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.
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.
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.
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.
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.
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.
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.
Addiction
May 22, 2007
Roberta Pacifici, Piergiorgio Zuccaro, Magı́ Farré et al.
39 citations
People who use both MDMA (ecstasy) and cannabis show long-term changes in immune function, including lower levels of interleukin-2 and higher levels of anti-inflammatory transforming growth factor beta-1, along with fewer total lymphocytes, CD4 cells, and natural killer cells. These immune alterations persisted over one year. Regular users of both drugs had a higher rate of mild infections compared to occasional users and those who used only cannabis or neither drug. Cannabis-only users showed intermediate immune changes. The findings suggest that sustained disruption of immune balance may lead to poorer general health and greater susceptibility to infections.
Frontiers in Pharmacology
July 11, 2017
Drew J. Puxty, Johannes G. Ramaekers, Rafael de la Torre et al.
33 citations
A single 75 mg dose of MDMA produces a dissociative state, marked by feelings of depersonalization and derealization, in healthy recreational users. Blocking the 5-HT2 receptor with ketanserin did not prevent this effect, indicating that the 5-HT2 receptor does not mediate MDMA-induced dissociation. Heart rate correlated with the dissociative state after MDMA alone, but not when ketanserin was given, suggesting heart rate changes do not directly cause dissociation. Cortisol levels and MDMA blood concentrations showed no clear relationship with dissociation. The exact neurobiological mechanism remains unknown and may be relevant to MDMA's therapeutic use.
Frontiers in Pharmacology
January 28, 2020
Esther Papaseit, Clara Pérez-mañá, Elizabeth B. de Sousa Fernandes Perna et al.
27 citations
Combining mephedrone with alcohol amplifies cardiovascular effects and intensifies euphoria and well-being compared to either drug alone, while mephedrone reduces the sedative effects of alcohol. In a double-blind, placebo-controlled trial with 11 male volunteers, the combination increased blood pressure, heart rate, and subjective feelings of euphoria. Mephedrone alone and alcohol alone were also tested. The results suggest that the abuse liability of mephedrone is greater when taken with alcohol, similar to other psychostimulants like amphetamines and MDMA.
Frontiers in Pharmacology
March 18, 2020
Esther Papaseit, Marta Torrens, Mireia Ventura et al.
20 citations
2C-E, a psychedelic phenylethylamine similar to mescaline, acts as a partial agonist at serotonin 2A, 2B, and 2C receptors and inhibits norepinephrine and serotonin uptake. In an observational study, ten recreational psychedelic users self-administered single oral doses of 2C-E (6.5–25 mg). The drug induced alterations in perception, hallucinations, and euphoric mood, with saliva concentrations peaking 2 hours after administration. The effects resembled those of 2C-B and other serotonin-acting drugs.
Biomedicine & Pharmacotherapy
March 24, 2022
Francisco Madrid-Gambín, Àlex Gomez‐gómez, Arnau Busquets-García et al.
14 citations
Consumption of ayahuasca increases N-acyl-ethanolamine endocannabinoids, decreases 2-acyl-glycerol endocannabinoids, and alters several large-neutral amino acids (LNAAs) in human plasma. Most LNAAs were inversely associated with nine of eleven subscales of the 5-Dimension Altered States of Consciousness Rating Scale, except tryptophan, which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in pathways involved in serotonin and dopamine synthesis. A crosstalk between circulating LNAAs and subjective effects is suggested, independent of alkaloid concentrations, providing insights into the metabolic fingerprint and mechanism of action underlying ayahuasca experiences.
British Journal of Clinical Pharmacology
February 1, 2000
Rafael de la Torre, Magı́ Farré, Jordi Ortuño et al.
MDMA (ecstasy) shows nonlinear pharmacokinetics in humans: as the dose increases, plasma concentrations rise disproportionately, meaning small dose increases lead to much higher drug levels. In a controlled trial with 14 healthy volunteers given 50–150 mg, urinary recovery of the metabolite HMMA stayed constant while MDMA recovery rose, suggesting saturation or inhibition of the demethylenation metabolic step. Nonrenal clearance was dose-dependent while urinary clearance remained constant. This nonlinearity occurs regardless of CYP2D6 genotype, implying that even moderate dose increases in recreational use can produce unexpectedly high plasma concentrations, raising the risk of acute toxicity for all users, not just the 10% genetically deficient in CYP2D6.