Daytime Ayahuasca administration modulates REM and slow-wave sleep in healthy volunteers.

OBJECTIVES: Ayahuasca is a traditional South American psychoactive beverage and the central sacrament of Brazilian-based religious groups, with followers in Europe and the United States. The tea contains the psychedelic indole N,N-dimethyltryptamine (DMT) and beta-carboline alkaloids with monoamine oxidase-inhibiting properties that render DMT orally active. DMT interacts with serotonergic neurotransmission acting as a partial agonist at 5-HT(1A) and 5-HT(2A/2C) receptor sites. Given the role played by serotonin in the regulation of the sleep/wake cycle, we investigated the effects of daytime ayahuasca consumption in sleep parameters. MEASUREMENTS AND RESULTS: Subjective sleep quality, polysomnography (PSG), and spectral analysis were assessed in a group of 22 healthy male volunteers after the administration of a placebo, an ayahuasca dose equivalent to 1 mg DMT kg(-1) body weight, and 20 mg d-amphetamine, a proaminergic drug, as a positive control. Results show that ayahuasca did not induce any subjectively perceived deterioration of sleep quality or PSG-measured disruptions of sleep initiation or maintenance, in contrast with d-amphetamine, which delayed sleep initiation, disrupted sleep maintenance, induced a predominance of 'light' vs 'deep' sleep and significantly impaired subjective sleep quality. PSG analysis also showed that similarly to d-amphetamine, ayahuasca inhibits rapid eye movement (REM) sleep, decreasing its duration, both in absolute values and as a percentage of total sleep time, and shows a trend increase in its onset latency. Spectral analysis showed that d-amphetamine and ayahuasca increased power in the high frequency range, mainly during stage 2. Remarkably, whereas slow-wave sleep (SWS) power in the first night cycle, an indicator of sleep pressure, was decreased by d-amphetamine, ayahuasca enhanced power in this frequency band. CONCLUSIONS: Results show that daytime serotonergic psychedelic drug administration leads to measurable changes in PSG and sleep power spectrum and suggest an interaction between these drugs and brain circuits modulating REM and SWS.

Fármacos que pueden producir somnolencia excesiva / Drugs promoting excessive sleepiness

La somnolencia es un acontecimiento frecuente y fisiológico en ciertas circunstancias. La somnolencia excesiva durante el día se caracteriza por una sensación anormal de sueño con fuerte tendencia a dormirse en situaciones o momentos inapropiados, que debe diferenciarse de la fatiga. Entre las posibles causas de una somnolencia excesiva diurna está el consumo de fármacos. Hay dos posibilidades por las que los fármacos pueden considerarse como agentes etiológicos: a) a través de un mecanismo indirecto (compuestos que alteran la cantidad y la calidad del sueño y condicionan su fragmentación o deprivación) o b) por un efecto directo que propicia de forma mediada un aumento de la somnolencia diurna. Este favorecimiento de la somnolencia diurna debería identificarse como reacción adversa. Se describen los nuevos términos que la investigación de los mecanismos implicados en el control de la sucesión de sueño-vigilia está introduciendo en la farmacología de los fármacos productores de sueño: hipnóticos, promotores del sueño, intensificadores del sueño, modificadores de la biestabilidad y cronobióticos. Se identifican los factores farmacocinéticos que principalmente determinan la duración del efecto hipnótico tras administración única (volumen de distribución) y tras administración múltiple (eliminación) y se expone la importante variación interindividual en la frecuencia e intensidad con que los fármacos inducen una somnolencia excesiva. Por último, se completa la visión del posible impacto de los fármacos sobre el ciclo sueño-vigilia refiriendo los posibles efectos durante la noche de los fármacos tomados por la mañana, enfatizando la importancia de considerar el proceso como un todo continuo y no como compartimentos estancos (AU)

In certain circumstances sleepiness is a frequent and physiological event. Excessive daytime sleepiness is characterized by an abnormal sleep sensation with a strong tendency to fall asleep in inappropriate situations and time moments, which should be differentiated from fatigue. Among the possible causes of excessive daytime sleepiness there is drug consumption. There are two different possibilities to consider drugs as etiological agents: a)thought an indirect mechanism (compounds disrupting sleep quantity and quality resulting in sleep fragmentation or deprivation) or b) by a straight effect directly promoting an increase of daytime sleepiness. This promotion of daytime sleepiness should be identified as an adverse reaction. The new terms that research on the mechanisms which control the wake-sleep cycle is introducing in the pharmacology of drugs favouring sleep are described: hypnotics, sleep promoters, sleep enhancers, bi-stability modifiers and chronobiotics. The pharm acokinetic factors which mainly determine the duration of the hypnotic effects are identified, either after a single administration (volume of distribution) or after a repetitive administration (elimination) and the important interindividual variation in frequency and intensity of drug induced excessive sleepiness is explained. Lastly, the description of the potential drug impact on the wake-sleep cycle is completed by referring thee ventual effects that drug ingestion at morning time could induce during the night, highlighting the importance to consider the process as a continuum non-compartmental one (AU)

Effects of tobacco smoking on the kinetics of the pupillary light reflex: a comparison between smokers and non-smokers.

