Therapeutic Drug Monitoring
March 19, 2004
Rafael de la Torre, Magı́ Farré, Pere N. Roset et al.
445 citations
MDMA (ecstasy) is a widely misused psychostimulant that increases energy, euphoria, and sociability while also producing distinctive 'entactogen' effects such as feeling close to others and increased empathy. It works by promoting the release and blocking the reuptake of serotonin, dopamine, and norepinephrine. Acute toxic effects include serotonin syndrome, characterized by muscle rigidity, hyperreflexia, and hyperthermia. MDMA metabolism involves two main pathways; one is partially regulated by the polymorphic enzyme CYP2D6, but mechanism-based inhibition after two consecutive doses limits the impact of CYP2D6 genetics on acute toxicity. Metabolism may also contribute to long-term neurotoxic effects through progressive degeneration of the serotonergic system.
Journal of Clinical Psychopharmacology
August 1, 2000
Jordi Camı́, Magı́ Farré, Marta Más et al.
237 citations
In a randomized, double-blind, crossover, controlled trial with eight healthy male volunteers, MDMA at recreational doses (75 and 125 mg) produced marked euphoria and well-being, as measured by increased scores on the Addiction Research Center Inventory MBG and A scales and visual analog scales for 'stimulated,' 'good effects,' 'liking,' and 'high.' The 125 mg dose also caused mild sedation, dysphoria, and a slight decrease in performance on the digit-symbol substitution test, along with esophoria. Amphetamine (40 mg) produced similar euphoric effects but improved psychomotor performance. No hallucinations or psychoses occurred. These findings support MDMA's abuse liability.
PLoS Biology
July 9, 2015
Xavier Viñals, Estefanía Moreno, Laurence Lanfumey et al.
211 citations
Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) causes negative effects including memory deficits, limiting therapeutic use. Behavioral studies in mice lacking 5-HT2A receptors (5-HT2AR) showed a dissociation: THC's antinociceptive effects remained, but its amnesic, anxiolytic-like, and social interaction effects depended on 5-HT2AR, while hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects did not. Biochemical studies revealed CB1R and 5-HT2AR form heteromers in brain regions involved in memory, altering cell signaling and G-protein coupling. Synthetic peptides disrupting heteromerization selectively prevented THC-induced memory impairments, identifying CB1R-5-HT2AR heteromers as targets to separate cognitive deficits from beneficial pain relief.
Annals of the New York Academy of Sciences
September 1, 2000
Rafael de la Torre, Magı́ Farré, P. N. Roset et al.
178 citations
Recreational doses of MDMA (50 to 150 mg) in healthy volunteers cause pupil dilation, increases in systolic and diastolic blood pressure, heart rate, and pupillary diameter. Oral temperature changes are biphasic: a slight decrease at 1 hour followed by increases at 2 and 4 hours. Psychomotor performance shows slight dose-dependent impairment. Plasma cortisol and prolactin concentrations rise markedly. The drug's elimination half-life is about 8-9 hours. Peak drug concentrations and physiological effects occur between 1 and 2 hours and return to baseline 4-6 hours after administration.
Clinical Chemistry
October 1, 2001
Mèonica Navarro, Simona Pichini, Magí Farré et al.
135 citations
After a single 100-mg dose of MDMA, concentrations in saliva ranged from 1728.9 to 6510.6 μg/L, peaking at 1.5 hours, then declining to a mean of 126.2 μg/L at 24 hours. The saliva-to-plasma ratio varied from 32.3 to 1.2, with a peak of 18.1 at 1.5 hours. Salivary pH decreased by 0.6 units after drug administration, from a predose mean of 7.4 to 6.9 at 1.5 hours and 6.8 at 4 hours. Measuring MDMA in saliva offers a noninvasive alternative to plasma testing for clinical and toxicologic studies.
Annals of the New York Academy of Sciences
August 1, 2006
Sergio Abanades, Magı́ Farré, Mireia Segura et al.
124 citations
Gamma-hydroxybutyrate (GHB) produces dose-related changes in subjective effects, showing a mixed stimulant-sedative pattern: initial feelings of euphoria, high, and liking, followed by mild-to-moderate sedation with impaired performance and balance. Single oral doses of 40, 50, 60, and 72 mg/kg were given to eight volunteers. Mean peak plasma concentrations ranged from 79.1 to 130.1 μg/L. Physiological and subjective effects were dose-dependent and related to plasma concentrations. Urinary excretion was mainly related to dose. The results suggest high abuse liability at the doses typically consumed.
Journal of Analytical Toxicology
April 1, 2002
Nieves Pizarro, Jordi Ortuño, Mercè Farré et al.
