cannabis in the workplace...ng/ml subjects dosed ur cmax, oral cannabis (thccooh) 10 mg 25 mg 50 mg...

Ryan Vandrey, PhD

Johns Hopkins University School of Medicine

Cannabis in the Workplace

Disclosures• Paid consultant to Zynerba

Pharmaceuticals, Battelle Memorial Institute and CW Hemp. Received honorarium from Insys Therapeutics.

• None of my consulting is directly related to the work I will present

• Funding for the studies provided by the Substance Abuse and Mental Health Services Administration (SAMHSA)

Current State Laws

Workplace Implications• What are the effects of cannabis?• What kind of impairment can be expected?• How can we detect cannabis use?• Does product type or route impact effects?• Is there a biomarker for impairment?• What about secondhand exposure?• Can/should you test for legal cannabis use?• What about treatment for problematic use?

Acute Effects• Positive: Euphoria, relaxed, easier to laugh,

increased appetite, potential medical benefit• Negative: rapid heart rate, dry mouth, red

and irritated eyes, paranoia, anxiety, nausea/vomiting, hallucinations, cognitive impairment (memory, attention, time estimation, complex cognition)

• Driving impairment: increased risk for accident, impairment on vehicle following, lane position, and emergency maneuvers

Chronic Use Effects• Cannabis Use Disorder; tolerance/withdrawal• Increased rate of mental health problems• Decreased memory, attention, IQ • Cannabinoid Hyperemesis Syndrome• Altered brain structure; Age of onset important• Unclear if effects are reversed with abstinence• Correlations only; cannot infer causality• Functional significance not well established;

difficult to determine “fit for duty” impact

Cannabis and the Workplace• 62% of the workforce in the U.S. lives in a

state where medical use of cannabis is legal• 21% of the workforce in the U.S. lives in a

state where adult non-medical use of cannabis is legal

• Rates of use are higher in states where cannabis is legal versus those where it is not

Approximately 21% of U.S. adults 18 and older entering substance treatment for the

first time reported their employment status as full-time

(FT) on the 2012 Treatment Episode Dataset (TEDS).

21%

Marijuana

Prescription drugs

Illicit drugs

Percentage of FT workers who indicated their primary drug at admission was…

9.5%

12.2%

17.2%

Incident Treatment Admissions

Federal Guidelines• SAMHSA Mandatory Guidelines for

workplace drug testing• Living document outlining regulations for

workplace drug testing• SAMHSA Division of Workplace Programs• Current cannabis test standard:

EIA screen: 50ng/mLGC/MS confirmation: 15 ng/mL

• Oral fluid and hair testing in development

Cannabis Research• Primary interest in PK to inform federal

workplace drug testing• Incorporated subjective, cardiovascular,

performance assessments• Enrolled non-tolerant healthy adults• Varied route of administration and dose• Same protocol across studies• Evaluation of sex differences• Ensuring consistent/complete dose delivery

Dosing• Cannabis obtained from NIDA• Passive, vaporized, ingested, smoked• PL, 10mg, 25mg, and 50mg* doses

* Oral administration only

14

Assessments

2

Biological Specimens• Whole blood: THC, 11-OH-THC, and

THCCOOH (LOQ = 0.5ng/mL)• Urine: THCCOOH (LOQ = 0.75ng/mL)• Saliva/oral fluid: THC and THCCOOH (LOQ =

2 and 0.02 ng/mL respectively)

Passive Exposure Study• 3 test sessions; 12 participants per session

5.3% THC cannabis; no ventilation11% THC cannabis; no ventilation11% THC cannabis; ventilation

• 6 smokers (ad-lib) and 6 passively exposed• 60-minute exposure period

Test Chamber

Effect of Ventilation

Can I Get a Contact High?

Can I Get a Contact High?

