Mechanisms Involved in the Neurotoxicity and Abuse Liability of Nitrous Oxide: A Narrative Review.

The recreational use of nitrous oxide (N2O) has increased over the years. At the same time, more N2O intoxications are presented to hospitals. The incidental use of N2O is relatively harmless, but heavy, frequent and chronic use comes with considerable health risks. Most importantly, N2O can inactivate the co-factor cobalamin, which, in turn, leads to paresthesia's, partial paralysis and generalized demyelinating polyneuropathy. In some patients, these disorders are irreversible. Several metabolic cascades have been identified by which N2O can cause harmful effects. Because these effects mostly occur after prolonged use, it raises the question of whether N2O has addictive properties, explaining its prolonged and frequent use at high dose. Several lines of evidence for N2O's dependence liability can be found in the literature, but the underlying mechanism of action remains controversial. N2O interacts with the opioid system, but N2O also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, by which it can cause dopamine disinhibition. In this narrative review, we provide a detailed description of animal and human evidence for N2O-induced abuse/dependence and for N2O-induced neurotoxicity.

The neuropharmacology of cannabinoid receptor ligands in central signaling pathways.

The endocannabinoid system is a complex neuronal system involved in a number of biological functions, like attention, anxiety, mood, memory, appetite, reward, and immune responses. It is at the centre of scientific interest, which is driven by therapeutic promise of certain cannabinoid ligands and the changing legalization of herbal cannabis in many countries. The endocannabinoid system is a modulatory system, with endocannabinoids as retrograde neurotransmitters rather than direct neurotransmitters. Neuropharmacology of cannabinoid ligands in the brain can therefore be understood in terms of their modulatory actions through other neurotransmitter systems. The CB1 receptor is chiefly responsible for effects of endocannabinoids and analogous ligands in the brain. An overview of the neuropharmacology of several cannabinoid receptor ligands, including endocannabinoids, herbal cannabis and synthetic cannabinoid receptor ligands is given in this review. Their mechanism of action at the endocannabinoid system is described, mainly in the brain. In addition, effects of cannabinoid ligands on other neurotransmitter systems will also be described, such as dopamine, serotonin, glutamate, noradrenaline, opioid, and GABA. In light of this, therapeutic potential and adverse effects of cannabinoid receptor ligands will also be discussed.

Cognitive Impairment Following Clinical or Recreational Use of Gammahydroxybutyric Acid (GHB): A Systematic Review.

BACKGROUND: GHB (gamma-hydroxybutyric acid; sodium oxybate) is a general anaesthetic that is clinically used for the treatment of narcolepsy, cataplexy, alcohol withdrawal and alcohol relapse prevention. In addition, GHB is recreationally used. Most clinical and recreational users regard GHB as an innocent drug devoid of adverse effects, despite its high dependence potential and possible neurotoxic effects. At high doses, GHB may lead to a comatose state. This paper systematically reviews possible cognitive impairments due to clinical and recreational GHB use. METHODS: PubMed and PsychINFO were searched for literature data about the acute and residual cognitive deficits following GHB use. This review is conducted using the PRISMA protocol. RESULTS: A total of 43 reports covering human and animal data on GHB-induced cognitive impairments were eligible and reviewed. This systematic review found no indication for cognitive impairments after clinical GHB use. However, it supports the view that moderate GHB use may result in acute short-term cognitive impairments, whereas regular high-dose GHB use and/or multiple GHB-induced comas are probably neurotoxic resulting in long-term residual cognitive impairments. CONCLUSION: These results emphasize the need for awareness among clinicians and recreational users to minimize negative health consequences of recreational GHB use, particularly when high doses are used and GHB-induced comas occur.

Hard Boiled: Alcohol Use as a Risk Factor for MDMA-Induced Hyperthermia: a Systematic Review.

