A Study of Pupil Response to Light as a Digital Biomarker of Recent Cannabis Use

Abstract

Introduction: Given the traffic safety and occupational injury prevention implications associated with cannabis impairment, there is a need for objective and validated measures of recent cannabis use. Pupillary light response may offer an approach for detection.

Method: Eighty-four participants (mean age: 32, 42% female) with daily, occasional, and no-use cannabis use histories participated in pupillary light response tests before and after smoking cannabis ad libitum or relaxing for 15 min (no use). The impact of recent cannabis consumption on trajectories of the pupillary light response was modeled using functional data analysis tools. Logistic regression models for detecting recent cannabis use were compared, and average pupil trajectories across cannabis use groups and times since light test administration were estimated.

Results: Models revealed small, significant differences in pupil response to light after cannabis use comparing the occasional use group to the no-use control group, and similar statistically significant differences in pupil response patterns comparing the daily use group to the no-use comparison group. Trajectories of pupillary light response estimated using functional data analysis found that acute cannabis smoking was associated with less initial and sustained pupil constriction compared to no cannabis smoking.

Conclusion: These analyses show the promise of pairing pupillary light response and functional data analysis methods to assess recent cannabis use.

Keywords: Cannabis; Functional data analysis; Pupillary light reflex; Pupillometry; Substance use detection.

Fig. 1.

A typical pupillary response to light during the light reflex test, which we refer to as a pupillary light response trajectory throughout the paper. At the onset of illumination (time 0 on the x-axis), the pupil begins to constrict in size until the diameter reaches a minimum, called the point of minimal constriction, and then it begins to increase in size back toward its original diameter. The area under zero on the y-axis from the point of minimal constriction to the end of the light response test is a measure of rebound dilation. The larger the magnitude of this area (i.e., larger shaded in Fig. 1), the less rebound dilation that has occurred.

Fig. 2.

The plot shows the individual participant, right eye, pupil trajectories after cannabis consumption during the pupil response to light test by cannabis use group.

Fig. 3.

a Histogram depicts the distribution of the TD from cannabis use to the pupillary light response test, in minutes. The vertical dotted red line indicates the mean of the distribution at 62.2 min. Interquartile range is 59–66 min. b Differences in the average pupil light response as the time from cannabis smoking increases from 60 min to 70 min (lighter color). The purple line shows the average pupil response for the no-use group. As time since cannabis consumption increases, the point of minimal constriction approaches that of the no-use group while the slope of the rebound appears to remain distinct.

Fig. 4.

a ROCs for our two LogRegr models. Higher accuracy in predicting recent cannabis use is indicated by a higher AUC and the ROC following the left and top edge of the graph. The blue line is an ROC for a traditional LogRegr model using single-value summary features of pupil light response. The yellow line is an ROC for a functional LogRegr model using full trajectory of pupil light response. The functional logistic model better differentiates between recent cannabis use and no use. b Solid black line depicts the OR of recent cannabis over the 10 s of the pupillary light response test. The dashed lines indicate the 95% confidence interval around the OR estimate. The red segments indicate regions where the confidence interval for the OR does not contain zero, demonstrating statistically significant differences between the recent cannabis use and no use.

Fig. 5.

a Average pupil light response trajectories plotted by cannabis use frequency. An additional dotted lined based on the average trajectory for all recent cannabis users, occasional and daily, was included to show differences between recent use and no-use groups. b–d Difference in average trajectories between pairs of occasional, daily, and no use of cannabis. Zero on the y-axis corresponds to no difference between the average trajectory of two groups, while the region indicated by the solid red line, where the confidence interval (both dashed lines) is above or below zero on the y-axis, indicates statistically significant differences between trajectories. The figure demonstrates significant regions of difference between occasional and no-use groups and daily and no-use groups, while there is no significant difference between occasional and daily cannabis use groups.