Standardised cannabis metrics: Opportunities for tracking how cannabis use affects neurodevelopmental trajectories in youth cohorts worldwide

Developmental cohort studies of youth provide unprecedented opportunities to map mental health and neurodevelopmental trajectories in youth who consume cannabis. A major challenge in achieving such endeavours has been the lack of standardised measures for cannabis consumption. There are limitations in the precision of existing cannabis use measures. For example, the use of interval scales to measure cannabis use frequency (e.g., use on 0, 1–2, 3–5, 5 days or more) prevents the running of correlational analyses between cannabis metrics and health outcomes and the precise measurement of more severe forms of use (e.g., youth using cannabis on 5 and on 10 days would belong to the same category). In turn, this issue prevents to determine how variability in exposure levels affects health outcomes during neurodevelopment. Another example is that many studies measure the age of cannabis use onset without discerning if it refers to the age of first cannabis use, or the age of regular cannabis use onset, the age of onset of problematic use or than the age when the current pattern of use commenced. Consequently, it is unclear how the onset of different forms of cannabis use behaviour affects neurodevelopment. Another limitation is the lack of harmonisation of cannabis metrics across international studies (e.g., the construct of cannabis ‘age of onset’ reflects the onset of different cannabis use behaviours in distinct studies). Together, these methodological limitations seriously limit the quality of evidence for understanding relationships between the exposure (cannabis use) and outcomes of interest (such as mental health and brain development). Recent developments in the field—namely, the Standard THC Unit and the iCannToolkit—hold promise as timely cost-effective methods to robustly measure exposure to medical and nonmedical cannabis use in youth over time. These new standardised measures of cannabis exposure can be used to track the relationship between cannabis use and developmental outcomes in developmental cohort studies (e.g., ABCD study, the Longitudinal Adolescent Brain Study— LABS, and the IMAGEN cohort). The Standard THC Unit (5 mg of THC) has been endorsed by NIDA, NIMH and major health organisations (NOT-DA-21-049). As such, it is now a recommended reporting requirement for all investigators funded by these funding organisations. This will ultimately increase methodological consistency and quality of evidence in research investigating the possible harms and benefits of cannabis use. Because the Standard THC Unit applies to all cannabis products and methods of administration, integration of this tool into developmental cohort studies holds promise for measuring youth cannabis use and its consequences. Of relevance for neuromaturation and youth health, THC drives cannabis' psychoactive, addictive, Received: 9 January 2023 Revised: 19 April 2023 Accepted: 7 June 2023


| INTRODUCTION
Developmental cohort studies of youth provide unprecedented opportunities to map mental health and neurodevelopmental trajectories in youth who consume cannabis. A major challenge in achieving such endeavours has been the lack of standardised measures for cannabis consumption. 1 There are limitations in the precision of existing cannabis use measures. For example, the use of interval scales to measure cannabis use frequency (e.g., use on 0, 1-2, 3-5, 5 days or more) prevents the running of correlational analyses between cannabis metrics and health outcomes and the precise measurement of more severe forms of use (e.g., youth using cannabis on 5 and on 10 days would belong to the same category). In turn, this issue prevents to determine how variability in exposure levels affects health outcomes during neurodevelopment. Another example is that many studies measure the age of cannabis use onset without discerning if it refers to the age of first cannabis use, or the age of regular cannabis use onset, the age of onset of problematic use or than the age when the current pattern of use commenced. Consequently, it is unclear how the onset of different forms of cannabis use behaviour affects neurodevelopment. Another limitation is the lack of harmonisation of cannabis metrics across international studies (e.g., the construct of cannabis 'age of onset' reflects the onset of different cannabis use behaviours in distinct studies). Together, these methodological limitations seriously limit the quality of evidence for understanding relationships between the exposure (cannabis use) and outcomes of interest (such as mental health and brain development). 1 Recent developments in the field-namely, the Standard THC Unit and the iCannToolkit 2,3 -hold promise as timely cost-effective methods to robustly measure exposure to medical and nonmedical cannabis use in youth over time. These new standardised measures of cannabis exposure can be used to track the relationship between cannabis use and developmental outcomes in developmental cohort studies (e.g., ABCD study, 4 the Longitudinal Adolescent Brain Study-LABS, 5 and the IMAGEN cohort 6 ).
The Standard THC Unit (5 mg of THC) has been endorsed by NIDA, NIMH and major health organisations 7 (NOT-DA-21-049). As such, it is now a recommended reporting requirement for all investigators funded by these funding organisations. This will ultimately increase methodological consistency and quality of evidence in research investigating the possible harms and benefits of cannabis use. Because the Standard THC Unit applies to all cannabis products and methods of administration, integration of this tool into developmental cohort studies holds promise for measuring youth cannabis use and its consequences. Of relevance for neuromaturation and youth health, THC drives cannabis' psychoactive, 8 addictive, 9 psychotogenic 10 and anxiogenic properties 11 and directly affects the endocannabinoid system that regulates youth neuromaturation, 12 via directly binding to brain cannabinoid receptors type 1. 13 The Standard THC Unit offers one single measure of cannabis use and cannot account for all cannabis exposure data of interest. Complementarily, the iCannToolkit has been proposed by expert consensus as an internationally relevant tool to measure both medical and nonmedical cannabis exposure parameters 3 and has been endorsed by prominent researchers. [14][15][16] The iCannToolkit is a three-layered framework (e.g., universal measures, setting-dependent measures such as the timeline follow-back, and biological measures). Therefore, the toolkit allows for flexibility in measuring cannabis exposure levels, depending on the costs (e.g., time and financial) and technical feasibility of the specific developmental cohort study that can change as a

