E. Menoyo

Pharmacology of MDMA in Humans

MDMA given at recreational doses (range tested 50 to 150 mg) to healthy volunteers, produced mydriasis and marked increases in systolic and diastolic blood pressure, heart rate, and pupillary diameter. MDMA induced changes on oral temperature. The time course of this observation was biphasic, as a slight decrease at 1 h and a slight increase at 2 and 4 h were observed. MDMA induced a slight dose‐dependent impairment on psychomotor performance. MDMA produced a marked rise in plasma cortisol and prolactin concentrations. The elimination half‐life of MDMA was about 8‐9 h. Drug concentrations increased, and a parallel increase in physiologic and hormonal measures was observed. Both peak concentrations and peak effects were obtained between 1 and 2 h and decreased to baseline values 4‐6 h after drug administration.

Cell‐Mediated Immune Response in MDMA Users After Repeated Dose Administration

Abstract: Acute administration of 3,4‐methylenedioxymethamphetamine (MDMA, “ecstasy”) produces time‐dependent immune dysfunction in humans. Recreational use of MDMA generally includes repeated drug consumption, often in association with other drugs, such as alcohol and cannabis. In the laboratory setting, repeated MDMA administration to healthy MDMA consumers produced a time‐dependent immune dysfunction similar to that observed with the ingestion of a single dose, and the first of the two administrations paralleled the time‐course of MDMA‐induced cortisol stimulation kinetics and MDMA plasma concentrations. A significant decrease in CD4 T‐helper cells with simultaneous increase in natural killer (NK) cell and a decrease in functional responsiveness of lymphocytes to mitogenic stimulation was observed. Response to the second dose was either long‐lasting compared with the first dose or disproportionate and did not show any parallelism with cortisol and MDMA plasma concentrations. This circumstance extended the critical period during which immunocompetence is highly impaired as a result of MDMA use. Accumulation of MDMA in the body of a poor metabolizer induced higher immunomodulatory effects with statistically significant differences in NK cell function compared with extensive metabolizers. When basal values of lymphocyte subsets were examined in a population of recreational MDMA users participating in different clinical trials, alterations in several immunological parameters were observed. The absolute number of lymphocytes, in particular T lymphocytes and CD4 T‐helper cell subsets, showed a trend toward reduced values, although cell counts were within normal limits. By contrast, NK cells in MDMA consumers were reduced to one‐third of those from healthy persons. A statistically significant decrease in affected immune parameters was recorded during a 2‐year observation period in a subgroup of recreational MDMA users. These permanent alterations in immunologic homeostasis may result in impairment of general health and subsequent increased susceptibility to infection and immune‐related disorders.

Effects of repeated doses of MDMA ("ecstasy") on cell-mediated immune response in humans.

Cell-mediated immune response after the administration of two repeated doses of 100 mg 3,4-methylenedioxymethamphetamine (MDMA) at 4-hour and 24-hour intervals was evaluated in two randomised, double-blind and cross-over clinical trials conducted in healthy male MDMA consumers. MDMA produced a time-dependent decrease in the CD4/CD8 T-cell ratio due to a decrease in the number of CD4 T-helper cells, a decrease in the functional responsiveness of lymphocytes to mitogenic stimulation, and a simultaneous increase in natural killer cells. In case of two 100 mg MDMA doses given 4 hour apart, immune alterations produced by the first dose were strengthened by the second one. At 24 hours after treatment, statistically significant residual effects were observed for all the altered immune parameters after the administration of two MDMA doses if compared to single dose and placebo. In the second clinical trial, the second 100 mg MDMA dose given 24 hours after the first dose produced immunological changes significantly greater than those induced by the initial drug administration and which seemed to show a delayed onset. Significant residual effects were observed for all the immune parameters as late as 48 hours after the second dose. These results show that repeated administration of MDMA with both a short and a long time interval between doses extends the critical period following MDMA administration, already observed after a single dose, in which immunocompetence is severely compromised.