Although MDMA (ecstasy) is a relatively safe recreational drug and is currently considered for therapeutic use for the treatment of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD), recreational MDMA use occasionally elicits hyperthermia and hyponatremia, sometimes with a fatal outcome. Specific risk factors for both adverse effects are profuse sweating while vigorously dancing under unfavorable conditions such as high ambient temperatures and insufficient fluid suppletion which result in dehydration. Concomitant use of MDMA and alcohol is highly prevalent, but adds to the existing risk, because alcohol facilitates the emergence of MDMA-induced adverse events, like hyperthermia, dehydration, and hyponatremia. Because of potential health-related consequences of concomitant use of MDMA and alcohol, it is important to identify the mechanisms of the interactions between alcohol and MDMA. This review summarizes the main drivers of MDMA-induced hyperthermia, dehydration, and hyponatremia and the role of concomitant alcohol use. It is shown that alcohol use has a profound negative impact by its interaction with most of these drivers, including poikilothermia, exposure to high ambient temperatures, heavy exercise (vigorous dancing), vasoconstriction, dehydration, and delayed initiation of sweating and diuresis. It is concluded that recreational and clinical MDMA-users should refrain from concomitant drinking of alcoholic beverages to reduce the risk for adverse health incidents when using MDMA.

Substances detected in used syringes of injecting drug users across 7 cities in Europe in 2017 and 2018: The European Syringe Collection and Analysis Project Enterprise (ESCAPE).

BACKGROUND AND AIMS: Injecting drug use is a matter of public health concern, associated with risks of overdoses, addiction and increased risk of bloodborne viral transmissions. Self-reported data on substances injected can be inaccurate or subject to bias or drug users might be oblivious to their injected substances or adulterations. Gathering of robust analytical information on the actual composition of substances injected might provide better information about the drugs that are being used. Therefore, this study aimed to analyse the residual content of discarded syringes collected across 7 European cities, collectively called the European Syringe Collection and Analysis Project Enterprise (ESCAPE). METHODS: Used syringes were collected at street automatic injection kit dispensers or at harm-reduction services in Amsterdam, Budapest, Cologne, Glasgow, Helsinki, Lausanne and Paris. Two sampling periods were executed thus far, in 2017 and 2018. Qualitative chemical analysis of the content of used syringes was performed combining gas chromatographic (GC) and ultra(high)performance liquid chromatographic ((U)HPLC) analytical techniques with detection by mass spectrometry (MS). RESULTS: Substances detected most frequently across both campaigns were cocaine, heroin, buprenorphine, amphetamines and synthetic cathinones. In Amsterdam, Cologne, Lausanne and Glasgow heroin and cocaine were the psychoactive substances most often detected, often in conjunction with each other. Helsinki showed a high presence of buprenorphine and amphetamines. In Budapest and Paris, synthetic cathinones were frequently detected. Less synthetic cathinones and cocaine was detected in 2018, whereas buprenorphine was detected almost twice as much. Inner-city variations were found, probably reflecting the types of people who inject drugs (PWID) in different areas of the city. CONCLUSION: Overall, laboratory-confirmed local data on injected substances showed resemblance to national surveys done among PWID. However, the ESCAPE data also showed some interesting differences, showing it can be used for local interventions and complementing existing monitoring data.

Comparing ecstasy users and non-users in a population-based and co-twin control design across multiple traits.

OBJECTIVE: Ecstasy is one of the most commonly used illicit substances in Western countries. The aim of this study is to identify characteristics of ecstasy users in a large population-based sample of adults aged 18-45 years. METHOD: With generalized estimating equation models we explored the association between self-reported lifetime ecstasy use and urbanicity, educational attainment, health, wellbeing, stress, other substance use, personality traits and psychopathology in a Dutch twin sample (N = 9578, 66.8% female, 18-45 years). We also explored the nature of the association (underlying genetic factors, shared environmental factors or a causal relationship) with the co-twin control method. RESULTS: Lifetime ecstasy users (N = 945, 9.9%) were more often male, younger, living more often in urban areas, higher educated, less satisfied with life and more stressed than non-users. Ecstasy users scored differently on most personality and psychopathology scales compared to non-users and were more likely to have used every other substance we investigated. Whereas smoking tobacco and alcohol use often preceded first use of ecstasy, first ecstasy use often preceded first use of other illicit substances. A combination of scenarios (both causal and environmental/genetic) explained the strong associations between ecstasy and substance use. CONCLUSIONS: Ecstasy users differ on many characteristics from non-users, and especially on illicit substance use. Our results indicate that causal effects may play a role in explaining the relationship between ecstasy use and other illicit substance use.

