A double-blind, daytime, placebo-controlled study was carried out in 12 healthy volunteers to investigate the effects of single doses of 5, 15 and 30 mg temazepam and of 5 and 10 mg nitrazepam on the EEG, psychomotor performance, subjective mental and emotional status, blood pressure and heart rate. Each subject received all 6 treatments in a random sequence at intervals of 1 week. The EEG tracings were evaluated quantitatively by spectral analysis. Psychomotor performance was assessed by means of the tapping test. Subjective mental and emotional status were assessed using the Bond and Lader analogue self-rating scale. Procedures were carried out before and at ½, 1,2,4, 6, 7, 8 and 9 h after drug administration, with the exception of the tapping test, which was carried out before and, again, after 2 and 7 h. EEG estimates of equipotency, based on magnitude of peak effect, were as follows: 15 mg temazepam ∼ 5 mg nitrazepam; and 30 mg temazepam ≧ 10 mg nitrazepam. At these approximately equipotent doses, temazepam had a somewhat earlier onset of action on the EEG, a clearly shorter duration of EEG action, and lesser impairment of psychomotor performance than nitrazepam. Qualitatively, both drugs had similar effects on the subjective mental and emotional states of the subjects. There were no clinically relevant changes in mean or individual sitting and standing blood pressure values. After temazepam, but not after nitrazepam, heart rate increased (maximal mean change 10 bpm) as part of a normal startle response to arousal. The results suggest that temazepam has less hangover potential than nitrazepam.

The central activity of ketotifen (Zaditen®), a benzocycloheptathiophene derivative for use in the prophylaxis of asthma, was determined by quantitative pharmaco-EEG in 7 healthy volunteers in a single-blind trial. During the 1st week of the trial, placebo was given twice daily followed by ketotifen 1 mg twice daily for 3 weeks. Placebo was again given for a further week. 15-min resting EEGs were taken immediately before and 3 and 6 h after medication on 8 defined days during the study, and the subjects were asked for side effects. Lead O₂–C_z was analyzed by spectral analysis, and the relative power of the delta, theta, and fast and slow alpha bands as well as the dominant alpha frequency were calculated. The mean of each of these parameters was calculated per subject for each of the three measurements on each study day and compared with the baseline by means of one-way analysis of variance. A statistically significant slowing of the dominant alpha frequency, a decrease of the relative power of the fast alpha activity, and an increase of the relative power of the theta rhythm were found. These effects, indicative of a mild sedation, were highest during the 1st week of treatment with ketotifen, with a peak at the 3rd day, and gradually decreased thereafter. In contrast to the sensitive pharmaco-EEG method, none of the subjects complained of sedation or tiredness while taking ketotifen.

One of the first routine applications of quantitative EEG analysis was in the field of human psychopharmacology. As early as the 1960's, quantitative techniques, mainly period and amplitude integration analyses or analogue filtering, were successfully applied to EEG data with the aim of quantifying and objectifying changes induced by psychoactive medidation. Thus, step by step, a new research field, pharmacoelectroencephalography, was developed. Many other sophisticated new techniques have been described in great detail from the engineering viewpoint. However, due to the language barriers common between representatives of the various disciplines involved, it is still difficult to view them in context with the experimental design as a whole. Therefore, based on examples taken from our routine work, an attempt is made to give a balanced judgement on the value of such techniques in pharmaco-electroencephalography, and their contribution to the CNS pharmacology.

A double-blind, placebo-controlled study was carried out in 10 young healthy volunteers to investigate the effects of single doses of 1 and 2 mg guanfacine hydrochloride (Estulic®) and 0.15 and 0.3 mg clonidine (Catapres®) on the electroencephalogram (EEG), subjective mental and emotional state, blood pressure and heart rate. These doses are considered to be equipotent with regard to their antihypertensive effects, as shown in long-term therapeutic trials. Each subject received all five treatments in random sequence at intervals of 1 week. The EEG tracings were evaluated quantitatively by spectral analysis. Procedures were carried out before and at 1, 2, 4, 6 and 8 h after drug administration. After clonidine the EEG showed increased slow-wave activity and decreased alpha activity, these effects being dose-dependent. They were of the sedative type and did not clearly indicate specific psychotropic properties. The subjective mental and emotional state questionnaire indicated a decrease of alertness, extroversion, concentration and mood (in that order), changes which paralleled the EEG changes. The changes observed after guanfacine were qualitatively similar to those after clonidine, but were of considerably lower intensity. Our data suggest that guanfacine has less central nervous system-depressant activity than clonidine.

A double-blind, crossover, placebo-controlled study was carried out in 10 healthy male volunteers to investigate the effects of subcutaneously administered single doses of 4 and 8 mg morphine and 2.5 and 5 mg of a new centrally acting analgesic with a benzomorphane structure. After an adaptation session, each subject received all five treatments in a random sequence at intervals of 1 week. Quantified EEG, cardiovascular and behavioral parameters, quantitative respiratory measurements, body temperature, symptom reports, pain threshold estimates, and blood drug assays were used to assess the effects of the drugs. The measurement battery was completed before injection and after 30, 60, 120, 240 and 360 min. In addition, EEG, blood samples and respiratory signals were also taken during/after the first 5, 10, 15, 20 and 25 min. As the new compound did not show any obvious advantages over morphine, only the results with the latter substance are reported here. As the main effects of morphine on the EEG a dose-dependent slowing and monorhythmization of alpha and an increase of the average frequency of fast beta activity were observed. Slow EEG waves tended to decrease. Heart rate and body temperature decreased, whereas there was no discernible effect on blood pressure. Subjects reported feelings of drowsiness, muzziness, lethargy and mental slowness. The pain threshold increased. All these effects had a maximum between min 120 and 240, although the highest blood levels of the parent drug were measured 10–25 min after drug administration. An explanation for this delay might be that the pharmacological effects are due not to free morphine but to one of its metabolites.