Cytotoxicity, crosslinking and biological activity of three mitomycins.

While interstrand crosslinks (ICLs) have been considered as one type of DNA damage in the past, there is mounting evidence suggesting that these highly cytotoxic lesions are processed differently by the cellular machinery depending upon the ICL structure. In this study, we examined the crosslinking ability of three mitomycins, the structure of the ICLs they produce and the cytotoxicity of the drugs toward three different cell lines. The drugs are: mitomycin C (1), decarbamoylmitomycin C (2), and a mitomycin-conjugate (3) whose mitosane moiety is linked to a N-methylpyrrole carboxamide. We found that, overall, both MC and compound 3 show strong similarities regarding their alkylation of DNA, while DMC alkylating behavior is markedly different. To gain further insight into the mode of action of these drugs, we performed high throughput gene expression and gene ontology analysis to identify gene expression and cellular pathways most impacted by each drug treatment in MCF-7 cell lines. We observed that the novel mitomycin derivative (3) specifically causes changes in the expression of genes encoding proteins involved in cell integrity and tissue structure. Further analysis using bioinformatics (IPA) indicated that the new derivative (3) displays a stronger downregulation of major signaling networks that regulate the cell cycle, DNA damage response and cell proliferation when compared to MC and DMC. Collectively, these findings demonstrate that cytotoxic mechanisms of all three drugs are complex and are not solely related to their crosslinking abilities or the structure of the ICLs they produce.

Microextraction sample preparation techniques in forensic analytical toxicology.

Sample preparation is a critical step in forensic analytical toxicology. Different extraction techniques are employed with the goals of removing interferences from the biological samples, such as blood, tissues and hair, reducing matrix effects and concentrating the target analytes, among others. With the objective of developing faster and more ecological procedures, microextraction techniques have been expanding their applications in the recent years. This article reviews various microextraction methods, which include solid-based microextraction, such as solid-phase microextraction, microextraction by packed sorbent and stir-bar sorptive extraction, and liquid-based microextraction, such as single drop/hollow fiber-based liquid-phase microextraction and dispersive liquid-liquid microextraction, as well as their applications to forensic toxicology analysis. The development trend in future microextraction sample preparation is discussed.

First metabolic profile of PV8, a novel synthetic cathinone, in human hepatocytes and urine by high-resolution mass spectrometry.

Novel psychoactive substances (NPS) are ever changing on the drug market, making it difficult for toxicology laboratory methods to stay current with so many new drugs. Recently, PV8, a synthetic pyrrolidinophenone, was detected in seized products in Japan (2013), The Netherlands (2014), and Germany (2014). There are no controlled PV8 administration studies, and no pharmacodynamic and pharmacokinetic data. The objective was to determine PV8's metabolic stability in human liver microsome (HLM) incubation and its metabolism following human hepatocyte incubation and high-resolution mass spectrometry (HRMS) with a Thermo Scientific Q-Exactive. Data were acquired with a full-scan data-dependent mass spectrometry method. Scans were thoroughly data mined with different data processing algorithms and analyzed in WebMetaBase. PV8 exhibited a relatively short 28.8 min half-life, with an intrinsic 24.2 µL/min/mg microsomal clearance. This compound is predicted to be an intermediate clearance drug with an estimated human 22.7 mL/min/kg hepatic clearance. Metabolic pathways identified in vitro included: hydroxylation, ketone reduction, carboxylation, N-dealkylation, iminium formation, dehydrogenation, N-oxidation, and carbonylation. The top three in vitro metabolic pathways were di-hydroxylation > ketone reduction > γ-lactam formation. Authentic urine specimen analyses revealed the top three metabolic pathways were aliphatic hydroxylation > ketone reduction + aliphatic hydroxylation > aliphatic carboxylation, although the most prominent peak was parent PV8. These data provide useful urinary metabolite targets (aliphatic hydroxylation, aliphatic hydroxylation + ketone reduction, aliphatic carboxylation, and di-hydroxylation) for forensic and clinical testing, and focus reference standard companies' synthetic efforts to provide commercially available standards needed for PV8 biological specimen testing. Graphical Abstract Top four PV8 metabolites identified in vitro. Biotransformations highlighted in blue. Markush structures presented when exact location of biotransformation is unknown.

Urinary cannabinoid disposition in occasional and frequent smokers: is THC-glucuronide in sequential urine samples a marker of recent use in frequent smokers?

