Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Fabritius, 2013

Type of study^[1]: placebo-controlled cannabis smoking study with a cross-over design

Setting and country: controlled unit, Switzerland

Funding and conflicts of interest: Swiss National Science Foundation (FNS_320030_127507/1), the Centre d’Imagerie BioMédicale (CIBM), and the Faculty of Biology and Medicine (interdisciplinary grant) at the University of Lausanne; Conflicts of interest not described

Inclusion criteria: healthy male volunteers, who completed the sessions successfully, are included in this study. The mean consumption of cannabis during the 3 months preceding inclusion in the study was set to a minimum of one joint per month and a maximum of one joint per week for occasional smokers, while it was set to a minimum of ten joints per month (i.e., 2.3 joints/week) and possibly less than three joints per day for heavy smokers. This was assessed by structured interview conducted by a medical staff (psychiatrist, clinician, and research technician).

Exclusion criteria: Very heavy cannabis smokers (up to several dozen joints per day). Volunteers who used any illegal drug (cocaine, amphetamines, and opiates) other than cannabis were also excluded from the study

N = 23 heavy smokers; 25 occasional smokers

Mean age ± SD: 23.9 for occasional smokers and 22.7 for heavy smokers

Sex:100 % M

Describe index test:

Joint was smoked under controlled conditions

Major cannabinoids (THC, 11-OH-THC and free THCCOOH) were analyzed by validated GC or LC–MS/(MS) methods in forensic laboratories (usual limit of quantification: 1 mg THCCOOH/L and 0.5 mg THC/L)

Describe reference test^[2]:

Placebo joint was smoked

Time between the index test and reference test: one week

For how many participants were no complete outcome data available?

N (%) not applicable

Reasons for incomplete outcome data described? Not applicable

Outcome measures and effect size (include 95%CI and p-value if available)⁴:

Median Concentration THC in blood 2,5H after smoking cannabis:

Heavy 4.2 µg/l

Occasional 2.1 µg/l

Median Concentration THCCOOH in blood 2,5H after smoking cannabis:

Heavy: 26 µg/l

Occasional: 7.1 µg/l

Using an ROC-curve a threshold of 40 µg/l

was proposed as this corresponded to >10 joints per month. Specificity 100%, Sensitivity 16%

Fabritius, 2014

Type of study^[3]: validation of cut-off of 40 µg/l s in real life

Setting and country: Switzerland

Funding and conflicts of interest: Swiss National Science Foundation (FNS_320030_127507/1) and the Faculty of Biology and Medicine (interdisciplinary grant) at the University of Lausanne for their financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Inclusion criteria: consecutive cases referred to the Unit of Psychology and Traffic Medicine of the university center of legal medicine of the canton of Vaud and Geneva for evaluation of the fitness to drive (long term impairment).

Exclusion criteria: cases that did not match the criteria for inclusion (15 cases) in the occasional (<=1 time/week) or heavy smokers group (>=10 times/month) were not considered

N= 146: 106 heavy users and 40 occasional users

Prevalence:

Mean age ± SD:

Heavy users: 27

Occasional users: 29

Sex:

Heavy users 97% M

Occasional users: 98%M

Frequency os use (mean times/week):

Heavy users: 12

Occasional users: 0,6

Alcohol

Heavy users:37 (35%)

Occasional users: 21 (53%)

Other psychoactive drugs:

Heavy users: 25 (24%)

Occasional users: 10 (25%)

Describe index test:

Whole blood levels of cannabinoids, including THCCOOH

Major cannabinoids (THC, 11-OH-THC and free THCCOOH) were analyzed by validated GC or LC–MS/(MS) methods in forensic laboratories (usual limit of quantification: 1 mg THCCOOH/L and 0.5 mg THC/L)

Describe reference test^[4]:

Blood specimens were collected during police controls or after

traffic crashes. During police investigations, Then, the administrative and judicial

authorities determined, based on police and medical reports and

on the toxicological investigations, whether the driver was under

the influence of cannabis at the time of the incident and whether

his/her

fitness to drive was long-term impaired. To demonstrate an

alteration of the

fitness to drive, a formal medical assessment was

carried out by forensic experts to evaluate whether cannabis had

been chronically and heavily used or not.

