Irma de Vries

Acute subjective effects after smoking joints containing up to 69 mg Δ9-tetrahydrocannabinol in recreational users: a randomized, crossover clinical trial

RationaleAn increase in the potency of the cannabis cigarettes has been observed over the past three decades.ObjectivesIn this study, we aimed to establish the impact of Δ9-tetrahydrocannabinol (THC) on the rating of subjective effects (intensity and duration of the effects), up to 23 % THC potency (69 mg THC) among recreational users.MethodsRecreational users (N = 24) smoked cannabis cigarettes with four doses of THC (placebo 29, 49 and 69 mg of THC) on four separate test days in a randomized, double-blind, placebo-controlled, crossover study. The participants filled in three different questionnaires measuring subjective effects during the exposure up to 8 h post-smoking. The ‘high’ feeling, heart rate, blood pressure and THC serum concentrations were also regularly recorded during these 8 h.ResultsTHC significantly increased the high feeling, dizziness, dry-mouthed feeling, palpitations, impaired memory and concentration, and ‘down’, ‘sedated’ and ‘anxious’ feelings. In addition, THC significantly decreased alertness, contentment and calmness. A cubic relationship was observed between ‘feeling the drug’ and ‘wanting more’. The THC-induced decrease in ‘feeling stimulated’ and increase in anxiety lasted up to 8 h post-smoking. Sedation at 8 h post-smoking was increased by a factor of 5.7 with the highest THC dose, compared to the placebo.ConclusionsThis study shows a strong effect of cannabis containing high percentages of THC on the rating of subjective effects. Regular users and forensic toxicologists should be aware that the THC-induced increase in ‘feeling sedated’ continues longer with a 69 mg THC dose than with a 29 mg THC dose.

Disposition of smoked cannabis with high Δ9-tetrahydrocannabinol content: a kinetic model.

INTRODUCTION No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69mg THC). METHODS Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3mg, 49.1mg, and 69.4mg THC. Blood samples were collected over a period of 0-8h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. RESULTS Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were Cmax=175ng/mL, Tmax=14min, and AUC0-8h=8150ng×min/mL for the 69.4mg THC dose. Median model results show an almost linear dose response relation for Cmax/Dose=2.8×10(-6)/mL and AUC0-8h/Dose=136×10(-6)min/mL. However, for increasing dose level, there was a clear decreasing trend: Cmax/Dose=3.4, 2.6 and 2.5×10(-6)/mL and AUC0-8h/Dose=157, 133 and 117×10(-6)min/mL for the 29.3, 49.1 and 69.4mg dose, respectively. Within the restriction of 8h of observation, the apparent terminal half life of THC was 150min. CONCLUSION The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8h after smoking cannabis with a high THC content (up to 23%).

A case series of xylometazoline overdose in children

Introduction. Serious intoxications associated with low doses of imidazolines have been reported. Therefore, the treatment advice for children with xylometazoline overdose is usually to observe the child in the hospital, even after exposure to very low doses. Our aim was to determine the frequency of severe symptoms after xylometazoline exposure, and the systemic dose of xylometazoline below which asymptomatic children do not need to be hospitalized for observation. Methods. From May 2002 until December 2004, we prospectively collected data on all consecutive cases of xylometazoline exposure in children <6 years old reported to our poisons centre. Follow-up information was collected. The systemic dose was calculated and the frequency of severe symptoms was observed. Results. During 32 months, we included 101 cases of xylometazoline exposure in children. For 63 out of these 101 cases, follow-up information could be collected. No severe symptoms were observed after exposure to xylometazoline doses reported to be below 0.4 mg/kg (95% confidence interval: 0–6%). Conclusion. We conclude that less than 6% of children exposed to xylometazoline, at doses reported to be less than 0.4 mg/kg body weight, may develop symptoms that require hospitalization.

Lamp oil poisoning: Did the European guideline reduce the number and severity of intoxications?