BACKGROUND: There is extended urinary excretion of Δ(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) in abstinent frequent cannabis smokers. We characterized THC, 11-OH-THC, THCCOOH, cannabidiol, cannabinol, THC-glucuronide, and THCCOOH-glucuronide disposition in urine of frequent and occasional cannabis smokers, and we propose a model to predict recent cannabis smoking. METHODS: Frequent and occasional smokers resided on a closed research unit and smoked one 6.8% THC cannabis cigarette ad libitum. Urinary cannabinoids were quantified in each void by liquid chromatography-tandem mass spectrometry within 24 h of collection. RESULTS: No urine samples had measureable THC, 11-OH-THC, cannabidiol, or cannabinol. THCCOOH, THC-glucuronide, and THCCOOH-glucuronide were measurable in all frequent smokers' urine and 60%, 100%, and 100% of occasional smokers' urine samples, respectively. Pre- and postdose maximal concentrations (non- and creatinine normalized) and probability of being positive were significantly higher in frequent smokers' samples. THC-glucuronide concentrations peaked 0.6-7.4 h after smoking; THCCOOH and THCCOOH-glucuronide concentrations were highly variable. At the newly adopted THCCOOH 175-µg/L World Anti-Doping Agency decision limit, only 50% of frequent smokers were positive 0-6 h postdose; no occasional smokers' samples were positive. An absolute %difference of ≥50% between 2 consecutive THC-glucuronide-positive samples with a creatinine-normalized concentration of ≥2 µg/g in the first sample predicted cannabis smoking with efficiencies of 93.1% in frequent and 76.9% in occasional smokers within 6 h of first sample collection. CONCLUSIONS: These controlled urinary cannabinoid data provide a possible means of identifying recent cannabis intake in cannabis smokers' urine within a short collection time frame after smoking.

Phase I and II cannabinoid disposition in blood and plasma of occasional and frequent smokers following controlled smoked cannabis.

BACKGROUND: Δ(9)-Tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) have been reported in blood from frequent cannabis smokers for an extended time during abstinence. We compared THC, 11-OH-THC, THCCOOH, cannabidiol, cannabinol, THC-glucuronide, and 11-nor-9-carboxy-THC-glucuronide (THCCOO-glucuronide) blood and plasma disposition in frequent and occasional cannabis smokers. METHODS: Frequent and occasional smokers resided on a closed research unit and smoked one 6.8% THC cannabis cigarette ad libitum. Blood and plasma cannabinoids were quantified on admission (approximately 19 h before), 1 h before, and up to 15 times (0.5-30 h) after smoking. RESULTS: Cannabinoid blood and plasma concentrations were significantly higher in frequent smokers compared with occasional smokers at most time points for THC and 11-OH-THC and at all time points for THCCOOH and THCCOO-glucuronide. Cannabidiol, cannabinol, and THC-glucuronide were not significantly different at any time point. Overall blood and plasma cannabinoid concentrations were significantly higher in frequent smokers for THC, 11-OH-THC, THCCOOH, and THCCOO-glucuronide, with and without accounting for baseline concentrations. For blood THC >5 µg/L, median (range) time of last detection was 3.5 h (1.1->30 h) in frequent smokers and 1.0 h (0-2.1 h) in 11 occasional smokers; 2 individuals had no samples with THC >5 µg/L. CONCLUSIONS: Cannabis smoking history plays a major role in cannabinoid detection. These differences may impact clinical and impaired driving drug detection. The presence of cannabidiol, cannabinol, or THC-glucuronide indicates recent use, but their absence does not exclude it.

In vitro stability of free and glucuronidated cannabinoids in urine following controlled smoked cannabis.