Modulation of rate of onset and intensity of drug effects reduces abuse potential in healthy males

Low, medium, and high doses of flunitrazepam were tested in three independent randomized, double-blind, balanced cross-over, placebo-controlled trials to study the influence of rate of onset of effects and dose administered on its acute effects. Three groups of 12 healthy male volunteers received six oral doses of placebo or flunitrazepam in slow and fast onset conditions as follows: six capsules of 0.16 mg (slow) and a single capsule of 0.8 mg (fast) in the low dose trial; six 0.25 mg (slow) and a single 1.25 mg (fast) capsules for medium dose; and six 0.4 mg (slow) and a single 2 mg (fast) capsule for high dose. At each dose level, slow or fast increasing flunitrazepam plasma concentrations lead to similar peak levels, but induced differential subjective and behavioral effects. In addition to objective and subjective sedation, flunitrazepam induced some pleasurable feelings, which were more intense in the fast than in the slow conditions. At the highest dose, unpleasant sedative effects surmounted positive effects, while at the lowest dose pleasurable effects were of low intensity. At the medium dose, the balance between pleasurable and unpleasant feelings resulted in euphorigenic effects, which were evident in the fast condition but were blunted in the slow condition.

Bilastine vs. hydroxyzine: occupation of brain histamine H1‐receptors evaluated by positron emission tomography in healthy volunteers

Aim A close correlation exists between positron emission tomography (PET)-determined histamine H1-receptor occupancy (H1RO) and the incidence of sedation. Antihistamines with H1RO <20% are classified as non-sedating. The objective was to compare the H1RO of bilastine, a second generation antihistamine, with that of hydroxyzine. Methods This randomized, double-blind, crossover study used PET imaging with [11C]-doxepin to evaluate H1RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H1ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated. Results The mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H1RO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine. Conclusions A single oral dose of bilastine 20 mg had minimal H1RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine.

Ethanol induces hydroxytyrosol formation in humans.

Previous studies in animals have shown an increase of hydroxytyrosol (OHTyr), a potent phenolic antioxidant and a minor metabolite of dopamine (also called 3,4-dihydroxyphenylethanol or DOPET), after ethanol intake. The interaction between ethanol and dopamine metabolism is the probable mechanism involved. The aim of the study was to establish the contribution of the dose of ethanol on OHTyr formation. 24 healthy male volunteers were included. Subjects were distributed in three different cohorts and each volunteer received two doses of ethanol or placebo. Doses of ethanol administered were 6, 12, 18, 24, 30 and 42 g. Study design was double-blind, randomized, crossover and controlled. Hydroxytyrosol, tyrosol (Tyr), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) urinary excretion, ethanol plasma concentrations and drunkenness were evaluated along a 6-h period. Urinary excretion of OHTyr and Tyr increased with ethanol administered dose. A reduction in the ratio DOPAC/OHTyr from placebo to the highest dose was observed, compatible with a shift in the dopamine metabolism to preferently produce OHTyr instead of DOPAC. Also a dose-dependent increase in plasma ethanol concentrations and subjective effects was observed. This study demonstrates an endogenous production of OHTyr and Tyr in relation to ethanol administered dose in humans. Biological effects of both phenols from this source should be investigated in future studies.

Cannabis Users Show Enhanced Expression of CB 1 -5HT 2A Receptor Heteromers in Olfactory Neuroepithelium Cells

Cannabinoid CB1 receptors (CB1R) and serotonergic 2A receptors (5HT2AR) form heteromers in the brain of mice where they mediate the cognitive deficits produced by delta-9-tetrahydrocannabinol. However, it is still unknown whether the expression of this heterodimer is modulated by chronic cannabis use in humans. In this study, we investigated the expression levels and functionality of CB1R-5HT2AR heteromers in human olfactory neuroepithelium (ON) cells of cannabis users and control subjects, and determined their molecular characteristics through adenylate cyclase and the ERK 1/2 pathway signaling studies. We also assessed whether heteromer expression levels correlated with cannabis consumption and cognitive performance in neuropsychological tests. ON cells from controls and cannabis users expressed neuronal markers such as βIII-tubulin and nestin, displayed similar expression levels of genes related to cellular self-renewal, stem cell differentiation, and generation of neural crest cells, and showed comparable Na+ currents in patch clamp recordings. Interestingly, CB1R-5HT2AR heteromer expression was significantly increased in cannabis users and positively correlated with the amount of cannabis consumed, and negatively with age of onset of cannabis use. In addition, a negative correlation was found between heteromer expression levels and attention and working memory performance in cannabis users and control subjects. Our findings suggest that cannabis consumption regulates the formation of CB1R-5HT2AR heteromers, and may have a key role in cognitive processing. These heterodimers could be potential new targets to develop treatment alternatives for cognitive impairments.