Novel Phenethylamines and Their Potential Interactions With Prescription Drugs: A Systematic Critical Review.

BACKGROUND: The novel phenethylamines 4-fluoroamphetamine (4-FA) and 2,5-dimethoxy-4-bromophenethylamine (2C-B) fall in the top 10 most used new psychoactive substances (NPSs) among high-risk substance users. Various phenethylamines and NPS are also highly used in populations with mental disorders, depression, or attention deficit hyperactivity disorder (ADHD). Moreover, NPS use is highly prevalent among men and women with risky sexual behavior. Considering these specific populations and their frequent concurrent use of drugs, such as antidepressants, ADHD medication, and antiretrovirals, reports on potential interactions between these drugs, and phenethylamines 4-FA and 2C-B, were reviewed. METHODS: The authors performed a systematic literature review on 4-FA and 2C-B interactions with antidepressants (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, bupropion, venlafaxine, phenelzine, moclobemide, and tranylcypromine), ADHD medications (atomoxetine, dexamphetamine, methylphenidate, and modafinil), and antiretrovirals. RESULTS: Limited literature exists on the pharmacokinetics and drug-drug interactions of 2C-B and 4-FA. Only one case report indicated a possible interaction between 4-FA and ADHD medication. Although pharmacokinetic interactions between 4-FA and prescription drugs remain speculative, their pharmacodynamic points toward interactions between 4-FA and ADHD medication and antidepressants. The pharmacokinetic and pharmacodynamic profile of 2C-B also points toward such interactions, between 2C-B and prescription drugs such as antidepressants and ADHD medication. CONCLUSIONS: A drug-drug (phenethylamine-prescription drug) interaction potential is anticipated, mainly involving monoamine oxidases for 2C-B and 4-FA, with monoamine transporters being more specific to 4-FA.

Synthetic Cathinones and Their Potential Interactions with Prescription Drugs.

PURPOSE: Substance use disorder often coexists with other psychiatric disorders, resulting in the simultaneous use of recreational and prescription drugs. The authors aimed to identify potential pharmacokinetic and pharmacodynamic interactions between new psychoactive substances of the cathinone class and specific prescription drugs. METHODS: The authors performed a systematic literature review on interactions between synthetic cathinones (mephedrone, methylone, methylenedioxypyrovalerone, and alpha-pyrrolidinopentiophenone) and antidepressants (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine), attention deficit hyperactivity disorder (ADHD) medications (atomoxetine, dexamphetamine, methylphenidate, modafinil) or HIV medications. RESULTS: Although no pharmacokinetic interactions have been reported in previous literatures, such interactions are likely to occur. Metabolic pathways of cathinones, antidepressants, and ADHD medications have been shown to overlap, including metabolism via cytochrome P450 enzymes and their inhibition. Consistent with this finding, interactions of bupropion (a cathinone) with antidepressants and ADHD medications have been found to increase their serum concentrations and half-lives. Additionally, limited pharmacodynamic interactions have been reported. However, as cathinones, antidepressants, and ADHD medications have been reported to increase the extracellular monoamine concentration by affecting reuptake transporters, interactions among these compounds are likely. Presumably, even higher monoamine concentrations could be observed when cathinones are combined with prescription drugs with a similar mode of action, as has been reported in animals exposed to duloxetine and bupropion. HIV medications have a different mode of action; thus, they have been reported to be less likely to have pharmacodynamic interactions with cathinones. CONCLUSIONS: Clinicians should be aware of possible interactions between synthetic cathinones and prescription drugs, which may increase the risk of drug toxicity or reduce the therapeutic efficacy of the drugs. Qualitative drug screening for cathinones using mass spectrometry methods may aid the early detection of these agents.

Unexpected Serotonin Syndrome, Epileptic Seizures, and Cerebral Edema Following 2,5-dimethoxy-4-bromophenethylamine Ingestion.