Analyte stability is an important factor in urine test interpretation, yet cannabinoid stability data are limited. A comprehensive study of Δ(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol, cannabinol, THC-glucuronide, and THCCOOH-glucuronide stabilities in authentic urine was completed. Urine samples after ad libitum cannabis smoking were pooled to prepare low and high pools for each study participant; baseline concentrations were measured within 24 h at room temperature (RT), 4 °C and -20 °C. Stability at RT, 4 °C and -20 °C was evaluated by Friedman tests for up to 1 year. THCCOOH, THC-glucuronide, and THCCOOH-glucuronide were quantified in baseline pools. RT THCCOOH baseline concentrations were significantly higher than -20 °C, but not 4 °C baseline concentrations. After 1 week at RT, THCCOOH increased, THCCOOH-glucuronide decreased, but THC-glucuronide was unchanged. In RT low pool, total THCCOOH (THCCOOH + THCCOOH-glucuronide) was significantly lower after 1 week. At 4 °C, THCCOOH was stable 2 weeks, THCCOOH-glucuronide 1 month and THC-glucuronide for at least 6 months. THCCOOH was stable frozen for 1 year, but 6 months high pool results were significantly higher than baseline; THC-glucuronide and THCCOOH-glucuronide were stable for 6 months. Total THCCOOH was stable 6 months at 4 °C, and frozen 6 months (low) and 1 year (high). THC, cannabidiol and cannabinol were never detected in urine; although not detected initially, 11-OH-THC was detected in 2 low and 3 high pools after 1 week at RT. Substantial THCCOOH-glucuronide deconjugation was observed at RT and 4 °C. Analysis should be conducted within 3 months if non-hydrolyzed THCCOOH or THCCOOH-glucuronide quantification is required.

The influence of cosmetic treatments in the uptake of in vitro cocaine contamination in hair.

Hair analysis is a powerful tool to assess drug use, yet the challenge of external contamination complicates its interpretation. Understanding the influence of cosmetic hair treatments is pivotal as their presence may affect this phenomenon. This study investigated the effects of four cosmetic treatments (bleach, henna, gel, and dry shampoo) on the external in vitro contamination of cocaine and its primary metabolite, benzoylecgonine (BE). Hair samples were divided into four groups: A-hair treated with cosmetics then contaminated; B-hair contaminated then subjected to cosmetic treatment; and C-hair solely contaminated (control group). Negative hair samples (n = 24) were immersed in a cocaine and BE aqueous solution of 1 µg/mL for 24 h. All hair samples were analyzed by a LC-MSMS procedure successfully validated according to ANSI/ASB Standard 036 guidelines (limit of quantification at 10 pg/mg). Henna in Group A (n = 13) resulted in the most substantial reduction for cocaine (92%), while bleach in Group B (n = 15) showed an 80% decrease. For BE, Group A henna (n = 13) exhibited a 50% reduction, and Group B bleach (n = 15) demonstrated a 71% decrease, all compared to Group C (n = 24). The study found no significant differences concerning hair color (black (n = 3), brown (n = 10), red (n = 5) and blond (n = 6)) or shape (straight (n = 6), wavy (n = 16), curly (n = 1), and coily (n = 1)). All analysis were performed in triplicate with variations below 20%. These findings emphasize that cosmetic treatments do affect cocaine/BE concentrations in hair when exposed to external contamination, highlighting the importance of considering an individual's cosmetic history prior to interpretation.

Nicotinic receptor modulation of the default mode network.

RATIONALE: Previous neuroimaging studies of cognition involving nicotinic acetylcholine receptor (nAChR) agonist administration have repeatedly found enhanced task-induced deactivation of regions of the default mode network (DMN), a group of brain systems that is more active at rest and mediates task-independent thought processes. This effect may be related to pro-cognitive nAChR agonist effects OBJECTIVES: The present study sought to test whether nAChR modulation of the DMN is bi-directional, i.e., whether a nAChR antagonist would reduce task-induced deactivation. METHODS: Eighteen healthy non-smokers underwent functional magnetic resonance imaging while performing a letter N-back task. Scans were performed after nicotine administration (7 mg/24 h, transdermally), after administration of the nAChR antagonist mecamylamine (7.5 mg, p.o.), and after double placebo, in counterbalanced sequence. Blood-oxygen-level-dependent (BOLD) signal was analyzed within ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC) regions of interest-central hubs of the DMN in which consistent nAChR agonist-induced changes had previously been identified. RESULTS: Nicotine enhanced hit rate in both the 0-back and 2-back condition, while mecamylamine slowed reaction time in the 2-back condition. Mecamylamine reduced task-induced deactivation of vmPFC and PCC. Nicotine had no significant effects on the BOLD signal. CONCLUSIONS: The finding that nAChR tone reduction by mecamylamine weakened task-induced DMN deactivation indicates that a constant tone of nAChR activation helps regulate DMN activity in healthy individuals. This suggests that low nAChR tone may play a causal role in DMN dysregulation seen in conditions such as mild cognitive impairment or Alzheimer's disease.

Assessment of Tobacco Exposure During Pregnancy by Meconium Analysis and Maternal Interview.