PK/PD Summary• Urine: Cmax, 2-11 hrs; >15 ng/mL, 2-30 hrs• OF: Cmax = 0.25 hr; > 4 ng/mL, 0.25-2 hrs• Blood: Cmax = 0.25-2 hrs; Two > 5 ng/mL• Room ventilation has a significant impact on

secondhand smoke exposure• Under extreme circumstances, intoxication

and positive drug tests can occur• Likelihood of positive test depends on the

biological matrix and cut-offs used

Oral Administration• Study 1: Pharmacokinetic Emphasis

- 3 doses of cannabis- Between subjects design- Assessments over 9 days (PD on Day 1)

• Study 2: Pharmacodynamic Emphasis- 3 doses plus placebo- Within-subjects crossover design- PK/PD for 8 hours post-administration

Study 1 Methods• 18 healthy adults recruited

- Prior cannabis use; not in past 3 months• 6-days residential; 3-days outpatient • Single dose of cannabis administered Day 1

- Whole plant cannabis baked into brownies with 10, 25, or 50mg THC

- 3M/3F administered each dose• Standard low-fat breakfast provided

Drug Preparation• Cannabis ground into powder• Heated for 30 min at 250°F (121°C)• Individual doses stirred into brownie batter

and baked for 30 min at 325°F (163°C)

25

0100200300400500600

0 50 100 150 200

ng/m

L

Hours

Oral Cannabis, THCCOOH, Urine

THCCOOH Mean UR, 10 mgTHCCOOH Mean UR, 25 mgTHCCOOH Mean UR, 50 mg15 ng/mL Cutoff

Urine PK

26

Urine PK

0

200

400

600

800

1000

1200

1 2 3 4 5 6 Mean

ng/m

L

Subjects Dosed

UR Cmax, Oral Cannabis (THCCOOH)

10 mg 25 mg 50 mg

0

50

100

150

200

1 2 3 4 5 6 MeanH

ours

Subjects Dosed

UR Detection Times, Last Positive 15 ng/mL, Oral Cannabis (THCCOOH)

10 mg 25 mg 50 mg

27

Oral Fluid THC

0

250

500

750

1000

0 2 4 6

ng/m

L

Hours

Oral Cannabis, THC, Oral Fluid

THC Mean OF 10 mg

THC Mean OF 25 mg

THC Mean OF 50 mg

28

Oral Fluid THCCOOH

0

50

100

150

200

250

0 50 100

pg/m

L

Hours

Oral Cannabis, THCCOOH, Oral Fluid

THCCOOH Mean OF 10 mgTHCCOOH Mean OF 25 mgTHCCOOH Mean OF 50 mg50 pg/mL Cutoff

29

Whole Blood THC

0

1

2

3

0 6 12 18 24 30

ng/m

L

Hours

Oral Cannabis, THC, Blood

THC Mean BL, 10 mgTHC Mean BL, 25 mgTHC Mean BL, 50 mg2 ng/mL Cutoff

30

Whole Blood 11-OH-THC

0

1

2

3

4

0 6 12 18 24 30

ng/m

L

Hours

Oral Cannabis, 11-OH-THC, Blood11-OH THC Mean BL, 10 mg

11-OH THC Mean BL, 25 mg

11-OH THC Mean BL, 50 mg

31

Whole Blood THCCOOH

0

10

20

30

0 40 80 120

ng/m

L

Hours

Oral Cannabis, THCCOOH, BloodTHCCOOH Mean BL, 10 mg

THCCOOH Mean BL, 25 mg

THCCOOH Mean BL, 50 mg

Oral Administration

• THC = Passive• THC = Smokers at baseline• Drug Effect much greater

Oral PK SummaryURINE• Long detection times for THCCOOHORAL FLUID• Short detection times for THC• THCCOOH was erraticBLOOD• Very low cannabinoid concentrations• 2/6 at 50 mg THC dose had 5 ng/mL peak• 2/6 at 10 mg did not have detectable THC• Moderate correlation with VAS Drug Effect, but

not performance impairment

Study 2 Methods• 17 healthy adults (9M, 8F)