Introduction. In 1997, a European guideline concerning the viscosity and surface tension of lamp oil was adopted to reduce instances and severity of lamp oil intoxications. In 2005, the Dutch National Poisons Information Centre investigated lamp oil intoxications to determine whether they differed in severity from the intoxications reported before the guideline was adopted. Methods. We compared the data prospectively collected on lamp oil intoxications reported to our center in 2005 and in 1996. Results. In 2005 and 1996, respectively 152 and 165 cases were included. The frequency of the symptoms and diagnosed pneumonitis did not differ significantly between those years. In 2005, ingestion of a transparent lamp oil seemed to be associated with a greater risk of serious respiratory symptoms than ingestion of colored oil. Conclusion. Despite the directive, frequency and severity of symptoms of lamp oil ingestions remain disturbing. Consequently, further actions concerning packaging and labeling of lamp oil, design of oil lamps, education of parents, and additions to the current guideline should be considered.

Fatalities, Cerebral Hemorrhage, and Severe Cardiovascular Toxicity After Exposure to the New Psychoactive Substance 4-Fluoroamphetamine: A Prospective Cohort Study

Study objective: We study adverse health effects after use of the new psychoactive substance 4‐fluoroamphetamine. Methods: All patients who reported 4‐fluoroamphetamine exposure and for whom the Dutch Poisons Information Center was consulted by their physician in 2016 were included in a prospective cohort study. The clinical course was investigated through telephone interviews with the physician and/or patient, using standardized questionnaires. 4‐Fluoroamphetamine was analyzed in remaining drug material and biological samples with liquid and gas chromatography–mass spectrometry techniques. Results: We included 45 patients, and follow‐up with the physician and/or patient was performed in 33 cases. All patients experienced adverse effects after 4‐fluoroamphetamine use. Severe toxicity was reported in 8 patients. In 5 of these patients, 4‐fluoroamphetamine exposure was confirmed in biological specimens. Severe toxicity that was reported included 2 fatalities, 4 patients with cerebral hemorrhage (1 fatal), 2 patients with inverted Takotsubo’s cardiomyopathy, 1 patient with myocardial infarction, 1 patient with acute heart failure, and an overall high prevalence of pronounced hypertension and tachycardia. Conclusion: Since the introduction of 4‐fluoroamphetamine to the Dutch drug market in 2007, its use continues to increase, possibly because users perceive it as “ecstasy light” and thus relatively safe. However, the proportion of patients with severe toxicity after 4‐fluoroamphetamine use is relatively large in our study population. Therefore, users should be warned about the risks of 4‐fluoroamphetamine.

Modelling dimercaptosuccinic acid (DMSA) plasma kinetics in humans

Abstract Context: No kinetic models presently exist which simulate the effect of chelation therapy on lead blood concentrations in lead poisoning. Objective: Our aim was to develop a kinetic model that describes the kinetics of dimercaptosuccinic acid (DMSA; succimer), a commonly used chelating agent, that could be used in developing a lead chelating model. Material and methods: This was a kinetic modelling study. We used a two-compartment model, with a non-systemic gastrointestinal compartment (gut lumen) and the whole body as one systemic compartment. The only data available from the literature were used to calibrate the unknown model parameters. The calibrated model was then validated by comparing its predictions with measured data from three different experimental human studies. Results: The model predicted total DMSA plasma and urine concentrations measured in three healthy volunteers after ingestion of DMSA 10 mg/kg. The model was then validated by using data from three other published studies; it predicted concentrations within a factor of two, representing inter-human variability. Conclusions: A simple kinetic model simulating the kinetics of DMSA in humans has been developed and validated. The interest of this model lies in the future potential to use it to predict blood lead concentrations in lead-poisoned patients treated with DMSA.

