Figure 1.
Schematic representation of the experimental day and of the fMRI task.
Panel A shows the general scheme of the whole protocol. It includes eight whole blood samplings (orange arrows), 4 of them rapidly after the fixed-pace inhalation procedure (violet bar) in order to construct the kinetics of the main metabolites. Volunteers were asked to perform two fMRI experiments (green bars), once before and once after smoking the joint, and two Critical Tracking Task (CTT) outside the scanner for the assessment of psychomotor skills (blue bars). On six occasions the volunteers filled out questionnaires on the subjectively experienced effects of smoking a joint and their willingness to drive (light blue arrows). After each fMRI, the volunteers filled out another questionnaire in order to detect any change in their tactical skills and in the way they performed the tracking tests (yellow arrows). Panel B summarizes the fMRI protocol organized in a block-design fashion where each cycle of the three experimental conditions (active, passive, and rest) was repeated five times. The rest period was 14 s long, whereas active and passive conditions lasted 40 s and 30 s, respectively. At the beginning of each experimental condition, subjects received a brief visual cue (2 s) regarding the type of task they were required to perform. In the active phase subjects were asked to track the position of a target square that moved along the horizontal meridian by keeping it at the center of a user-controlled square by means of an MRI-compatible joystick (left-most illustration in the bottom part of the panel). In the passive phase subjects were instructed only to visually follow the target square movement (right-most illustration in the bottom part of the panel).
Table 1.
Sociodemographic characteristics, self-rated patterns of cannabis use and subjective feeling of unwanted side-effects.
Figure 2.
Time profiles of the major cannabinoids taken from whole blood.
Time 0 corresponds to the last blood sample collected right before the smoking procedure; concentrations are expressed in ng/ml. We performed the fMRI when THC blood concentration roughly drops to one sixth of its maximum value (45 minutes after smoking). Vertical error bars represent standard deviation of the measurements, horizontal bars represent time variability in the collection of samples.
Table 2.
Cannabinoids concentrations (ng/ml). Time point zero is the beginning of the inhalation procedure.
Figure 3.
Self-evaluation of drug effects.
Joint scheme of the subjective estimation of drug effects after cannabis (red curve) and placebo (blue curve) smoking evaluated by questionnaires answered using a Visual Analog Scale ranging from 0 to 100. The time profile of THC concentrations measured in whole blood (green curve, concentrations on right vertical axe) is given as reference. Subjects ratings and concentrations are averaged across subjects. Error bars represent standard deviation.
Figure 4.
Questionnaire regarding the strategy used to perform the fMRI task.
Comparison of the answers given by the volunteers between two experimental sessions (Placebo/THC). The red central mark is the median, the edges of the box are the 25th and 75th percentiles, the whiskers extend to the most extreme datapoints that the algorithm considers not to be outliers (1.5 times the interquartile range), and the outliers are plotted individually with red crosses. Parameters of interest were: alteration in time perception (panel A), attention (panel B), anticipation of the target movement (panel C), and tactic (panel D). Black stars represent the significant difference of the variables of interest between the experimental conditions.
Figure 5.
Behavioural results during fMRI session.
(A) Comparison of the main behavioural data between two experimental sessions (Placebo/THC). Effects of THC/placebo inhalation were assessed by subtracting the performance during the second post-THC/placebo sessions from the performance during the first control sessions. The red central mark is the median, the edges of the box are the 25th and 75th percentiles, the whiskers extend to the most extreme datapoints that the algorithm considers not to be outliers (1.5 times the interquartile range), and the outliers are plotted individually with red crosses. Black stars represent the significant difference of the variable of interest in the two experimental conditions. (B) Linear correlation between the duration of correct tracking and the feeling of confusion (left panel) and linear correlation between the deviation between target and cursor and the feeling of confusion (right panel). Corresponding Pearson’s correlation coefficients (R) and p-values are displayed at the bottom of each plot.
Figure 6.
Effect of THC smoking on brain function during the visuo-motor tracking task.
When comparing the THC and the Placebo sessions, fMRI BOLD response changes in the Active tracking task vs Passive condition reveal major alteration of brain networks. Hot colour bar represents regions showing an increase in BOLD signal after the cannabis smoking. Cold colour bar represents the opposite contrast. Maps are thresholded at p<0.005 and k>40 and superposed on a standard brain in the MNI (Montreal Neurological Institute) space.
Table 3.
Local maxima of significant cluster of activation in the marijuana vs placebo contrast.
Table 4.
Local maxima of significant cluster of activation in the placebo vs marijuana contrast.
Figure 7.
Correlation between BOLD response and the feeling of confusion.
(A) Voxel-wise correlation analysis between the BOLD response and the feeling of confusion. Hot colour bar represents regions showing a positive correlation between these two variables, while cold colour bar represents the negative correlation. Maps, thresholded at p<0.005 and k>40 are superposed on a standard brain in the MNI (Montreal Neurological Institute) space and visualized in axial view with slices spaced 3 mm in the z axes. Regions highlighted by the blue circles are the ones plotted in panel B. (B) The left-most plot shows the linear correlation between the mean BOLD response in the cluster located in ACC and the feeling of confusion (p<0.001 corrected). The right-most shows the linear correlation between the BOLD response in the cluster located in the right parietal cortex and the feeling of confusion (p<0.001 corrected). Percent of signal change of BOLD response was averaged across all the voxels belonging to the cluster. Corresponding Pearson’s correlation coefficients (R) are displayed on the bottom of each plot.