Smoking during pregnancy can have serious obstetric and fetal complications. Therefore, it is essential to identify in utero exposure to tobacco, being meconium the matrix of choice for this purpose. Meconium (n = 565) was analyzed for nicotine, cotinine and hydroxycotinine by LC-MS-MS. Then, tobacco meconium results were compared with smoking habits during pregnancy and neonatal outcomes measures (birth weight, length, head circumference, gestational age and Apgar scores). Although meconium analysis increased identification of in-utero exposure to tobacco (17.7% meconium positive specimens vs 13.5% mothers admitting tobacco use during pregnancy), there was a statistically significant relationship between meconium results and interview answers (P < 0.001). Birth weight was significantly lower for newborns with meconium positive results in males (P = 0.023) and females (P = 0.001), while for length significance was only observed in females (P = 0.001); however, when excluding meconium specimens positive for other drugs, a statistically significant difference was only found for female weight (P = 0.045). Meconium analysis proved to be more reliable for tobacco prenatal exposure detection than maternal interview. In addition, positive meconium results increased the probability for low birth weight, especially in females.

Urinary excretion of buprenorphine, norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine-glucuronide in pregnant women receiving buprenorphine maintenance treatment.

BACKGROUND: Buprenorphine (BUP) is under investigation as a medication therapy for opioid-dependent pregnant women. We investigated BUP and metabolite disposition in urine from women maintained on BUP during the second and third trimesters of pregnancy and postpartum. METHODS: We measured BUP, norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and NBUP-Gluc concentrations in 515 urine specimens collected thrice weekly from 9 women during pregnancy and postpartum. Specimens were analyzed using a fully validated liquid chromatography-mass spectrometry method with limits of quantification of 5 microg/L for BUP and BUP-Gluc and 25 microg/L for NBUP and its conjugated metabolite. We examined ratios of metabolites across trimesters and postpartum to identify possible changes in metabolism during pregnancy. RESULTS: NBUP-Gluc was the primary metabolite identified in urine and exceeded BUP-Gluc concentrations in 99% of specimens. Whereas BUP-Gluc was identified in more specimens than NBUP, NBUP exceeded BUP-Gluc concentrations in 77.9% of specimens that contained both analytes. Among all participants, the mean BUP-Gluc:NBUP-Gluc ratio was significantly higher in the second trimester compared to the third trimester, and there were significant intrasubject differences between trimesters in 71% of participants. In 3 women, the percent daily dose excreted was higher during pregnancy than postpregnancy, consistent with other data indicating increased renal elimination of drugs during pregnancy. CONCLUSIONS: These data are the first to evaluate urinary disposition of BUP and metabolites in a cohort of pregnant women. Variable BUP excretion during pregnancy may indicate metabolic changes requiring dose adjustment during later stages of gestation.

Simultaneous quantification of buprenorphine, norbuprenorphine, buprenorphine glucuronide, and norbuprenorphine glucuronide in human placenta by liquid chromatography mass spectrometry.

A LCMS method was developed and validated for the determination of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and norbuprenorphine glucuronide (NBUP-Gluc) in placenta. Quantification was achieved by selected ion monitoring of m/z 468.4 (BUP), 414.3 (NBUP), 644.4 (BUP-Gluc), and 590 (NBUP-Gluc). BUP and NBUP were identified monitoring MS(2) fragments m/z 396, 414 and 426 for BUP, and 340, 364 and 382 for NBUP, and glucuronide conjugates monitoring MS(3) fragments m/z 396 and 414 for BUP-Gluc, and 340 and 382 for NBUP-Gluc. Linearity was 1-50 ng/g. Intra-day, inter-day and total assay imprecision (% RSD) were <13.4%, and analytical recoveries were 96.2-113.1%. Extraction efficiencies ranged from 40.7-68%, process efficiencies 38.8-70.5%, and matrix effect 1.3-15.4%. Limits of detection were 0.8 ng/g for all compounds. An authentic placenta from an opioid-dependent pregnant woman receiving BUP pharmacotherapy was analyzed. BUP was not detected but metabolite concentrations were NBUP-Gluc 46.6, NBUP 15.7 and BUP-Gluc 3.2 ng/g.

Wastewater analysis for nicotine, cocaine, amphetamines, opioids and cannabis in New York City.