Methylphenidate intoxications in children and adults : Exposure circumstances and evidence-based dose threshold for pre-hospital triage

Abstract Context. Methylphenidate intoxications mostly have a relatively mild course, although serious complications can occur. Objective. We aimed to characterize methylphenidate exposures and reassess our current dose threshold for hospital referral (2 mg/kg). Methods. In a prospective follow-up study, we analysed 364 consecutive methylphenidate exposures that were reported to the Dutch Poisons Information Center. Patients and/or physicians were surveyed by telephone using standardized questionnaires. Three physicians independently scored the observed severity of the intoxication of each patient as ‘no/mild’ (observation at home) or ‘moderate/severe’ (hospital referral necessary). Results. Unintentional exposures (40%) mostly occurred at home involving the patients’ own medication or those from a family member. Compared to unintentionally exposed patients, intentionally exposed patients were exposed to relatively high methylphenidate doses (3.1 vs 1.6 mg/kg), more often used immediate release methylphenidate formulations (62 vs 34%) and more frequently had concomitant exposures (71 vs 17%). Severe symptoms like convulsions or coma were reported only in patients with concomitant exposures. Following exposure to methylphenidate only (i.e. no concomitant exposures), the most commonly reported symptoms were dry mucosa, headache, agitation, sleepiness and tachycardia. Our results show that the reported methylphenidate dose is predictive of the observed severity of the intoxication and can therefore aid in pre-hospital triage. Conclusion. We increased our current dose threshold for hospital referral from 2 to 3 mg/kg. In addition, we will refer patients at lower doses when clinical symptoms indicate the need for hospital referral. Application of this new dose threshold optimizes triage, thereby reducing unnecessary hospital referral and thus costs, without jeopardising patient safety.

Modeling the effect of succimer (DMSA; dimercaptosuccinic acid) chelation therapy in patients poisoned by lead

Abstract Context: Kinetic models could assist clinicians potentially in managing cases of lead poisoning. Several models exist that can simulate lead kinetics but none of them can predict the effect of chelation in lead poisoning. Our aim was to devise a model to predict the effect of succimer (dimercaptosuccinic acid; DMSA) chelation therapy on blood lead concentrations. Materials and methods: We integrated a two-compartment kinetic succimer model into an existing PBPK lead model and produced a Chelation Lead Therapy (CLT) model. The accuracy of the model’s predictions was assessed by simulating clinical observations in patients poisoned by lead and treated with succimer. The CLT model calculates blood lead concentrations as the sum of the background exposure and the acute or chronic lead poisoning. The latter was due either to ingestion of traditional remedies or occupational exposure to lead-polluted ambient air. The exposure duration was known. The blood lead concentrations predicted by the CLT model were compared to the measured blood lead concentrations. Results: Pre-chelation blood lead concentrations ranged between 99 and 150 μg/dL. The model was able to simulate accurately the blood lead concentrations during and after succimer treatment. The pattern of urine lead excretion was successfully predicted in some patients, while poorly predicted in others. Conclusions: Our model is able to predict blood lead concentrations after succimer therapy, at least, in situations where the duration of lead exposure is known.

New legal requirements for submission of product information to poisons centres in EU member states

Abstract Introduction: In the past eight years, the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) has been intensively involved in a European Commission led process to develop EU legislation on the information of hazardous products that companies have to notify to EU Poisons Centres (or equivalent “appointed bodies”). As a result of this process, the Commission adopted Regulation (EU) No 2017/542, amending the CLP Regulation by adding an Annex on harmonised product submission requirements. Harmonised mixture information requirements: Detailed and consistent information on the composition of the hazardous product will become available to EU Poisons Centres (PC). The information will be submitted by companies to PCs (or equivalent “appointed bodies”) using a web-based software application or in-house software. Two new important features are introduced. Firstly, to be able to rapidly identify the product formula, a Unique Formula Identifier (UFI) on the product label links to the submitted information. Secondly, for better comparability of reports on poisonings between EU member states, a harmonised Product Categorisation System will specify the intended use of a product. Rapid product identification and availability of detailed composition information will lead to timely and adequate medical intervention. This may lead to considerable reduction in healthcare costs. Additionally, for companies trading across the EU, costs of submission of this information will be reduced significantly. Next steps: From 2017, an implementation period has started, consisting of a three-year period for stakeholders to implement the new requirements, followed by a gradual applicability for consumer products (2020), professional products (2021) and industrial use-only products (2024). Technical tools to generate the electronic format and the UFI together with guidance documents are expected to be made available by the end of 2017 by the European Chemicals Agency (ECHA). Guidance on interpretation of legal text and ECHA helpdesk support are planned to be ready at the end of 2018.