Estimated frequency of cannabis use as reported by the driver

Time between the index test and reference test:

For how many participants were no complete outcome data available?

N (%)

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available)⁴:

Area under the ROC-curve: 0.81

Cut-off 40 μg/L (

Sensitivity: 41%

Specificity:93%

Cut-off 75 μg/L

Sensitivity: 19%

Specificity:100%

The median blood levels of THCCOOH for cannabis occasional and heavy users were 9.4 and 33 mg/L, respectively. The ranges for the same groups were 1.0–74 mg/L and 1.0–312 mg/L

The authors propose the following procedure that can be very useful in the Swiss

context but also in other countries with similar traffic policies: if the whole blood THCCOOH

concentration is higher than 40 mg/L, traffic offenders must be directed

first and foremost toward medical

assessment of their

fitness to drive. This evaluation is not recommended if the THCCOOH concentration is

lower than 3 mg/L and if the self-rated frequency of cannabis use is less than 1 time/week. A THCCOOH

level between these two thresholds cannot be reliably interpreted. In such a case, further medical

assessment and follow-up of the

fitness to drive are also suggested, but with lower priority.

Huestis, 2007

Type of study: controlled oral and smoked drug administration studies

Setting and country: secure drug research unit, New York, USA

Funding and conflicts of interest: This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse and the American Registry of Pathology; conflicts of interest not reported

Inclusion criteria: male cannabis users that had completed a drug use habits questionnaire. In addition to self-reports drug use was documented by admitting only those subjects that had a positive urine test at a cannabinoid immunoassay cut-off concentration of 50 ng/mL

Exclusion criteria: not reported

N= 38 (53 head hair specimens ???)

Prevalence: 18 daily users; 20 non-daily users

Age 21 to 42

Sex: 100% M

Other important characteristics: not reported

Describe index test:

Hair sample collected at admission, after smoking protocol and after 10 days after oral smoking protocol.

For the smoking protocol, 13 subjects smoked a 2.7% THC cigarette (approximately 24 mg THC). Seven days later they smoked a second 2.7% THC cigarette. Later the same day, the post-drug hair specimens were collected.

For the oral dosing protocol, 2 subjects ingested hemp oils of differing THC concentrations

and dronabinol in divided doses at meals over 10 weeks. Doses were 0, 0.39, 0.47, 7.5

(dronabinol, synthetic THC), and 14.8 mg per day for five consecutive days with 10 days between dosing regimens. The two highest doses were in the last month of administration. The

total THC administered was 116 mg. Hair specimens were collected at the end of the 10-week

period 7-10 days after the last dose was administered.

Describe reference test:

Urine specimens

At admission: daily urine specimens until cannabinoids were less than 20 ng/mL by immunoassay, a period of time ranging from 9 to 24 days.

Drug use habits questionnaire

Time between the index test and reference test: same day- 10 weeks

For how many participants were no complete outcome data available? 13 subjects followed smoking protocol and 2 oral dosing protocol; other participants had only baseline measurements

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available):

All specimens were analysed together.

19 (36%) of 53 hair specimens had no detectable THC or THCCOOH at or above the GCMSMS LOQs, 1.0 and 0.1 pg/mg

Daily users: 17/20

Non-daily users: 17/33

As only 2 subjects were included in the oral dosing study and 13 in the smoking protocol it is not possible to compare these data. Especially not since hair sample was taken on the same day as smoking.

Hadener,

2017

Type of study: placebo-controlled cannabis smoking study; with crossover design

Setting and country: Switzerland

Funding and conflicts of interest: not reported

Inclusion criteria: self-reported average frequency of cannabis consumption of at least one joint per month and at most one joint per week (occasional smokers) or at least ten joints per month (heavy smokers) during the three months prior to the study

Exclusion criteria: very heavy smokers (>3 joints/day); subjects that consumed any illegal drug other than cannabis

N= 23 heavy smokers (average 20 occasions/week), 25 occasional smokers (3,5 times/month)

Mean age ± SD: 18-30

Sex:100 % M

Other important characteristics:

Describe index test:

smoked either a cigarette of pure cannabis (0.7 g Bedrobinol, 11% THC, < 1% CBD). The smoked amount of THC averaged about 42 mg. Whole blood samples were taken during the screening visit, on admission (5 h before smoking), a few minutes (t = 0 h) before inhalation, and 0.2, 0.3, 0.4, 0.65, 1.9, 2.5, and 3.5 h after the start of smoking (actual times of blood sampling varied slightly among participants).