According to current surveys and overdoses data, there is a drug crisis in the USA. Wastewater-based epidemiology (WBE) is an evolving discipline that analyses wastewater samples to detect drugs and metabolites to estimate drug consumption in a certain community. This study demonstrates how drug relative presence could be tracked by testing wastewater, providing real-time results, in different boroughs in New York City throughout 1 year. We developed and fully validated two analytical methods, one for 21 drugs and metabolites, including nicotine, cocaine, amphetamines, opioids and cannabis markers; and another for the normalization factor creatinine. Both methods were performed by liquid chromatography tandem mass spectrometry (LC-MS/MS) using positive electrospray ionization, achieving a limit of quantification of 5-10 ng/L for drugs and metabolites, and 0.01 mg/L for creatinine. These methods were applied to 48 one-time grab wastewater samples collected from six wastewater treatment plants in New York City (Manhattan, The Bronx, Queens and Brooklyn), eight different times throughout 2016, before and after major holidays, including Memorial Day, 4th of July, Labour Day and New Year's. In this study, the drug group normalized concentrations present in the wastewater samples, in decreasing order, were cocaine, nicotine, opioids, cannabis and amphetamines. When looking at individual compounds, the one with the highest normalized concentration was benzoylecgonine (BE), followed by cotinine, morphine and 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH). To estimate community use, these concentrations were multiplied by the corresponding correction factor, and the most present were THCCOOH, followed by BE, cotinine and morphine. When comparing the treatment plants by drug group (nicotine, cocaine, amphetamines, opioids and cannabis), samples collected from The Bronx had the highest normalized concentrations for nicotine, cocaine and opioids; The Bronx and Manhattan for cannabis; and Manhattan and Queens for amphetamines. In most of the cases, no effect due to holiday was observed. This study provides the first snapshot of drug use in New York City and how that changes between key calendar dates employing wastewater analysis.

Development and validation of a liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of buprenorphine, norbuprenorphine, and metabolites in human urine.

A liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and norbuprenorphine glucuronide (NBUP-Gluc) in human urine was developed and fully validated. Extensive endogenous and exogenous interferences were evaluated and limits of quantification were identified empirically. Analytical ranges were 5-1,000 ng/mL for BUP and BUP-Gluc and 25-1,000 ng/mL for NBUP and NBUP-Gluc. Intra-assay and interassay imprecision were less than 17% and recovery was 93-116%. Analytes were stable at room temperature, at 4 degrees C, and for three freeze-thaw cycles. This accurate and precise assay has sufficient sensitivity and specificity for urine analysis of specimens collected from individuals treated with BUP for opioid dependence.

One Hundred False-Positive Amphetamine Specimens Characterized by Liquid Chromatography Time-of-Flight Mass Spectrometry.

Some amphetamine (AMP) and ecstacy (MDMA) urine immunoassay (IA) kits are prone to false-positive results due to poor specificity of the antibody. We employed two techniques, high-resolution mass spectrometry (HRMS) and an in silico structure search, to identify compounds likely to cause false-positive results. Hundred false-positive IA specimens for AMP and/or MDMA were analyzed by an Agilent 6230 time-of-flight (TOF) mass spectrometer. Separately, SciFinder (Chemical Abstracts) was used as an in silico structure search to generate a library of compounds that are known to cross-react with AMP/MDMA IAs. Chemical formulas and exact masses of 145 structures were then compared against masses identified by TOF. Compounds known to have cross-reactivity with the IAs were identified in the structure-based search. The chemical formulas and exact masses of 145 structures (of 20 chemical formulas) were compared against masses identified by TOF. Urine analysis by HRMS correlates accurate mass with chemical formulae, but provides little information regarding compound structure. Structural data of targeted antigens can be utilized to correlate HRMS-derived chemical formulas with structural analogs.

In vitro, in vivo and in silico metabolic profiling of α-pyrrolidinopentiothiophenone, a novel thiophene stimulant.

BACKGROUND: Little or no pharmacological or toxicological data are available for novel psychoactive substances when they first emerge, making their identification and interpretation in biological matrices challenging. MATERIALS & METHODS: A new synthetic cathinone, α-pyrrolidinopentiothiophenone (α-PVT), was incubated with hepatocytes and samples were analyzed using liquid chromatography coupled to a Q Exactive™ Orbitrap mass spectrometer. Authentic urine specimens from suspected α-PVT cases were also analyzed. Scans were data mined with Compound Discoverer™ for identification and structural elucidation of metabolites. RESULTS/CONCLUSION: Seven α-PVT metabolites were identified in hepatocyte incubations, and in the authentic urine samples, also with an additional monohydroxylated product and a glucuronide of low intensity. α-PVT dihydroxypyrrolidinyl, α-PVT 2-ketopyrrolidinyl, α-PVT hydroxythiophenyl and α-PVT thiophenol had the most intense in vivo signals.