BACKGROUND: The time course of the pupillary light reflex (PLR) is determined by the successive activation of parasympathetic and sympathetic innervations of the iris, latency and amplitude reflecting parasympathetic activity and recovery time showing mainly sympathetic activity. OBJECTIVE: To determine the effects of tobacco cigarette smoking on the PLR in smokers after an abstinence period of at least 12 h. METHODS: Ten smokers (mean 15.7 cigarettes/day) and 10 non-smokers participated in a randomised, non-intervention controlled, cross-over study that included a parallel control group. Smokers underwent two sessions with a time interval between 3 and 8 days; two recordings were taken at each session, separated by 20 min: session 1, without smoking, and session 2, smoking 3 cigarettes within a 30-min period. Non-smokers underwent one session; two recordings were taken separated by 20 min. At each recording, in both groups, PLR was elicited with four light flashes of increasing luminance. RESULTS: The relationship between PLR parameters and light intensity was linear in each subject. The slope of the regression line for relative amplitude increase versus intensity was significantly flatter in abstinent smokers than in non-smokers (p=0.033); the slope returned significantly after smoking (p=0.043). No other significant effects were obtained. CONCLUSIONS: Kinetic parameters of PLR provide a sensitive pharmacological test to detect cholinergic neurotransmission manipulation effects, as they seem to detect changes in moderate smokers after 12 h of abstinence, and their reversal on return to smoking. These results suggest an enhancement in the suppression of the parasympathetic oculomotor reflex arc rather than a facilitation of the sympathetic drive to the iris.

Acción de los antidepresivos sobre las fases del sueño: componentes tónicos y fásicos / Action of antidepressants on the phases of sleep: tonic and phasic components

Se presentan los efectos descritos para los antidepresivos sobre el sueño (actividad REM, sueño de ondas lentas, continuidad del sueño, microestructura y ensoñaciones). Se describen como numerosos, diversos y no siempre consistentes, con lo que se reconoce la limitación del conocimiento actualmente disponible. Se exponen las diferencias en el perfil farmacológico que podrían estar implicadas, básicamente: a) la participación del sistema serotoninérgico, aunque con implicación controvertida de los distintos subtipos de receptores, en la supresión REM; b) el antagonismo de los receptores 5HT2A/2C, el incremento del sueño de ondas lentas y la promoción de la continuidad del sueño; c) la participación en este último efecto del antagonismo α1 y H1, y d) la limitada responsabilización del sistema noradrenérgico. Se explicita la compleja relación entre ensoñaciones, fármacos antidepresivos, sueño REM y depresión. También se identifican las diferencias que implican los efectos agudos frente a los crónicos; las distintas dosis y perfiles farmacocinéticos en voluntarios sanos frente a pacientes deprimidos, y los cambios en la macroestructura (evaluación tradicional visual) frente a la microestructura (evaluación cuantitativa computarizada). Con el objetivo de disponer de una descripción más precisa de la relación entre la depresión, el sueño y el efecto antidepresivo, se sugiere la necesidad de llevar a cabo estudios en los que directamente se comparen distintos antidepresivos, utilizando diseños que comporten el control de todas las variables de confusión identificadas (AU)

The effects described for antidepressants on sleep (REM activity, slow wave sleep (SWS), sleep continuity, microstructure of sleep and dreams) are presented. These are described as numerous, diverse and not always consistent, the reason why the limitation of knowlege at the moment available is recognized.The differences in the pharmacological profile that could be implied basically are exposed below: (i) participation of serotonergic system although with a controversial implication of different types of receptors in REM sleep supression; (ii) the antagonism of 5HT 2A/2C receptors, the increase of SWS and the promotion of sleep continuity; (iii) the participation in this last effect of α1 and H1 antagonism; (iv) the limited implication of noradrenergic system. The complex relationship between dreams, antidepressants, REM sleep and depression is shown. Differences involved between acute effects vs chronic effects, different dosages and pharmacokinetic profiles in healthy volunteers vs depressed patients and changes in the macrostructure (traditional visual evaluation) vs microstructure (quantitative computerized evaluation) are also recognized. With the aim of having a more precise description of the relationship between depression, sleep and antidepressant effect, the necessity to carry out studies comparing directly different types of antidepressants using designs to control all the identified variables of confusion, is suggested (AU)

Evaluation of an automatic ocular filtering method for awake spontaneous EEG signals based on independent component analysis.

