used. The sample included 33 heavy ecstasy users (mean 322 pills lifetime). Neurocognitive brain function in three domains: working memory, attention, and associative memory, was assessed with performance measures and fMRI. Independent effects of the use of ecstasy, amphetamine, cocaine, cannabis, alcohol, tobacco, and of gender and IQ were assessed and separated by means of multiple regression analyses. Use of ecstasy had no effect on working memory and attention, but drug use was associated with reduced associative memory performance. Multiple regression analysis showed that associative memory performance was affected by amphetamine much more than by ecstasy. Both drugs affected associative memory-related brain activity, but the effects were consistently in opposite directions, suggesting that different mechanisms are at play. This could be related to the different neurotransmitter systems these drugs predominantly act upon, that is, serotonin (ecstasy) vs dopamine (amphetamine) systems.

Differential genetic regulation of motor activity and anxiety-related behaviors in mice using an automated home cage task.

Traditional behavioral tests, such as the open field test, measure an animal's responsiveness to a novel environment. However, it is generally difficult to assess whether the behavioral response obtained from these tests relates to the expression level of motor activity and/or to avoidance of anxiogenic areas. Here, an automated home cage environment for mice was designed to obtain independent measures of motor activity levels and of sheltered feeding preference during three consecutive days. Chronic treatment with the anxiolytic drug chlordiazepoxide (5 and 10 mg/kg/day) in C57BL/6J mice reduced sheltered feeding preference without altering motor activity levels. Furthermore, two distinct chromosome substitution strains, derived from C57BL/6J (host strain) and A/J (donor strain) inbred strains, expressed either increased sheltering preference in females (chromosome 15) or reduced motor activity levels in females and males (chromosome 1) when compared to C57BL/6J. Longitudinal behavioral monitoring revealed that these phenotypic differences maintained after adaptation to the home cage. Thus, by using new automated behavioral phenotyping approaches, behavior can be dissociated into distinct behavioral domains (e.g., anxiety-related and motor activity domains) with different underlying genetic origin and pharmacological responsiveness.

Dopamine gene variants in opioid addiction: comparison of dependent patients, nondependent users and healthy controls.

AIM: To determine whether specific dopaminergic system gene variants are associated with opioid dependence. PATIENTS & METHODS: Subjects included 153 healthy controls, 163 opioid exposed, but not dependent and 281 opioid dependent. Genotypes of 90 variants in 13 genes were examined. RESULTS: The most significant results were obtained for DA ß-hydroxylase variants, rs2073837 and rs1611131, which were associated with protection from addiction (q = 0.0172, 0.0415, respectively) and the functional TH variant, rs2070762, was associated with more risk (q = 0.0387). The three variants also showed a combined effect that remained significant after correction for multiple testing (pfinal = 0.0039). CONCLUSION: These data offer support that dopaminergic gene variants have a role in opioid dependence and warrant further study.

Incidental use of ecstasy: no evidence for harmful effects on cognitive brain function in a prospective fMRI study.

RATIONALE: Heavy ecstasy use in humans has been associated with cognitive impairments and changes in cognitive brain function supposedly due to damage to the serotonin system. There is concern that even a single dose of 3,4-methylenedioxymethamphetamine may be neurotoxic, but very little is known about the consequences of a low dose of ecstasy for cognitive brain function. OBJECTIVES: The objective of the study was to assess the effects of a low dose of ecstasy on human cognitive brain function using functional magnetic resonance imaging (fMRI). MATERIALS AND METHOD: We prospectively studied, as part of the NeXT (Netherlands XTC toxicity) study, sustained effects of a low dose of ecstasy on brain function in 25 subjects before and after their first episode of ecstasy use (mean 2.0 +/- 1.4 ecstasy pills, on average 11.1 +/- 12.9 weeks since last ecstasy use), compared to 24 persistent ecstasy-naive controls, also measured twice and matched with the novice users on age, gender, IQ, and cannabis use. Cognitive brain function was measured in the domains of working memory, selective attention, and associative memory using fMRI. RESULTS: No significant effects were found of a low dose of ecstasy on working memory, selective attention, or associative memory neither at the behavioral level nor at the neurophysiological level. CONCLUSIONS: This study yielded no firm evidence for sustained effects of a low dose of ecstasy on human cognitive brain function. The present findings are relevant for the development of prevention and harm reduction strategies. Furthermore, the study is relevant to the discussion concerning potential therapeutic use of ecstasy.