4-bromo-2,5-dimethoxyphenethylamine (2C-B) is a designer drug. In Europe, 2C-B is easily obtained and used for recreational purposes. It is known for its stimulating effects similar to those of 3,4-methylenedioxymethamphetamine, although in higher doses it has more hallucinogenic effects. Here, we report a case of 2C-B ingestion, confirmed by liquid chromatography-tandem mass spectrometry, in an 18-year-old man. The neurological consequences were severe, including the development of serotonin syndrome and severe brain edema. Supportive therapy resulted in a stable condition, although, after several months, the patient still suffered from severe neurological impairment due to the drug-induced toxicity. This case showed that 2C-B could not be identified with the drugs of abuse screening routinely used in Dutch hospitals. The use of 2C-B carries many risks, with potentially profound neurological damage, that both consumers and healthcare physicians are unaware of.

Psychopathological symptoms associated with synthetic cannabinoid use: a comparison with natural cannabis.

BACKGROUND: Synthetic cannabinoids (SCs) are a class of new psychoactive substances that have been rapidly evolving around the world throughout recent years. Many different synthetic cannabinoid analogues are on the consumer market and sold under misleading names, like "spice" or "incense." A limited number of studies have reported serious health effects associated with SC use. In this study, we compared clinical and subclinical psychopathological symptoms associated with SC use and natural cannabis (NC) use. METHODS: A convenience sample of 367 NC and SC users was recruited online, including four validated psychometric questionnaires: The Drug Use Disorders Identification Test (DUDIT), Insomnia Severity Index (ISI), Altman Mania Scale (Altman), and Brief Symptom Inventory (BSI). The two groups were compared with analysis of variance (ANOVA) and covariance (ANCOVA), chi2 tests, and logistic regression when appropriate. RESULTS: The SC user group did not differ in age from the NC user group (27.7 years), but contained less females (21% and 30%, respectively). SC users scored higher than NC users on all used psychometric measures, indicating a higher likelihood of drug abuse, sleep problems, (hypo)manic symptoms, and the nine dimensions comprising the BSI, somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Odds ratios (95% CI) for the SC user group vs NC user group were, respectively, drug dependence 3.56 (1.77-7.16), (severe) insomnia 5.01 (2.10-11.92), (hypo-)mania 5.18 (2.04-13.14), and BSI psychopathology 5.21 (2.96-9.17). DISCUSSION: This study shows that SC use is associated with increased mental health symptomatology compared to NC use.

Metabolomics predicts the pharmacological profile of new psychoactive substances.

BACKGROUND: The unprecedented proliferation of new psychoactive substances (NPS) threatens public health and challenges drug policy. Information on NPS pharmacology and toxicity is, in most cases, unavailable or very limited and, given the large number of new compounds released on the market each year, their timely evaluation by current standards is certainly challenging. AIMS: We present here a metabolomics-targeted approach to predict the pharmacological profile of NPS. METHODS: We have created a machine learning algorithm employing the quantification of monoamine neurotransmitters and steroid hormones in rats to predict the similarity of new drugs to classical ones of abuse (MDMA (3,4-methyl enedioxy methamphetamine), methamphetamine, cocaine, heroin and Δ9-tetrahydrocannabinol). RESULTS: We have characterized each classical drug of abuse and two examples of NPS (mephedrone and JWH-018) following alterations observed in the targeted metabolome profile (monoamine neurotransmitters and steroid hormones) in different brain areas, plasma and urine at 1 h and 4 h post drug/vehicle administration. As proof of concept, our model successfully predicted the pharmacological profile of a synthetic cannabinoid (JWH-018) as a cannabinoid-like drug and synthetic cathinone (mephedrone) as a MDMA-like psychostimulant. CONCLUSION: Our approach allows a fast NPS pharmacological classification which will benefit both drug risk evaluation policies and public health.

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.

Heritability of lifetime ecstasy use.