Electroencephalographic artifacts associated with eye movements are a potential source of error in the EEG analysis when its interpretation is performed for evaluating the influence of drugs and the diagnosis of neurological disorders. In this study, a new automatic method for artifact filtering based on independent component analysis (ICA) is proposed. Automatic artifact identification is based on frequency domain and scalp topography aspects of the independent components. A comparative study between ICA and the 'gold standard' method based on linear regression analysis is performed. The latter does not take into account the mutual contamination between EEG and electrooculographic activity, reducing not only the ocular movements but also interesting cerebral activity, mainly in anteriorly placed electrodes. This limitation is overcome by ICA and the efficiency of this approach is shown for a double-blind, placebo-controlled crossover drug trial in healthy volunteers.

Transcranial magnetic stimulation for treating depression.

BACKGROUND: Transcranial magnetic stimulation can either excite or inhibit cortical areas of the brain, depending on whether the speed of the repetitive stimulation is applied at high or low frequencies. It has been used for physiological studies and it has also been proposed as a treatment for depression. OBJECTIVES: To assess the clinical efficacy and safety of transcranial magnetic stimulation for treating depression. SEARCH STRATEGY: An electronic search was performed including the Cochrane Collaboration Depression, Neurosis and Anxiety Review Group trials register (last searched June, 2001), the Cochrane Controlled Trials Register (Issue 2, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), PsycLIT (1980-2001), and bibliographies from reviewed articles. Unpublished data and grey literature were searched through personal communications with researchers. SELECTION CRITERIA: Randomised controlled trials assessing the therapeutic efficacy and safety of transcranial magnetic stimulation for depression. DATA COLLECTION AND ANALYSIS: All reviewers independently extracted the information and verified it by cross-checking. Disagreements were resolved through discussion. Continuous data: When similar studies were grouped, the overall standardised mean difference was calculated under a fixed effect model weighted by the inverse variance method with 95% confidence intervals. (In the presence of statistical heterogeneity, a random effects model was to be used.) MAIN RESULTS: Sixteen trials were included in the review and fourteen contained data in a suitable form for quantitative analysis. Most comparisons did not show differences between rTMS and other interventions. No difference was seen between rTMS and sham TMS using the Beck Depression Inventory or the Hamilton Depression Rating Scale, except for one time period (after two weeks of treatment) for left dorsolateral prefrontal cortex and high frequency; and also for right dorsolateral prefrontal cortex and low frequency, both in favour of rTMS and both using the Hamilton scale. Comparison of rTMS (left dorsolateral prefrontal cortex and high frequency) with electroconvulsive therapy showed no difference except for psychotic patients after two weeks treatment, using the Hamilton scale, which indicated that electroconvulsive therapy was more effective than rTMS. REVIEWER'S CONCLUSIONS: The information in this review suggests that there is no strong evidence for benefit from using transcranial magnetic stimulation to treat depression, although the small sample sizes do not exclude the possibility of benefit.

Proof of safety of drugs: focus on vigilance.

It is well accepted that all new compounds, before administration to patients, should undergo safety evaluations in healthy subjects, including central nervous system (CNS) toxicity and as such the assessment of vigilance effects a relevant hallmark. The original concept of vigilance as a phenomenon observed only under conditions of monotony and signal regularity is increasingly falling into disfavor, embracing at present a much broader spectrum of behavior. Currently, vigilance may be regarded as a "readiness to adopt the appropriate behavior in a given situation, which thus finds outward expression through the quality and quantity of the behavior occurring in response to a given (internal or external) stimulus situation". The assumption that vigilance is a multifactorial phenomenon and not merely EEG data should be taken into account in order to study it accurately. Specifically, in drug research, apart from subjective reports and psychomotor performance tests, neurophysiological evaluations are regularly used such as Multiple Sleep Latency Test, Vigilance Epoch Classification or Parameters within a continuous scale. Although with limitations, temporal patterns of changes in activity of different frequency bands, indexes as the alpha slow-wave or the alpha anteriorization, computed from the EEG quantification, yielded different definitions of the intermediate states of the transition from wakefulness to sleep through the so-called subvigil stages. Spatial patterns are less documented. The recently proposed mathematical models to explain and predict variations in alertness are presented. Examples of the effects of different classes of drugs with the methods reported and its theoretical and practical relevance to vigilance research are introduced.