A test of the cognitive self-medication hypothesis of tobacco smoking in schizophrenia.

BACKGROUND: Heavier tobacco smoking among people with schizophrenia (SCZ) has been suggested to reflect self-medication of cognitive deficits. The idea that cognitive-enhancing effects of nicotine are a primary motivator of tobacco consumption in SCZ and that abstinence would deprive SCZ of such beneficial effects might explain hesitation among providers to pursue smoking cessation in SCZ. This study tested predictions of the cognitive self-medication hypothesis. METHODS: In three counterbalanced sessions, 17 SCZ and 17 healthy control subjects (HCS), all smokers, were tested under ad libitum smoking or 3.5 hours after abstaining and receiving a nicotine (14 mg/24 hours) or placebo patch. RESULTS: Attention task performance was improved by transdermal nicotine relative to placebo, with intermediate performance by ad libitum smoking. These effects were of similar size in SCZ and HCS and did not reflect remediation of functions disproportionately impaired in SCZ. Although more SCZ reported that the need to concentrate influenced their smoking, this was not reflected by the actual behavior of these patients. Self-reported ability to concentrate changed with nicotine status in HCS but not SCZ, suggesting insensitivity of SCZ to nicotine-derived performance benefits. Nicotine plasma concentrations after ad libitum smoking were not associated with performance benefits but instead with the propensity to experience nicotine withdrawal upon abstinence. This association was seen selectively in SCZ, suggesting a possible reason for heavier smoking. CONCLUSIONS: These findings suggest that subjective or objective attentional benefits are unlikely the primary driving force of tobacco consumption in SCZ and should not discourage providers from supporting quit attempts.

Drogas y teratogenia / Drug of abuse and teratogenicity

Las drogas más usadas en el embarazo siguen siendo el tabaco y el alcohol, dentro de las legales, y el cannabis, seguido de la cocaína dentro de las ilegales. Aunque se ha asociado el consumo de drogas con un amplio abanico de malformaciones estructurales, las drogas de abuso tienen un escaso potencial teratogénico, entendido en el sentido estricto de malformación física, con la excepción del alcohol, que se asocia al síndrome alcohol fetal. Sin embargo, sí se está encontrando asociación entre la exposición prenatal a las drogas de abuso y alteraciones específicas del comportamiento, habitualmente muy sutiles, pero que no deben pasar desapercibidas, y que entran en el concepto actual de teratogénesis. La exposición intraútero a las drogas es un factor de riesgo para la gestación, con frecuencia asociado a otros factores de riesgo concomitantes, como la desnutrición, las enfermedades maternas y la pobreza, y cuyos efectos se solapan, se potencian y se confunden con frecuencia. En este trabajo se abordan de modo resumido los aspectos generales que regulan la teratogénesis (factores que determinan que una determinada exposición pueda ser considerada o no de riesgo, el papel de la placenta, etc), la epidemiología del consumo de drogas durante el embarazo y los factores que dificultan el estudio de estos efectos para estas sustancias. También se hace un análisis de los principales efectos teratogénicos relacionados con las drogas

The problem of the malformed children has concerned the humanity for ever, and this also includes the prenatal exposure to drugs of abuse. Tobacco and alcohol are the most common legal drugs used in pregnancy, and cannabis and cocaine, the most common illegal drugs. The use of drugs has been associated with a wide range of structural malformations, but with the exception of the alcohol and the fetal alcohol syndrome, drugs of abuse seem to have a weak teratogenic potential, in the classical structural malformation conception. Nevertheless, there has been found association between the prenatal exposure to these drugs and specific behavioural alterations, usually very subtle but that should not be ignored. This kind of alterations are now included in the conception of teratogenesis. So, drug use during pregnancy is a risk factor, usually associated to other concomitant risk factors like nutrition deficits, maternal illness and poverty, and these effects are overlapped, potentiated and very often confounded. In this review the main variables involved in the development of teratogenesis (factors that should be take into account in a specific exposition to evaluate the potential risk, the roll of the placenta, etc) are analysed. The epidemiology of the drug abuse in pregnancy and the concomitant factors that make difficult this evaluation are also studied. Finally a review of the main teratogenic effects related to the most common abused drugs was done