113 citations
A gas chromatography-mass spectrometry method simultaneously measured MDMA and its metabolites MDA, HMMA, and HMA in plasma and urine from healthy volunteers given 100 mg of MDMA. Samples were hydrolyzed, extracted with solid-phase columns, and analyzed as trifluoroacyl derivatives. Linear calibration covered plasma and urine ranges of 25–400 ng/mL and 250–2000 ng/mL for MDMA and HMMA, and 2.5–40 ng/mL and 100–1000 ng/mL for MDA and HMA. A capillary electrophoresis method using (2-hydroxy)propyl-beta-cyclodextrin as chiral selector resolved enantiomers without derivatization, with linear ranges for each enantiomer of MDMA, MDA, and HMMA. Stereoselective disposition of MDMA and MDA was confirmed, while HMMA showed an enantiomer ratio near 1 and constant over time, contradicting MDMA findings.
Frontiers in Genetics
January 1, 2012
Rafael de la Torre, Samanta Yubero‐lahoz, Ricardo Pardo‐lozano et al.
108 citations
The metabolism of amphetamine-like psychostimulants is regulated by the polymorphic enzyme CYP2D6. Methamphetamine acts as a weak substrate and competitive inhibitor of CYP2D6, while MDMA is a high-affinity substrate and potent mechanism-based inhibitor, causing all users to phenocopy the poor metabolizer phenotype regardless of genotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than in vitro studies suggest, with other cytochrome P450 isoenzymes and renal excretion contributing significantly. Overall, the clinical relevance of CYP2D6 polymorphism is lower than predicted by in vitro findings.
Chemical Research in Toxicology
August 2, 2001
Mireia Segura, Jordi Ortuño, Magı́ Farré et al.
105 citations
A new method using strong cation-exchange solid-phase extraction and high-performance liquid chromatography with electrochemical detection was validated for measuring the metabolite 3,4-dihydroxymethamphetamine (HHMA) in plasma and urine. Applied to samples from healthy volunteers given MDMA (ecstasy), HHMA appeared as a major metabolite, with peak plasma concentrations (154.5 microg/L) and overall exposure (AUC 1990.9 microg/L h) similar to those of MDMA itself. Urinary recovery of HHMA over 24 hours accounted for 17.7% of the 100 mg MDMA dose, raising total recovery of MDMA and its metabolites to 58%. The method is accurate and precise for pharmacokinetic studies, and measuring HHMA may help clarify its role in MDMA metabolism and potential neurotoxicity.
Journal of Psychopharmacology
May 20, 2006
Jiansong Yang, Masoud Jamei, Amir Heydari et al.
89 citations
A physiologically-based model of drug metabolism predicted that a typical recreational dose of MDMA (ecstasy) inactivates most hepatic CYP2D6 within an hour, and that recovery to basal CYP2D6 levels takes at least 10 days. The analysis suggests that genetic polymorphism of CYP2D6 and coadministration of CYP2D6 inhibitors may have less impact on MDMA's pharmacokinetics and acute toxicity risk than previously thought, consistent with clinical observations showing no obvious link between inherited CYP2D6 deficiency and acute MDMA intoxication.
PLoS ONE
June 27, 2014
Kim P. C. Kuypers, Rafael de la Torre, Magı́ Farré et al.
88 citations
A single 75 mg dose of MDMA selectively enhances emotional empathy—the ability to share and understand others' feelings—without affecting cognitive empathy (understanding others' mental states), trust, or reciprocity in social interactions. This effect was not altered by adding pindolol, a drug that blocks the 5-HT1A serotonin receptor. Oxytocin nasal spray, a hormone often linked to social bonding, had no effect on any empathy or social interaction measure. Changes in emotional empathy were unrelated to oxytocin levels in the blood. The findings suggest that MDMA's empathy-enhancing effects do not depend on peripheral oxytocin and may instead involve other receptors such as serotonin 2A or vasopressin 1A.
Journal of Chromatography B
October 11, 2002
Mercedes Yritia, Jordi Riba, Jordi Ortuño et al.
84 citations
A method to measure the four main alkaloids in ayahuasca (DMT, harmine, harmaline, and tetrahydroharmine) plus two major metabolites (harmol and harmalol) in human plasma is described. DMT is extracted with n-pentane and quantified by gas chromatography with nitrogen-phosphorus detection, achieving 74% recovery, precision and accuracy better than 9.9%, and a limit of quantification of 1.6 ng/ml. The beta-carbolines and metabolites are measured by high-performance liquid chromatography with fluorescence detection after solid-phase extraction, with recoveries above 87%, accuracy and precision better than 13.4%, and limits of quantification from 0.3 to 1.0 ng/ml. The methods allow adequate characterization of the pharmacokinetics of these compounds, including two major metabolites not previously described.
Journal of Clinical Psychopharmacology
December 1, 2007
Sergio Abanades, Magı́ Farré, Diego Barral et al.