BACKGROUND: Ecstasy is a widely used psychoactive drug that users often take because they experience positive effects such as increased euphoria, sociability, elevated mood, and heightened sensations. Ecstasy use is not harmless and several immediate and long term side effects have been identified. Lifetime ecstasy use is likely to be partly influenced by genetic factors, but no twin study has determined the heritability. Here, we apply a classical twin design to a large sample of twins and siblings to estimate the heritability of lifetime ecstasy use. METHODS: The sample comprised 8500 twins and siblings aged between 18 and 45 years from 5402 families registered at the Netherlands Twin Registry. In 2013-2014 participants filled out a questionnaire including a question whether they had ever used ecstasy. We used the classical twin design to partition the individual differences in liability to ecstasy use into that due to genetic, shared environmental, and residual components. RESULTS: Overall, 10.4% of the sample had used ecstasy during their lifetime, with a somewhat higher prevalence in males than females. Twin modelling indicated that individual differences in liability to lifetime ecstasy use are for 74% due to genetic differences between individuals, whereas shared environmental and residual factors explain a small proportion of its liability (5% and 21%, respectively). Although heritability estimates appeared to be higher for females than males, this difference was not significant. CONCLUSIONS: Lifetime ecstasy use is a highly heritable trait, which indicates that some people are genetically more vulnerable to start using ecstasy than others.

Characterizing users of new psychoactive substances using psychometric scales for risk-related behavior.

INTRODUCTION: Studies investigating risk-related behavior in relation to new psychoactive substance (NPS) use are sparse. The current study investigated characteristics of NPS users by comparing risk-related behavior of NPS users to that of illicit drugs (ID) users and licit substances users and non-users (NLC) users. METHODS: In this cross-sectional study we included 528 individuals across an age range of 18-72years. Using a web-based questionnaire we collected self-report data on substance use, sensation seeking, impulsivity, peer substance use and risk perception of substance use. RESULTS: NPS and ID users had a higher level of sensation seeking compared to NLC users (NPS users: p<0.001; ID users: p<0.001). NPS users (p<0.001), but not ID users (p=0.16), had increased levels of impulsivity compared to NLC users. NPS users had significantly higher scores for sensation seeking (F1,423=51.52, p<0.001) and impulsivity (F1,423=6.15, p=0.01) compared to ID users. Additionally, NPS users had significantly more peers who use substances compared to ID and NLC users. Also, NPS and ID users had lower risk perception for most substances than NLC users. NPS users had lower risk perception for most substances than ID users. CONCLUSIONS: The findings highlight that NPS users show substantial more risk-related behavior than both ID and NLC users. Therefore, NPS users might be considered as a distinctive group of substance users that need another approach in terms of prevention.

Drug testing in Europe: monitoring results of the Trans European Drug Information (TEDI) project.

Drug testing is a harm reduction strategy that has been adopted by certain countries in Europe. Drug users are able to hand in their drugs voluntarily for chemical analysis of composition and dose. Drug users will be alerted about dangerous test results by the drug testing systems directly and through warning campaigns. An international collaborative effort was launched to combine data of drug testing systems, called the Trans European Drug Information (TEDI) project. Drug testing systems of Spain, Switzerland, Belgium, Austria, Portugal, and the Netherlands participated in this project. This study presents results of some of the main illicit drugs encountered: cocaine, ecstasy and amphetamine and also comments on new psychoactive substances (NPS) detected between 2008 and 2013. A total of 45 859 different drug samples were analyzed by TEDI. The drug markets of the distinct European areas showed similarities, but also some interesting differences. For instance, purity of cocaine and amphetamine powders was generally low in Austria, whilst high in Spain and the Netherlands. And the market for ecstasy showed a contrast: whereas in the Netherlands and Switzerland there was predominantly a market for ecstasy tablets, in Portugal and Spain MDMA (3,4-methylenedioxymethamphetamine) crystals were much more prevalent. Also, some NPS appearing in ecstasy seemed more specific for one country than another. In general, prevalence of NPS clearly increased between 2008 and 2013. Drug testing can be used to generate a global picture of drug markets and provides information about the pharmacological contents of drugs for the population at risk. Copyright © 2016 John Wiley & Sons, Ltd.

Purity, adulteration and price of drugs bought on-line versus off-line in the Netherlands.

