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. 2025 Jan 7:18:1492246.
doi: 10.3389/fnins.2024.1492246. eCollection 2024.

Eye reactions under the influence of drugs of abuse as measured by smartphones: a controlled clinical study in healthy volunteers

Kiki W K Kuijpers  1 , Karl Andersson  2   3 , Maria Winkvist  4 , Marieke Niesters  1 , Monique van Velzen  1 , Fred Nyberg  5 , Albert Dahan  1 , Markku D Hämäläinen  4
Affiliations

Eye reactions under the influence of drugs of abuse as measured by smartphones: a controlled clinical study in healthy volunteers

Kiki W K Kuijpers et al. Front Neurosci. .

Abstract

Background: It is known that illicit and prescribed drugs impact pupil size, eye movement and function. Still, comprehensive quantitative evaluations under known ambient light conditions are lacking, when smartphones are used for monitoring.

Methods: In this clinical study (NCT05731999), four medicinal products with addiction risks were administered to 48 subjects (18-70 years old, all with informed consent, 12 subjects per drug). Videos captured by smartphones at ~50 lux and ~ 500 lux documented the eye's reaction before and after controlled intake of single doses of oral oxycodone (20 mg), lorazepam (2 mg), lisdexamphetamine (70 mg) and inhaled cannabis flos (65 mg with 22% THC) over a 5-h test period. Data from three observational tests, non-convergence (NC, ability to cross the eyes), nystagmus (NY), and pupillary light reflex (PLR) were converted into 24 key features that represent different eye characteristics.

Results: Of the acquired data, 87-97% produced key features. At peak drug plasma concentration, oxycodone constricted pupils (p < 0.001); lorazepam induced non-convergence (p < 0.001); lisdexamphetamine induced dilated pupils (p < 0.001), irrespective of ambient light conditions. Inhaled cannabis induced miosis (p = 0.05 at ~50 lux, p = 0.10 at ~500 lux), a reduced light-induced amplitude (p = 0.003 at ~50 lux, p = 0.3 at ~500 lux) and redness of the sclerae (p = 0.14 at ~50 lux, p = 0.007 at ~500 lux). The drug effect lasted at least 5 h (p < 0.005) except for inhaled cannabis (2-3 h, p < 0.05).

Conclusion: The ocular response to oxycodone, lorazepam, lisdexamphetamine and cannabis, as measured under controlled light conditions using a smartphone-based assessment, demonstrated distinct and readily distinguishable patterns for each substance.

Clinical trial registration: Identifier, NTC05731999.

Keywords: benzodiazepines; cannabis; central stimulants; opioids; pupillometry; substance use disorder.

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Conflict of interest statement

MW and MH are employees of Kontigo Care AB that have made a product partly based on the results of the presented results (Previct Drugs). KA is an employee of Skillsta Teknik Design och Kvalitet AB, which is a subcontractor to Kontigo Care AB. KA and MH are co-inventors of two (MH) and three (KA) different patents that are related to the presented work (PCT/SE2023/050638 “Quality assurance in body images”, PCT/SE2023/051070; “Method for estimating pupil size” (only KA), PCT/SE2023/051071; “Method and system for self-administered surveillance of use of addictive stimulus”). FN is part of the advisory board of Kontigo Care AB. AD reports receiving personal fees from Trevena and Enalare outside the submitted work and awards/grants from the US Food and Drug Administration and from the Dutch Research Council (NWO, the Hague, the Netherlands). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Kontigo Care AB. The funder had the following involvement in the study: Study design, interpretation of data, decision to publish and preparation of the manuscript. The funder was not involved in collection and analysis of data. The study was conducted in compliance with ISO 14155 to ensure that the study produced accurate data and reported unbiased findings. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Description of the measurement area. Ten light sources (L) were mounted facing upwards near the ceiling. Light sources could be controlled in terms of intensity. Two fixed intensity levels were created, producing either 50 lux or 500 lux at calibration position C.
Figure 2
Figure 2
Score vector of principal components 2 plotted vs. 1. The analysis is based on all key features collected at both light conditions. Data is from 48 subjects: 12 subjects across 4 types of drug families including baseline measurements and 5–6 subsequent assessments during 1–5 h after drug administration on the day of intake. Data points originating from the time point with highest average eye reaction magnitude are shown as large size markers. In some cases, subjects failed to produce data at this time point due to intoxication, leading to fewer than 12 large size markers in some cases. Green square = opioid (oxycodone). Purple triangle = phenethylamine (lisdexamphetamine). Blue diamond = benzodiazepine (lorazepam). Red circles = cannabis (Bedrocan). Black oval = drug sober baseline (95% of collected data inside the oval).
Figure 3
Figure 3
(A,B) Plasma concentration of oxycodone and dexamphetamine over time (n = 12 subjects) and the key feature values for Dbase (z-transformed, from PLR) at sober baseline and 1, 2, 3, 4, and 5 h after drug administration. Ambient illumination was ~50 lux in a and 500 Lux in (B). (C) Blood concentration of lorazepam over time (n = 12 subjects) and key feature values for NCdiff (z-transformed, from NC, 50 Lux). (D) Blood concentration of THC over time (n = 12 subjects) and the key feature values for MCA (z-transformed, from PLR, 50 lux).
Figure 4
Figure 4
Key feature values for NCdiff for the 12 subjects exposed to lorazepam, baseline versus after drug administration, and values shown as before or after individualization.
Figure 5
Figure 5
Correlation of selected key feature z-transformed values (Dbase, left planel and MCA, right panel) collected at ~50 lux and ~500 lux.
Figure 6
Figure 6
Average time series profile for selected key features at ~50 lux (blue dotted) and ~ 500 lux (red solid). The line is a spline fit provided to improve interpretability.
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