Effects of frequent cannabis use on hippocampal activity during an associative memory task.

Interest is growing in the neurotoxic potential of cannabis on human brain function. We studied non-acute effects of frequent cannabis use on hippocampus-dependent associative memory, investigated with functional Magnetic Resonance Imaging (fMRI) in 20 frequent cannabis users and 20 non-users matched for age, gender and IQ. Structural changes in the (para)hippocampal region were measured using voxel-based morphometry (VBM). Cannabis users displayed lower activation than non-users in brain regions involved in associative learning, particularly in the (para)hippocampal regions and the right dorsolateral prefrontal cortex, despite normal performance. VBM-analysis of the (para)hippocampal regions revealed no differences in brain tissue composition between cannabis users and non-users. No relation was found between (para)hippocampal tissue composition and the magnitude of brain activity in the (para)hippocampal area. Therefore, lower brain activation may not signify neurocognitive impairment, but could be the expression of a non-cognitive variable related to frequent cannabis use, for example changes in cerebral perfusion or differences in vigilance.

Patterns of acquisitive crime during methadone maintenance treatment among patients eligible for heroin assisted treatment.

OBJECTIVE: To determine the patterns of acquisitive crime during methadone maintenance treatment among chronic, treatment-resistant heroin users eligible for heroin assisted treatment in the Netherlands. METHODS: We retrospectively assessed the type and number of illegal activities during 1 month of standard methadone maintenance treatment in 51 patients prior to the start of heroin assisted treatment. Data were collected using a semi-structured interview focussed on crime with special emphasis on property crime. Volume analyses consisted of frequencies and descriptives of mean numbers of offences per day and per type. RESULTS: In a Dutch population of problematic drug users eligible for and prior to commencing heroin assisted treatment, 70% reported criminal activities and 50% reported acquisitive crimes. Offending took place on 20.5 days per month with on average 3.1 offences a day. Acquisitive crime consisted mainly of shoplifting (mean 12.8 days, 2.2 times/day) and theft of bicycles (mean 5.8 days, 2.4 times/day); theft from a vehicle and burglaries were committed less frequently. The majority of these patients (63%) reported to have started offending in order to acquire illicit drugs and alcohol. CONCLUSION: During methadone maintenance treatment, 50% of criminally active, problematic heroin users eligible for heroin assisted treatment reported acquisitive crime. Shoplifting, thefts and/or other property crimes were committed on average two to three times on a crime day. This study discusses that the detail provided by self-reported crime data can improve cost estimates in economic evaluations of heroin assisted treatment.

Dissecting complex behaviours in the post-genomic era.

Identifying gene functions in behaviours has so far relied mainly on achievements in the field of molecular genetics. Further progress can be made by developing new approaches that allow refinement of behavioural phenotypes. The current availability of several thousand different mutant mice challenges behavioural neuroscientists to extend their views and methodologies, to dissect complex behaviours into behavioural phenotypes, and subsequently to define gene-behavioural phenotype relationships. Here, we plead for multi-day automated behavioural observations in carefully designed environments.

Population pharmacokinetics of heroin and its major metabolites.