69 citations
A single oral dose of gamma-hydroxybutyric acid (GHB) at 40 or 60 mg/kg produces euphoria and pleasurable effects with slightly higher ratings than those from flunitrazepam (1.25 mg) or ethanol (0.7 g/kg) in healthy male recreational club drug users. GHB shows a biphasic time profile: an initial stimulant-like effect as plasma concentrations rise, followed by a later sedative effect unrelated to its kinetics. GHB increases blood pressure and pupil diameter, while flunitrazepam produces marked sedation. Both GHB and flunitrazepam impair psychomotor performance, including digit symbol substitution and balance tasks, whereas ethanol only mildly affects balance. The findings suggest a high abuse liability of GHB and flunitrazepam in this population.
Journal of Clinical Psychopharmacology
September 12, 2008
Brian O’Mathúna, Magı́ Farré, Amin Rostami‐hodjegan et al.
68 citations
MDMA (ecstasy) strongly inhibits the liver enzyme CYP2D6, which is responsible for metabolizing many drugs. In a controlled trial with 15 healthy men, a single 1.5 mg/kg oral dose of MDMA increased blood levels of the probe drug dextromethorphan about tenfold and reduced its breakdown product dextrorphan. The urinary metabolic ratio rose nearly 100-fold, and two-thirds of participants temporarily showed a metabolic profile typical of poor metabolizers. CYP2D6 activity recovered after 10 days, with a half-life of 46.6 hours. Users should be warned that MDMA can dangerously alter the metabolism of other medications.
British Journal of Pharmacology
January 1, 2005
Isabel Escobedo, Esther O’shea, Laura Orío et al.
68 citations
MDMA itself does not cause the immediate release of dopamine or serotonin in the mouse brain; instead, peripheral injection of MDMA reduced striatal dopamine and modestly reduced serotonin one hour after the last dose, but direct injection into the striatum did not produce these acute effects. The metabolite HHMA also did not contribute to acute dopamine depletion, as its effects differed from MDMA after peripheral injection. Long-term dopamine loss seven days later was not due to MDMA itself, since only very high intrastriatal doses caused such loss, and HHMA did not alter striatal dopamine after peripheral injection. HHMA crossed the blood–brain barrier but was not detected in brain after peripheral MDMA, suggesting it is metabolized to other active compounds.
Therapeutic Drug Monitoring
February 1, 2007
Sergio Abanades, Magı́ Farré, Mireia Segura et al.
66 citations
After a single oral dose of 50 mg/kg sodium GHB, mean peak plasma concentrations reached 83.1 μg/mL at 30 minutes, then declined to 0.9 μg/mL at 6 hours. GHB appeared in oral fluid at levels one-third to one-fourth of plasma concentrations, with a half-life of about 1.2 hours compared to 0.7 hour in plasma. Less than 2% of the dose was excreted in urine, and sweat contained only low concentrations. Subjective effects followed a mixed sedative-stimulant pattern, peaking between 1 and 1.5 hours and lasting 2 hours, and were related to plasma concentrations. Oral fluid and sweat were not suitable for monitoring GHB consumption.
Journal of Analytical Toxicology
July 1, 2003
Simona Pichini, M.d. Sánchez Navarro, Roberta Pacifici et al.
66 citations
After a single 100-mg dose of MDMA, the drug appears in sweat within 1.5 hours and peaks at 24 hours, but the amount varies up to 30-fold between individuals, ranging from 3.2 to 1326.1 ng per patch. Only traces of the metabolite MDA are detected. An onsite sweat strip test is positive at 1.5 hours, though 18% false-negative results occur in the first 6 hours. Sweat patch and onsite strip testing offer noninvasive ways to monitor MDMA use.
Frontiers in Pharmacology
March 13, 2018
Esther Papaseit, Marta Torrens, Mireia Ventura et al.
61 citations
2C-B, a psychedelic similar to mescaline, acts on serotonin receptors and produces mild psychedelic and stimulant-like effects. In an observational study, 16 healthy experienced users took 10–20 mg orally. The drug increased blood pressure and heart rate, elevated scores on scales for euphoria, liking, and stimulation, and altered perceptions of distances, colors, shapes, and lights. Five participants reported mild hallucinations. Peak 2C-B levels in saliva occurred at 1 hour, and peak cortisol at 3 hours. The effects resemble those of other serotonin-acting drugs.
Journal of Psychopharmacology
January 21, 2008
Susana de Sola Llopis, Mónica Miguélez-Pan, Jordi Peña‐Casanova et al.
58 citations
Recreational ecstasy use, often alongside cannabis, is linked to lasting cognitive deficits. Over two years, regular ecstasy users performed worse than cannabis-only users and non-users on tests of verbal fluency, working memory, and processing speed. Heavier users (more than 100 tablets) also showed impairments in episodic memory. These deficits persisted across the study period. The findings suggest that ecstasy, possibly combined with cannabis, causes subtle but lasting cognitive harm, though pre-existing differences between groups cannot be ruled out.