Methylphenidate poisoning : relatively mild symptoms even after high-dose exposure

In our previous prospective follow-up study on methylphenidate overdoses, we showed that methylphenidate poisoning is generally characterized by mild symptoms such as agitation, sleepiness, tachycardia and headache. We proposed a dose threshold of 3mg/kg for hospital referral of patients exposed to methylphenidate [1]. Since limited information is available on the clinical course following exposure to high doses of methylphenidate, we have started a new prospective study on methylphenidate mono-intoxications (oral dose 3mg/kg) reported to the Dutch Poisons Information Center (9th May 2014–31th July 2015). Patients and/or physicians were interviewed using standardized telephone questionnaires [1]. The study was approved by the Medical Research Ethics Committee. Combining the data from the previous study [1] and this study, 101 patients with a methylphenidate mono-intoxication 3mg/kg were followed-up (15% lost-to-follow-up). The median age was 16 years [range: 1–46 years]. Most patients were male (57%) and methylphenidate users (69%). Modifiedrelease formulations were mostly involved (60%). Most exposures were intentional (66%) and the median reported dose was 4.8mg/kg [range: 3.0–25.0]. Eleven patients (11%) remained asymptomatic, whereas others reported agitation (44%), tachycardia (46%), hypertension (44%), mydriasis (23%), headache (22%), nausea (22%), tremor (19%), tachypnoea (18%), hallucinations (8%) and psychosis (5%). Severe effects like coma, cerebral haemorrhage, convulsions or cardiac arrest were not reported. One fifth of the patients visited a general practitioner, 84% visited the emergency department and 77% were hospitalized (12% intensive care unit) or kept for observation at the emergency department >4 h. The median length of stay was 12 h [range: 5–31]. Gastrointestinal decontamination was performed in 38% of the patients; benzodiazepines were administered in only 12%. To study the dose-response relationship following highdose methylphenidate exposure, we excluded patients with multiple methylphenidate exposures ( 1 h between exposures), patients with spontaneous emesis or in whom gastrointestinal decontamination was performed. Patient and exposure characteristics, reported symptoms, admission rate, length of stay, and the Poisoning Severity Score (PSS, [2]) of this selected group of patients (n1⁄4 46) are presented in Supplementary Table 1, ranked by reported methylphenidate dose. PSS was reviewed by three clinical toxicologists and included a Delphi process [1]. Eight patients (17%) remained asymptomatic and even after high-dose methylphenidate (up to 21mg/kg), no severe effects were reported. Five out of nine patients with a methylphenidate dose above 7mg/kg showed mild symptoms, whereas four patients developed moderate symptoms, such as agitation, hallucinations, tachycardia and hypertension. In our previous study, hallucinations were only reported in patients with methylphenidate exposures above 3mg/kg (range: 3.3–17.0mg/kg). Though these additional data show that our earlier proposed dose threshold of 3mg/kg for hospital referral of patients with a methylphenidate mono-intoxication may still be valid, it is equally clear that in this higher dose range, the severity of the poisoning does not correspond well with the ingested dose. In addition, we have previously reported that around half of the patients with a methylphenidate exposure have concomitant exposures [1]. Clearly, in these patients, the estimated severity of the intoxication should take into account all exposures. When comparing the 46 patients included for studying the dose-response relationship (Supplementary Table 1) with the 55 patients that were excluded (Supplementary Table 2), a lower admission rate was shown for the included patients (65% vs. 87%, p< .01). However, included and excluded patients had comparable PSS (moderate PSS in 24% vs. 20%, p1⁄4 .64), ICU admission rate (11% versus 15%, p1⁄4 .58) and median length of stay (12 vs. 14 h, p1⁄4 .39). In conclusion, the clinical course following high-dose methylphenidate exposure is relatively mild, characterized by sympathomimetic effects and central nervous system stimulation. Even after high-dose exposure, we have observed no severe symptoms such as convulsions, coma or pronounced cardiotoxicity.