BACKGROUND: In several European countries and in Canada, clinical trials are being conducted in which heroin-addicted patients are treated with pharmaceutically prepared heroin in order to reduce the destructive behaviour that is so often associated with this drug. OBJECTIVE: To develop an integrated population pharmacokinetic model for heroin (diamorphine) and its pharmacodynamically active metabolites 6-acetylmorphine, morphine, morphine-3-glucuronide and morphine-6-glucuronide. Additionally, the influence on heroin pharmacokinetics of several covariates that are typical for this population was determined. METHOD: Plasma concentration data from 106 heroin-dependent patients in The Netherlands (74 heroin inhalers and 32 injectors) were obtained. The 'chasing the dragon' technique was used for inhalation, in which the fumes of heroin base, heated on aluminum foil, were inhaled. Heroin doses varied between 66 and 450 mg. Heroin, 6-acetylmorphine and morphine data were fitted simultaneously using sequential two-compartment models. Morphine-3-glucuronide and morphine-6-glucuronide data were fitted separately to one-compartment models. All data analysis was performed using nonlinear mixed-effect modelling. RESULTS: The bioavailability of inhaled heroin was estimated to be 53% (95% CI 43.7, 62.3). The terminal half-lives of heroin and 6-acetylmorphine were estimated to be 7.6 and 21.8 minutes, respectively. The clearances of morphine and the morphine-glucuronides were estimated to be 73.6 L/h (95% CI 62.8, 84.4) and between 6 and 10 L/h, respectively. The terminal half-life of 6-acetylmorphine was 13% lower in cocaine users (p < 0.05). No other significant relationships between covariates and pharmacokinetic parameters were discovered. CONCLUSIONS: Pharmacokinetic parameters of heroin and its five major metabolites were assessed simultaneously in one integrated model. Covariate analyses revealed that sex, bodyweight, benzodiazepine use and creatinine clearance (>60 mL/min) do not need to be taken into account in the medical prescription of pharmaceutically prepared heroin for the treatment of heroin dependency.

Long-term effects of frequent cannabis use on working memory and attention: an fMRI study.

RATIONALE: Excessive use of cannabis may have long-term effects on cognitive abilities. Mild impairments have been found in several cognitive domains, particularly in memory and attention. It is not clear, however, whether these effects also occur with moderate, recreational use of cannabis. Furthermore, little is known about underlying brain correlates. OBJECTIVES: The aim of this study is to assess brain function in frequent but relatively moderate cannabis users in the domains of working memory and selective attention. METHODS: Functional magnetic resonance imaging was used to examine verbal working memory and visuo-auditory selective attention in ten frequent cannabis users (after 1 week of abstinence) and ten non-using healthy controls. Groups were similar in age, gender and estimated IQ. RESULTS: Cannabis users and controls performed equally well during the working memory task and the selective attention task. Furthermore, cannabis users did not differ from controls in terms of overall patterns of brain activity in the regions involved in these cognitive functions. However, for working memory, a more specific region-of-interest analysis showed that, in comparison to the controls, cannabis users displayed a significant alteration in brain activity in the left superior parietal cortex. CONCLUSION: No evidence was found for long-term deficits in working memory and selective attention in frequent cannabis users after 1 week of abstinence. Nonetheless, frequent cannabis use may affect brain function, as indicated by altered neurophysiological dynamics in the left superior parietal cortex during working memory processing.

Cerebral metabolic consequences in the adult brain after neonatal excitotoxic lesions of the amygdala in rats.