| UTILITY OF THE STANDARD THC UNIT AND ICANNTOOLKIT FOR MEASURING CONTEMPORARY CANNABIS USE
The Standard THC Unit and the iCannToolkit offer strong potential for measuring contemporary cannabis use by youth, which is rapidly changing in cannabis markets internationally, which is rapidly changing in cannabis markets internationally, as well as the risks associated with youth cannabis use. Such changes include the increase in potency of cannabis products 17 with consequences for youth mental health 18 and the developing brain. 19 The ongoing changes in cannabis markets also include the diversification of new cannabis products and methods of administration (such as vaping, dabbing, consumption of concentrated extracts and edibles) 20 known to be used youth and to affect continuation of cannabis use over time. 21 The Standard THC Unit can account for major changes in international cannabis markets across all products and over time by providing a single standardised index of THC exposure. Meanwhile, the iCannToolkit enables the measurement of the types of products used and how they are consumed by youth 22 and can provide a proxy of quantity of cannabis consumed when measurement of THC level is not feasible (e.g., due to costs, technical limitations or the illicit status of cannabis).
An important dimension to measure in youth longitudinal studies is when cannabis use commences, in order to identify periods in which youth may be most vulnerable or resilient to the onset of cannabis use related behaviours. The age of cannabis use onset is a multifaceted construct that can capture distinct timeframes-i.e., the age when cannabis is first tried, when regular use commences and when problematic use starts. Given inter-individual variability in the ages when cannabis use commences, it can be a challenge for longitudinal studies to determine when would be the best/most appropriate times (i.e., age-groups) to utilise these standardised measures of cannabis exposure. The administration of a screening measure (such as item 1 from the base layer of the iCannToolkit: "Have you ever used cannabis?") to identify if any cannabis exposure has occurred could occur from the beginning of youth (e.g., age 12 as per previous neurodevelopmental evidence) and might be instrumental to identify the earliest onset cannabis users. Another challenge for longitudinal studies is to determine the starting ages for testing. To understand which variables predate and underlie the origin for the onset of cannabis use and problematic forms of use, it might be proven useful to commence testing of participants during childhood, as well as participants' parental substance use and wellbeing, including women during gestation (e.g., as implemented in the ABCD study).

| IMPLICATIONS OF IMPLEMENTING STANDARDISED CANNABIS METRICS IN DEVELOPMENTAL COHORT STUDIES
The integration of these newly established standardised cannabis metrics in developmental cohort studies worldwide could have other significant implications for research and strategic plans of major health organisations internationally. Amongst these is the establishment of causality between exposure to THC and cannabis products and brain developmental changes 1 ; the development of awareness in schoolaged youth and their families 23 ; and the delaying of exposure to cannabis products, 24 which will ultimately help to alleviate the health and psychosocial risks associated with youth cannabis use, 25

CONFLICT OF INTEREST STATEMENT
VL and TPF have no competing interests to declare.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as, no new data were created or analysed in this study.