Cannabinoid effects on ventilation and breathlessness: a pilot study of efficacy and safety.

Based on the neurophysiology of dyspnoea and the distribution of cannabinoid receptors within the central nervous system, we hypothesize that the unpleasantness of breathlessness will be ameliorated in humans by cannabinoids, without respiratory depression. Five normal and four chronic obstructive pulmonary disease (COPD) subjects entered a double blind, randomized, placebo-controlled crossover study with two test days. Subjects received sublingual cannabis extract or placebo. A maximum of 10.8 mg tetrahydrocannabinol and 10 mg cannabidiol were given. Breathlessness was simulated using fixed carbon dioxide loads. Measurements taken were of breathlessness (visual analogue scale [VAS] and breathlessness descriptors), mood and activation, end-tidal carbon dioxide tension and ventilatory parameters. These were measured at baseline and 2 hours post placebo and drug administration. Normal and COPD subjects showed no differences in breathlessness VAS scores and respiratory measurements before and after placebo or drug. After drug administration, COPD subjects picked 'air hunger' breathlessness descriptors less frequently compared to placebo. We have shown that breathlessness descriptors may detect an amelioration of the unpleasantness of breathlessness by cannabinoids without a change in conventional breathlessness ratings (VAS). A stimulus more specific for air hunger may be needed to demonstrate directly a drug effect on breathlessness. However, this study shows that the inclusion of respiratory descriptors may contribute to the assessment of drug effects on breathlessness.

Ventilation is unstable during drowsiness before sleep onset.

Ventilation is unstable during drowsiness before sleep onset. We have studied the effects of transitory changes in cerebral state during drowsiness on breath duration and lung volume in eight healthy subjects in the absence of changes in airway resistance and fluctuations of ventilation and CO2 tension, characteristic of the onset of non-rapid eye movement sleep. A volume-cycled ventilator in the assist control mode was used to maintain CO2 tension close to that when awake. Changes in cerebral state were determined by the EEG on a breath-by-breath basis and classified as alpha or theta breaths. Breath duration and the pause in gas flow between the end of expiratory airflow and the next breath were computed for two alpha breaths which preceded a theta breath and for the theta breath itself. The group mean (SD) results for this alpha-to-theta transition was associated with a prolongation in breath duration from 5.2 (SD 1.3) to 13.0 s (SD 2.1) and expiratory pause from 0.7 (SD 0.4) to 7.5 s (SD 2.2). Because the changes in arterial CO2 tension (PaCO2) are unknown during the theta breaths, we made in two subjects a continuous record of PaCO2 in the radial artery. PaCO2 remained constant from the alpha breaths through to the expiratory period of the theta breath by which time the duration of breath was already prolonged, representing an immediate and altered ventilatory response to the prevailing PaCO2. In the eight subjects, the CO2 tension awake was 39.6 Torr (SD 2.3) and on assisted ventilation 38.0 Torr (1.4). We conclude that the ventilatory instability recorded in the present experiments is due to the apneic threshold for CO2 being at or just below that when awake.