- Prior cannabis use; not in past month- No cannabis use between sessions

• 4 outpatient sessions; 1 week between • Within-subjects crossover design

- 10, 25, and 50mg THC doses- Placebo = 250mg cannabis < 1% THC

• Standard low-fat breakfast provided

VAS: Drug Effect

*

**

VAS: Good Effect

*

**

VAS: Unpleasant Effect

**

Other Subjective Effects• Increased ratings of Tired/Sleepy, Heart

Racing, Nervous/Anxious, Hungry/Have Munchies; Decreased rating of Alert following 25 and 50mg doses

• Increased ratings of Paranoid, Irritable, Sick and Restless at 50mg dose

Heart Rate

**

DSST: # Correct

**

PASAT: # Correct

**

Div Attention: Tracking

**

PK/PD Correlations

PK/PD Correlations

Oral PD Summary• Orderly dose effects observed across

pharmacodynamic measures • 25mg and 50mg THC doses consistently

different from placebo; subjective intoxication and performance impairment evident

• 10mg THC dose generally not different from placebo on negative effects

• Greater drug effects for females on select outcomes

Smoke Vs. Vapor• 17 healthy adults (9M, 8F)

- Prior cannabis use; not in past month- No cannabis use between sessions

• 6 outpatient sessions; 1 week between • Within-subjects crossover design

- PL, 10, and 25mg THC doses- Clustered by route, counterbalanced- Random order within route

• Standard low-fat breakfast provided

Drug Administration• Smoked: exact dose of cannabis placed in

pipe; covered; participants instructed to smoke entire contents ad-lib; checked for completion by pharmacist

• Vaporized: exact dose of cannabis placed in Volcano vaporizer; Temp set to 400°F (204°C); opaque bag covered “balloon”; participant inhaled 3 “balloons” ad-lib

VAS: Drug Effect

0

10

20

30

40

50

60

70

80

90

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

SmokedSmoke PL

Smoke 10mg

Smoke 25mg

0

10

20

30

40

50

60

70

80

90

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

VaporizedVape PL

Vape 10mg

Vape 25mg

VAS: Good Effect

0

10

20

30

40

50

60

70

80

90

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

SmokedSmoke PL

Smoke 10mg

Smoke 25mg

0

10

20

30

40

50

60

70

80

90

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

VaporizedVape PL

Vape 10mg

Vape 25mg

VAS: Unpleasant Effect

0

10

20

30

40

50

60

70

80

90

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

SmokedSmoke PL

Smoke 10mg

Smoke 25mg

0

10

20

30

40

50

60

70

80

90

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

VaporizedVape PL

Vape 10mg

Vape 25mg

Heart Rate

60

65

70

75

80

85

90

95

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

SmokedSmoke PL

Smoke 10mg

Smoke 25mg

60

65

70

75

80

85

90

95

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

VaporizedVape PL

Vape 10mg

Vape 25mg

DSST: # Correct

40

42

44

46

48

50

52

54

56

58

60

-1 0.5 1 1.5 2 3 4 5 6 8Hours

Smoked

Smoke PL

Smoke 10mg

Smoke 25mg

40

42

44

46

48

50

52

54

56

58

60

-1 0.5 1 1.5 2 3 4 5 6 8Hours

Vaporized

Vape PL

Vape 10mg

Vape 25mg

PASAT: # Correct

60

65

70

75

80

85

90

-1 0.5 1 1.5 2 3 4 5 6 8Hours

Smoked

Smoke PL

Smoke 10mg

Smoke 25mg

60

65

70

75

80

85

90

-1 0.5 1 1.5 2 3 4 5 6 8Hours

Vaporized

Vape PL

Vape 10mg

Vape 25mg

Div Attention: Tracking

10

15

20

25

30

35

40

45

50

55

60

-1 0.5 1 1.5 2 3 4 5 6 8Hours

SmokedSmoke PL

Smoke 10mg

Smoke 25mg

10

15

20

25

30

35

40

45

50

55

60

-1 0.5 1 1.5 2 3 4 5 6 8Hours

VaporizedVape PL

Vape 10mg

Vape 25mg

Blood THC

0

2

4

6

8

10

12

14

16

BL 0.16 0.5 1 1.5 2 3 4 5 6 8

ng/m

L

Hours

10mg smoke

25mg smoke

10mg vape

25mg vape

Oral Fluid THC

0

100

200

300

400

500

600

BL 0.16 0.5 1 1.5 2 3 4 5 6 8

ng/m

L

Hours

10mg smoke

25mg smoke

10mg vape

25mg vape

* THCCOOH less than 0.01ng/mL for all samples

Smoke/Vape Summary• Orderly dose effects observed• Vaporization produced greater THC exposure