Efectos farmacológicos y farmacocinética del éxtasis tras la administración de dos dosis repetidas en humanos

Introduccion La metilenodioximentanfetamina (MDMA, extasis, pastillas) es una de las drogas de abuso mas utilizadas entre la juventud espanola. Ademas de provocar casos de intoxicaciones agudas e incluso la muerte, la gran preocupacion de su uso es la posibilidad de que produzca efectos toxicos y degeneracion en las neuronas serotonergicas. Esta neurotoxicidad se ha demostrado en modelos experimentales en animales. Los efectos neurotoxicos en humanos son aun motivo de investigacion, aunque se ha descrito que los grandes consumidores pueden presentar alteraciones leves de la memoria y mayor incidencia de psicopatologia. El consumo de MDMA se realiza en grupos, predominando su uso en fiestas y actos multitudinarios (raves). Es frecuente que se utilice la MDMA junto a otras drogas de abuso en la misma sesion festiva. Mas de la mitad de los consumidores toman mas de una dosis, con un promedio de unas 2,5 pastillas (intervalo entre menos de una y hasta varias docenas). El intervalo de tiempo entre dosis es variable. No existen estudios experimentales en humanos de la administracion a dosis repetida de la MDMA. En el caso de otros estimulantes como la cocaina y anfetamina se ha descrito la aparicion de tolerancia aguda (taquifilaxia) a sus efectos. Este estudio fue disenado para investigar los efectos farmacologicos y la farmacocinetica de la MDMA tras la administracion de dos dosis separadas por 4 horas. Sujetos, material y metodos Se seleccionaron 8 varones consumidores recreacionales de MDMA. Participaron voluntariamente tras ser informados en cuatro sesiones experimentales separadas por una semana. En cada sesion se administro uno de los siguientes tratamientos (intervalo de cuatro horas): placebo ± placebo (placebo); placebo ± MDMA 100 mg (segunda administracion); MDMA 100 mg + placebo (primera administracion); MDMA 100 mg + MDMA 100 mg (dosis repetida). Los tratamientos se administraron enmascarados a doble ciego, fueron asignados de forma aleatoria y el diseno fue cruzado. Se evaluaron variables de efectos fisiologicos (presion arterial, frecuencia cardiaca, temperatura, diametro pupilar), rendimiento psicomotor (ala de Maddox, tiempo de reaccion, DSST, Test de Pauli), efectos subjetivos (escalas analogicas visuales, cuestionario ARCI-reducido), se extrajeron muestras de sangre para determinar las concentraciones de MDMA y sus metabolitos (HMMA, HMA, MDA) y de hormonas (cortisol y prolactina). Resultados Las concentraciones de MDMA tras la dosis repetida fueron superiores en un 20% a las esperadas por el principio farmacocinetico de superposicion. Pero las concentraciones de la HMMA fueron inferiores en un 45% a las esperadas. Parece que existe una inhibicion de la formacion de este metabolito. En cuanto a los efectos farmacologicos, a pesar de que las concentraciones en sangre eran mas del doble, en algunos de ellos los efectos de la segunda dosis fueron similares a los observados tras una dosis unica (frecuencia cardiaca, diametro pupilar, ARCI). En otras variables los efectos de la segunda dosis fueron mayores que los de la primera (presion arterial, efectos subjetivos de las EAV). En ambos casos teniendo en cuenta las concentraciones plasmaticas se observo una tolerancia aguda clara. En los efectos psicomotores y la temperatura la dosis repetida produjo efectos mucho mayores de los esperados, que demostraron que no existio tolerancia. Incluso podria existir hipersensibilidad. Conclusiones La administacion de dos dosis repetidas de MDMA no produce incrementos proporcionales de los efectos placenteros pero incrementa los efectos musculares y la temperatura. Puede por ello incrementarse el riesgo de toxicidad. Agradecimientos Este estudio se ha realizado gracias a las ayudas FIS 98/0181, CIRIT 1999SGR00246 y Plan Nacional sobre Drogas.