In the present study the effects of neonatal excitotoxic lesions of the amygdala or ventral hippocampus on local cerebral glucose utilisation in the adult rat were studied by means of the [14C]2-deoxyglucose autoradiographic method. Our hypothesis was that damage to the brain during early development leads to long-term functional activity changes in brain regions outside the primary lesioned area which might underlie the behavioural deficits observed in animals with neonatal brain damage. Cerebral glucose utilisation in animals with a neonatal amygdala lesion was significantly decreased in the amygdala itself and in several other brain regions. The neonatal ventral hippocampal lesion did not cause significant changes in cerebral glucose utilisation, except for a decrease in the primary damaged region (i.e. caudal ventral hippocampus). Behaviourally, animals lesioned in the amygdala displayed increased ambulatory activity both before and after puberty when exposed to a novel open field, while neonatal ventral hippocampal lesions did not affect adult exploratory behaviour as compared to sham controls. These results support our hypothesis that neonatal brain damage leads to long-term functional activity changes in brain regions outside the primary lesioned area. Moreover, they suggest that this long-term effect depends on the primary area lesioned since only damage to the amygdala, and not to the ventral hippocampus, affects the functional organisation of the brain of the animals later in life. Additionally, the findings may suggest that the functional changes in the brain may underlie the behavioural deficits observed after neonatal amygdala lesion in the rat.

Anxiety and ethanol consumption in victorious and defeated mice; effect of kappa-opioid receptor activation.

Alcohol consumption and addiction have been related to anxiety and the anxiolytic effect of ethanol. It has been shown in mice that losers with repeated experience of social defeats are more anxious than winners with repeated experience of victories. Mice with a different social status were tested for their oral ethanol consumption using a free two bottle choice paradigm and for their social approach behaviour after ethanol consumption using the partition test, in which anxiety is an important component. In addition, the sensitivity of the animals for the kappa-opioid receptor agonist U-50,488H (2.5 mg/kg, s.c.) was assessed using the partition test, in which this drug has been shown to induce anxiolytic-like effects. Further, the effect of daily treatment with U-50,488H for 8 days on ethanol consumption was tested in animals that had consumed ethanol and were subjected during these 8 days to a period of 5 days of interruption of ethanol supply and subsequently to a period of 3 days of renewed access to ethanol. Losers consumed more ethanol than winners. Consumption of ethanol was accompanied by a decrease of anxiety level, as evidenced by an increased approach behaviour in the partition test. U-50,488H stimulated ethanol consumption after a period of 5 days of interruption of ethanol supply and drug treatment in the losers, but not in the winners. U-50,488H increased approach behaviour in the losers not consuming ethanol and decreased this behaviour in the winners, especially in those that had consumed ethanol. It is postulated that U-50,488H acts as a partial agonist in this respect. The increased anxiety may be related to the enhanced ethanol consumption in the losers, which may be of relevance for the etiology of alcohol addiction.

Validity of the EQ-5D as a generic health outcome instrument in a heroin-dependent population.

OBJECTIVE: To evaluate the validity of the EuroQol (EQ-5D) in a population of chronic, treatment-resistant heroin-dependent patients. METHODS: The EQ-5D is studied relative to the Maudsley Addiction Profile (MAP), the Symptom Checklist (SCL-90) and the European Addiction Severity Index (EuropASI) which were used to assess the participant's physical functioning, mental health and social integration, respectively. Data were gathered from 430 patients participating in the Dutch heroin trials with an intended 12-month treatment period. The EQ-5D was used as a separate health outcome measure. Statistical analyses were conducted using Spearman's and Pearson's correlations. RESULTS: The EQ-5D dimensions mobility, self-care and usual activities generally showed low correlations with relevant parameters of the MAP-HSS, SCL-90 and EuropASI (r=0.132-0.369). The EQ-5D dimension pain/discomfort showed low to moderate hypothesized correlations with all disease-specific measures (r=0.153-0.496). The EQ-5D dimension anxiety/depression showed moderate to high correlations with the SCL-90 (including the sum score) and some of the EuropASI parameters (r=0.133-0.615). The EQ-5D utility scores were moderately correlated with the MAP-HSS (r=-0.468) and the SCL-90 (r=-0.491) total score and with response to treatment at month 12. CONCLUSION: The majority of hypothesized associations between the EQ-5D and the disease or domain-specific measures could be confirmed. The validity of the EQ-5D-based utility score appears to be suitable in the evaluation of chronic, heroin-dependent populations.