Rapid communications in mass spectrometry : RCM
January 1, 2005
Simona Pichini, Sergio Abanades, Magí Farré et al.
58 citations
A gas chromatography–mass spectrometry method was developed and validated to measure Salvinorin A, the main active compound in the hallucinogenic plant Salvia divinorum, in plasma, urine, saliva, and sweat. The method uses 17-alpha-methyltestosterone as an internal standard and extracts the compound with a chloroform/isopropanol mixture. It was validated over a concentration range of 0.015–5 microg/mL for plasma, urine, and saliva, and 0.01–5 microg/patch for sweat, with mean recoveries of 77.1–92.7% and precision and accuracy better than 15%. When applied to two consumers after smoking 75 mg of plant leaves, Salvinorin A was detected in urine (2.4 and 10.9 ng/mL) and saliva (11.1 and 25.0 ng/mL), but not in sweat patches.
Annals of the New York Academy of Sciences
June 1, 2002
Roberta Pacifici, P. Zuccaro, Magı́ Farré et al.
58 citations
Repeated use of MDMA ('ecstasy') causes time-dependent immune dysfunction similar to a single dose, but the second dose extends the period of impaired immunocompetence. The drug decreases CD4 T-helper cells, increases natural killer (NK) cells, and reduces lymphocyte responsiveness to stimulation. In poor metabolizers, MDMA accumulation produces greater immunomodulatory effects, including significant differences in NK cell function. Recreational MDMA users show long-term alterations: reduced lymphocytes, T cells, and CD4 cells (though within normal limits), and NK cells reduced to one-third of healthy levels. Over two years, a subgroup showed statistically significant decreases in immune parameters, potentially increasing susceptibility to infection and immune disorders.
Journal of Analytical Toxicology
March 1, 2001
Roberta Pacifici, Magı́ Farré, Simona Pichini et al.
50 citations
After a single 100 mg oral dose of MDMA, the Drugwipe immunochemical strip test detected the drug in sweat from two volunteers as early as 2 hours and up to 12 hours later. However, one volunteer showed a faint positive result before dosing, when plasma and urine were negative, and this persisted beyond 48 hours. Gas chromatography-mass spectrometry measured peak plasma concentrations of MDMA and its metabolite HMMA at 2-4 hours, with levels above 20 ng/mL and 40 ng/mL respectively still present at 24 hours. Urine remained positive for both substances over 48 hours. These results suggest sweat testing with Drugwipe may be useful for monitoring MDMA use.
Annals of the New York Academy of Sciences
September 1, 2000
Roberta Pacifici, P. Zuccaro, Magı́ Farré et al.
44 citations
MDMA (ecstasy) use produces neurochemical, behavioral, and endocrine changes similar to acute stress, acting as a chemical stressor. In rats, MDMA rapidly suppressed lymphocyte proliferation, decreased circulating lymphocytes, and increased plasma corticosterone. In humans, acute MDMA caused time-dependent immune dysfunction: CD4+ T-cells and lymphocyte responsiveness to stimulation decreased, while natural killer cells increased; total leukocyte count remained unchanged. Cortisol rose similarly to the rat model, suggesting MDMA triggers corticotrophin-releasing factor release from the hypothalamus, activating the HPA axis and sympathetic nervous system. These findings indicate MDMA ingestion may increase risk for immune system-related diseases.
Journal of Analytical Toxicology
October 3, 2016
Eulàlia Olesti, Mitona Pujadas, Esther Papaseit et al.
41 citations
Mephedrone, a synthetic cathinone increasingly used by young people and linked to acute intoxication and fatalities, was studied in a controlled clinical trial. A gas chromatography-mass spectrometry method was developed to measure mephedrone in human plasma and urine. Six healthy men received 150 mg of mephedrone orally. Peak plasma concentration averaged 122.6 ng/mL, reached within 0.5–2 hours, and the drug was eliminated rapidly with a half-life of 2.2 hours. Less than 15% of the dose appeared unchanged in urine, and concentrations varied widely among individuals.
European Journal of Neuroscience
July 15, 2004
Patricia Robledo, Victoria Mendizábal, Jordi Ortuño et al.
40 citations
The rewarding effects of MDMA do not require µ-opioid receptors, unlike those of opioids, ethanol, nicotine, and THC. In mice lacking µ-opioid receptors, MDMA still produced a conditioned place preference and increased dopamine release in the nucleus accumbens, while decreasing dopamine metabolites DOPAC and HVA. Basal dopamine and metabolite levels were similar between knockout and wild-type mice. The findings indicate that MDMA's effects on dopamine neurons are independent of µ-opioid receptor activation.