and was associated with higher drug effects• Blood biomarkers decreased rapidly and

returned to baseline before drug effects

Comparison of Outcomes by Route of

Administration

“Drug Effect” by Route

0

10

20

30

40

50

60

70

80

90

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

25mg THCSmoke

Vape

Oral

0

10

20

30

40

50

60

70

80

90

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

10mg THCSmoke

Vape

Oral

Heart Rate (BPM)

60

65

70

75

80

85

90

95

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

10mg THCSmoke

Vape

Oral

60

65

70

75

80

85

90

95

100

-1 0.16 0.5 1 1.5 2 3 4 5 6 8Hours

25mg THC Smoke

Vape

Oral

PASAT Number Correct

-25

-20

-15

-10

-5

0

5

10

-1 0.5 1 1.5 2 3 4 5 6 8

Hours

10mg THC

Smoke

Vape

Oral

-25

-20

-15

-10

-5

0

5

10

-1 0.5 1 1.5 2 3 4 5 6 8

Hours

25mg THC

Smoke

Vape

Oral

DSST Number Correct

-15

-10

-5

0

5

-1 0.5 1 1.5 2 3 4 5 6 8

Hours

10mg THC

Smoke

Vape

Oral

-15

-10

-5

0

5

-1 0.5 1 1.5 2 3 4 5 6 8

Hours

25mg THC

Smoke

Vape

Oral

Blood THC Levels (ng/mL)

0

5

10

15

20

BL 0.16 0.5 1 1.5 2 3 4 5 6 8

Hours

10mg THC

Smoke

Vape

Oral

0

5

10

15

20

BL 0.16 0.5 1 1.5 2 3 4 5 6 8

Hours

25mg THC

Smoke

Vape

Oral

Adverse Events• 6 instances of vomiting (4 oral, 1 smoke, 1

vape)• 3 instances of moderate to severe

panic/anxiety reactions (2 oral, 1 vape)• 1 panic case also included hallucinations and

a self-reported dissociative experience• Nausea, dizziness, somnolence, common at

higher doses and with vaped > oral/smoked

Comparative Summary• Type and magnitude of effects similar, but

vaporized > oral and smoked • Same individuals showed comparable

likelihood for adverse effects across- Adverse events included nausea/vomiting, dizziness,

anxiety/paranoia, and dry mouth

• Different time course for oral vs inhaled; cardiovascular vs subjective vs performance; frequent users vs infrequent-users

Testing Issues• Window of detection in urine exceeds drug

effects and increases with frequency of use• Can’t reliably differentiate acute use from

residual cannabinoids in frequent users• No biomarker that predicts impairment• Employers in most states can still restrict

employment based on drug testingMaine law now negates this

Treatment of CUD• Subset of cannabis users develop problems• Same types of problems as other drugs• Extreme difficulty in quitting• Effective treatments available• Most community clinics/providers have

programs

Limitations• Only infrequent cannabis users enrolled• Assessed the low end of doses • Only one type of cannabis (high THC, low

CBD) studied • Other routes of administration and product

types still need to be evaluated (transdermal, suppository, oils/concentrates, etc.)

Summary• Cannabis testing and policy is incredibly

complex• No good way to determine time of last use or

impairment except when use was very recent• Big differences by route of administration• Tolerance is a factor• Future studies will explore other product

types and novel methods of determining impairment

Thanks!!• Collaborators: Ed Cone, Evan Herrmann, Nick

Schlienz, George Bigelow, John Mitchell, Ron Flegel, Charlie LoDico, Eugene Hayes

• NIDA Drug Supply Program• Johns Hopkins ICTR• Heroic efforts of support staff and my family

• Contact Info: rvandrey@jhmi.edu410-550-4036