Pharmacokinetics and pharmacodynamics of high doses of pharmaceutically prepared heroin, by intravenous or by inhalation route in opioid-dependent patients.

A pharmacokinetic-pharmacodynamic study was performed in opioid-dependent patients in the Netherlands, who were currently treated with high doses of pharmaceutically prepared heroin on medical prescription. Besides intravenous heroin, heroin was prescribed for inhalation by "chasing the dragon" method. In this technique, heroin base is heated on aluminium foil, and heroin vapours are inhaled into the lungs. Not much is known about the pharmacokinetics profile and bioavailability of this specific administration method. Therefore, a study was performed on pharmacokinetics and pharmacodynamics of heroin inhalation and intravenous use. Eleven patients who injected heroin and 9 patients who inhaled heroin entered the study. They were on steady-state heroin treatment for at least 12 months. For safety reasons, there was no crossing-over between heroin injection or inhalation. In a double-blind randomised study, 67-100-150% of the regular heroin maintenance dose was administered to each patient. Maximal single heroin dose was 450 mg. Plasma concentrations of heroin and its metabolites 6-monoacetylmorphine, morphine and morphine-glucuronides were analysed using LC-MS-MS. Blood pressure, heart rate, skin temperature and reaction time were assessed. Furthermore, visual analogue scales regarding craving and appreciation of heroin effect were scored by the subjects. Both in inhaling and injecting patients, the areas under curve of heroin and all measured metabolites were linearly related to heroin dose. Mean C(max) of heroin and its metabolites were 2-6 times lower after inhalation, than after intravenous injection. Bioavailability (F) of heroin inhalation was estimated as 52% (95% CI 44-61%). Heroin was rapidly cleared from plasma. Cl/F was 930 l/hr (95% CI 799-1061 l/hr) after intravenous administration, and 1939 l/hr (95% CI 1661-2217 l/hr) after inhalation. Heroin Cl and Vd were correlated to body weight (R(2) 15-19%). Morphine-glucuronides levels were inversely related to creatinine clearance. After heroin administration, the reaction time was significantly prolonged with 28+/-5.3 msec. in injecting and 13+/-4.9 msec. in inhaling patients. Cardiovascular changes were only mild after heroin administration. Craving-scores declined immediately after heroin administration in both administration groups. Subjective heroin effect was rated more positively in heroin inhaling than in injecting patients, despite the lower C(max) levels following heroin inhalation. In both groups, in this blinded study heroin dose increments were more appreciated than dose reductions. Increments of 50% of the regular heroin dose did not cause any serious side effect.

Analysis of diacetylmorphine, caffeine, and degradation products after volatilization of pharmaceutical heroin for inhalation.

Pharmaceutical smokable heroin was developed for a clinical trial on medical co-prescription of heroin and methadone. This product, consisting of 75% w/w diacetylmorphine base and 25% w/w caffeine anhydrate, was intended for use via "chasing the dragon", that is, inhalation after volatilization. This procedure involves heating the powder mixture, which may lead to formation of degradation products that could subsequently be inhaled. We developed a method that used a high-performance liquid chromatography system that was compatible with photodiode-array detection and mass spectrometric detection to separate diacetylmorphine- and caffeine-related compounds in a wide polarity range for analysis of the vapor. This method was used to analyze the contents of the plastic drinking straws that were used by patients to inhale the vapors from pharmaceutical heroin used via chasing the dragon, which were considered to be representative of the vapors the patients inhaled. They contained primarily unchanged diacetylmorphine, its main metabolite 6-acetylmorphine, caffeine, and some morphine. Several unidentified peaks were observed in the straw chromatograms. Chemical structures were proposed for nine degradation products: morphine derivatives with different substitution patterns of the C(3), C(6), and/or N(17) positions, which comprised 0.4-9.7% of the straw sample residue weight. Activity and toxicity of most of these compounds are unknown and require further investigation.