BACKGROUND AND AIMS: On-line drug markets flourish and consumers have high expectations of on-line quality and drug value. The aim of this study was to (i) describe on-line drug purchases and (ii) compare on-line with off-line purchased drugs regarding purity, adulteration and price. DESIGN: Comparison of laboratory analyses of 32 663 drug consumer samples (stimulants and hallucinogens) purchased between January 2013 and January 2016, 928 of which were bought on-line. SETTING: The Netherlands. MEASUREMENTS: Primary outcome measures were (i) the percentage of samples purchased on-line and (ii) the chemical purity of powders (or dosage per tablet); adulteration; and the price per gram, blotter or tablet of drugs bought on-line compared with drugs bought off-line. FINDINGS: The proportion of drug samples purchased on-line increased from 1.4% in 2013 to 4.1% in 2015. The frequency varied widely, from a maximum of 6% for controlled, traditional substances [ecstasy tablets, 3,4-methylenedioxy-methamphetamine (MDMA) powder, amphetamine powder, cocaine powder, 4-bromo-2,5-dimethoxyphenethylamine (2C-B) and lysergic acid diethylamide (LSD)] to more than a third for new psychoactive substances (NPS) [4-fluoroamphetamine (4-FA), 5/6-(2-aminopropyl)benzofuran (5/6-APB) and methoxetamine (MXE)]. There were no large differences in drug purity, yet small but statistically significant differences were found for 4-FA (on-line 59% versus off-line 52% purity for 4-FA on average, P = 0.001), MDMA powders (45 versus 61% purity for MDMA, P = 0.02), 2C-B tablets (21 versus 10 mg 2C-B/tablet dosage, P = 0.49) and ecstasy tablets (131 versus 121 mg MDMA/tablet dosage, P = 0.05). The proportion of adulterated samples purchased on-line and off-line did not differ, except for 4-FA powder, being less adulterated on-line (χ2  = 8.3; P < 0.02). Drug prices were mainly higher on-line, ranging for various drugs from 10 to 23% higher than that of drugs purchased off-line (six of 10 substances: P < 0.05). CONCLUSIONS: Dutch drug users increasingly purchase drugs on-line: new psychoactive substances in particular. Purity and adulteration do not vary considerably between drugs purchased on-line and off-line for most substances, while on-line prices are mostly higher than off-line prices.

Is online information on ecstasy tablet content safe?

BACKGROUND AND AIMS: In recent years, the prevalence of ecstasy use has increased in most European countries. Users can acquire information on ecstasy tablet composition through the internet. This study compares online information from two websites, Pillreports and Partyflock, to the validated Dutch Drugs Information and Monitoring System (DIMS) database, and aims to measure its accuracy and potential danger or value. DESIGN, SETTING, PARTICIPANTS: The drug-related information posted on Pillreports.net and Partyflock.nl between 1 January 2014 and 31 December 2015 was investigated for accuracy and several information characteristics such as picture inclusion and dose range inclusion. In total, 471 informatory statements on ecstasy tablet content were analysed relative to the Dutch ecstasy market. MEASUREMENTS: Informatory statements on the content of specific ecstasy tablets were scored as 'too high' or 'too low' if their concentrations deviated > 10 mg from the entries in the DIMS database within a 12-week time-frame, and scored as 'dangerous' if their concentration was > 40 mg too low. Unreported substances were scored as 'dangerous' if listed as an illegal or dangerous substance in the DIMS database and if present in relevant quantities. Also scored were the report characteristics 'picture inclusion', 'spread inclusion' and 'website source', which were tested for their association with report safety/danger. FINDINGS: On average, reports on ecstasy tablets from Pillreports and Partyflock show concentrations which are 10.6 mg too high [95% confidence interval (CI) = 6.7-14.4]. Qualitatively, 39.7% of the reports scored as 'too high' (95% CI = 35.2-44.4), 17.6% scored as 'too low' (95% CI = 14.0-21.2) and 15.5% had 'unreported substances' (95% CI = 12.3-18.9), resulting overall in 15.3% of the reports being scored as 'dangerous' (95% CI = 11.9-18.5). The report characteristic 'spread inclusion' associated inversely with report danger [Exp(b) = 0.511, 95% CI = 0.307-0.850, P = 0.01]. CONCLUSION: Information from the popular Pillreports and Partyflock websites tends to overestimate 3,4-methylenedioxymethamphetamine (MDMA) concentrations in ecstasy tablets. In addition, 15.3% of the reports omit the relevant concentration spread, fail to report additional illegal or dangerous substances contained in the tablets or underestimate MDMA concentration by > 40 mg.