Whole blood THCCOOH concentrations were measured within a few days after blood collection by GC- or LC-MS/MS as described by Fabritius et al.

For the present study, the occasional

and heavy smokers’ blood samples were thawed after storage at -80 °C and were re-analyzed by a recently developed LC-MS/MS method for rapid and simultaneous quantification of free and glucuronidated THCCOOH.

Cut-off point(s):

Comparator test:

Cut-off point(s):

Describe reference test:

placebo (0.8 g Santhica variety, no THC, < 0.1% CBD) according to a fixed-paced puffing procedure

Cut-off point(s):

Time between the index test en reference test: one week

For how many participants were no complete outcome data available?

N (%)

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available):

Area under the ROC-curve:

The overall ability of the cannabinoid blood levels as diagnostic markers to discriminate between occasional and heavy smokers was evaluated by the area under the ROC curve (AUC). AUC was 0.96 and 0.94, respectively, thus indicating that THCCOOH-glucuronide and total THCCOOH blood levels have a high discriminatory power for the recognition of heavy use, as previously hypothesized

Cut-off (discriminating heavy from occasional users):

At specificity 100% for THCOOH-glucuronide and total THCCOOH concentrations higher than 51.6 μg/L and 57.9 μg/L, respectively (Figure 2). Following two blood concentration decision thresholds proposed for discriminating heavy from occasional users: 52 μg/L of THCCOOH-glucuronide and 58 μg/L of total THCCOOH. This correlates with sensitivities of 41% and 43%, respectively

Cut-off (to rule out heavy users) 5 μg/L:

Sensitivities 41% and 43%

The majority of the occasional users’ blood samples were free of THCCOOH-glucuronide during placebo conditions, resulting in median values of zero μg/L for all time points. In the heavy users, THCCOOH-glucuronide was detectable in all samples within a range of < LLOQ – 191.0 μg/L. Median (range) concentrations decreased from 41.5 μg/L (< LLOQ – 191.0 μg/L) to 32.7 μg/L (< LLOQ – 119.0 μg/L) between 5 h before and 3 h after smoking the placebo cigarette

Koster, 2014

Type of study: Validation study of liquid chomatography mass spectrometry

Setting and country: Forensic laboratory; The Netherlands

Funding and conflicts of interest: authors declare no funding or conflict of interest

Inclusion criteria: there were 47 subjects, no details were provided about them

Exclusion criteria: unclear

N= 47

Prevalence: >

Mean age ± SD: ?

Sex: % M / % F: ?

Other important characteristics: ?

Describe index test:

liquid chomatography mass spectrometry

Describe reference test:

Known concentrations of the substances tested: 4 different concentrations were used:

LLOQ 30.0 pg/mg

Low 80.0 pg/mg

Medium 200 pg/mg

High 2000 pg/mg

Time between the index test and reference test:

For how many participants were no complete outcome data available? unclear

Reasons for incomplete outcome data described? No

Outcome measures and effect size (include 95%CI and p-value if available):

Within run coefficient of variation:

Between run coefficient of variation:

LLOQ: 12.3

Low: 9.7

Medium: 3.7

High: 1.8

THC cut-off 80 pg/mg

LLOQ: 12.8

Low: 0

Medium: 0

High: 3.2

No risk of bias assessment included in table below; this is another type of study

Study reference

Patient selection

Index test

Reference standard

Flow and timing

Comments with respect to applicability

Fabritius, 2014

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

No

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Fabritius, 2013

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

No

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Yes

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Hadener, 2017

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

No

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

No

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: HIGH

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW