Acute vs Chronic Frequent Cannabis IntakeACMT Seminars in Forensic Toxicology December 9, 2015Professor Dr. Dr. (h.c.) Marilyn A. HuestisChief, Chemistry & Drug Metabolism, IRPNational Institute on Drug Abuse, NIH

Cannabinoid Pharmacokinetics

Plasma PharmacokineticsAfter Acute Smoked Cannabis

Absorption: Inhalation• Highly efficient route of drug delivery to the brain, similar to iv route • Rapid onset of effects due to speed of drug delivery to the brain• Effective drug delivery contributes to high abuse liability of smoked drugs

THC, 11-OH-THC & THCCOOH Plasma Concentrations After Single THC Cigarette180150120

906030

0-2 2 6 10 14 18 22

THCµg/L

Minutes

THC11-OH THCTHCCOOHInhaleN = 6

3.55% THC

Absorption: Inhalation• Rapid, peak occurs during smoking• Systemic availability 18 - 50%• Smoking dynamics important: # puffs, duration

& volume of inhalation, hold time, time between puffs, smoking time, experience of smoker

• Individuals titrate their smoked or vaporized dose• THC disposition attributed to 1° & 2° tissue distribution, metabolism & excretion

Inter-subject Variability in Plasma Concentrations

µg/L

0

100

200

300

-0.2 0.0 0.2 0.4 0.6 0.8 1.0

Subject BSubject CSubject ESubject FSubject GSubject H

HoursSmoking

3.55% THC

Cannabinoid Metabolism∆9-Tetrahydrocannabinol

(THC)

11-hydroxy-THC(11-OH-THC)

11-nor-9-carboxy-THC(THCCOOH)

Glucuronidation

Cannabinol (CBN)

Cannabidiol (CBD)

CYP 2C9CYP 2C19CYP 2D6

Alcohol dehydrogenase ormicrosomal alcohol oxygenase

& aldehyde oxygenase

UGT 1A3UGT 1A1

UGT 1A9UGT 1A10

UGT 1A9UGT 1A10

Chronic Daily Cannabis SmokersAfter Acute ExposureUrinary Cannabinoid Excretion in Occasional Cannabis Smokers

Excretion• Urine excretion ≈ 15-30%, fecal 27-65%• Calculated half-lives affected by sampling time, assay sensitivity & specificity, frequency of use • Plasma THC t 1/2 estimates range from 20 h to 12 d, best estimate ≈ 4.3 days• Urine THCCOOH t 1/2 best estimate ≈ 3.0 days

Urinary THCCOOH ExcretionAmt Remaining to be Excreted Method

t 1/2 = 29.9 hr = 0.92

2.53.03.54.04.55.05.5

0 24 48 72 96 120 144 168Hours

199.7 µg excreted in 7 d0.54% of 33.8 mg THC dose

Subject B 3.55% THC

Urinary Cannabinoid Excretion• Common assumption that cannabinoids positive in

urine for weeks after last use• Huestis et al 1995 J Anal Toxicology

– Acute smoked THC (1.75; 3.55%)– Collected all specimens for 21 days– EMIT immunoassay last positive test

• 50 ng/mL 1 - 2 days– GCMS

• 15 ng/mL up to 5 days

Differentiating New Cannabis Use From Residual Cannabinoid Excretion in Less than Daily Cannabis Smokers: Creatinine-Normalized Urine THCCOOH Concentrations

Detecting New Cannabis Use in Occasional Smokers• Urine THCCOOH concentrations in 2 specimens collected at known times• Was cannabis smoked between collections?• Frequent problem faced by:

– Drug treatment programs– Drug courts– Workplace drug testing program– Parole officers– Military commanders

Calculation of NormalizedTHCCOOH Concentrations:• Urine Cannabinoids = ng/mL• Urine Creatinine = mg/mL• ng/mL = ng Cannabinoids

mg/mL mg Creatinine• Later normalized value divided

by the earlier normalized value

Creatinine Normalization Improves Differentiation of New Cannabinoid Use from Residual Drug Excretion

ng/mg

Hours

ng/mL After controlled administration of 3.55% smoked THC

0255075

100125150

0255075

100125150

0 30 60 90 120 150 180

THCCOOH/creatinine (ng/mg)THCCOOH (ng/mL)

Differentiating New Drug Use from Residual Drug Excretion• Normalized ratio ≥ 1.5 • Current prediction accuracy: 74.2% • Sensitivity: 33.4% Specificity: 99.8%• FP: 0.1% FN: 27.0% • Normalized ratio ≥ 0.5• Best prediction accuracy: 85.4%• Sensitivity: 80.1% Specificity: 90.2%• FP: 5.6% FN: 8.6%

Actual Case• Urine collections:

Time THCCOOH Creatinine NormalizedDate/h ng/mL mg/dL ng/mg

9 Aug/1300 273 135 20213 Aug/0800 86 31.6 272

• New use indicated by pattern of excretion profile• If punitive outcome: U2/U1 must be >1.5 • Individual’s U2/U1 = 1.34

Actual Case: Findings• Prosecution position: new use was indicated by

pattern of excretion profile• Defense position: U2/U1 must be >1.5 to prove

new use beyond reasonable doubt. • Accused U2/U1 = 1.34• Accused acquitted of multiple uses of cannabis• Guilty of single use

New Model To Predict New Use• Smith et al, J Anal Toxicol 2009• Creatinine normalized urine pairs segregated by time interval between collection

– 0 - 24 h– 24 - 48h– 48 - 72h– 72 - 96h– > 96h

• U2/U1 calculated• Compare to minimum, median & maximum ratio for the specific timeframe between urine collections

Minimum, Median & Maximum Ratios for each 24 h Interval with Urine THCCOOH ≥15 µg/L

00.5

11.5

22.5

33.5

0-24 24-48 48-72 72-96 96+

Min Median Max

U2/U1

Time Interval between U2 & U1 (h)

Actual Case: Findings• This individual with urine cannabinoids/creatinine concentrations >200 ng/mg • 91 h between urine specimen collections & U2/U1 ratio 1.34• Max ratio for 72-96 h 0.3; highly likely smoked cannabis between U1 & U2• New U2/U1 ratio ranges for intervals between urine specimens improves differentiation of new cannabis use & residual urinary excretion of THCCOOH

Blood & Plasma Cannabinoids in Chronic Frequent Cannabis Smokers

Chronic Daily Cannabis SmokersAfter Acute ExposureChronic Frequent Cannabis Smokers Cannabinoid Concentrations in Blood & Plasma After Acute Smoked Cannabis

Smoked Cannabis Study• Smoked 6.8 % THC cannabis cigarette ~ 54 mg

1st blood10 min

after smoking1st blood = 10 min

Markers of Recent Cannabis Smoking in Blood

Chronic Daily Cannabis SmokersAfter Acute ExposureOccasional (N=10) & Chronic (N=10) Daily Cannabis Smokers Cannabinoid Concentrations in Blood After Acute Smoked Cannabis

Median Blood THC

Median Blood THCCOOH

Median Blood THCCOOH-glucuronide

Time of Last DetectionAnalyte Frequent Smoker (h) Occasional Smoker (h) Significant?

THC >30 (24.0->30) 4.0 (1.0-6.0) Y11-OH-THC 12.0 (3.1->30) 3.0 (1.0-5.0) YTHCCOOH >30 >30 N

CBD 0 (0-0.5) 0 NCBN 0.6 (0-2.1) 0 (0-1.1) Y

THC-glucuronide 0 (0-0.5) 0 (0-0.6) NTHCCOOH-glucuronide >30 27.0 (0->30) Y

Cannabinoids in Blood of Chronic

Frequent Cannabis Smokers During

Sustained Abstinence?

Participants• IRB approved, written informed consent• 28 subjects, 19 - 38 yrs, 50% male, 82.1% AA• Continuously resided on closed clinical unit • Whole blood collected upon admission & each 24 h

thereafter for 7 days• 12.8 ± 9.1 jts or blunts/day (2 – 40)

Whole Blood THC in 28 Frequent Cannabis SmokersDay N

≥ 0.25 µg/L% N

≥ 1 µg/L%

1 15 53.6 4 14.32 14 50.0 3 10.73 12 42.9 2 7.14 9 32.1 3 10.75 11 39.3 2 7.16 10 35.7 3 10.77 6 21.4 3 10.7

µg/L

Day

Whole Blood THC Positive All 7 Days

Participant Demographics for Whole Blood THC Positive All 7 DaysSubject Self report J or B/day Days used past 14 days BMI Gender

A 20 14 24.4 FB 7 11 26.6 FC 8 3 22.8 FD 32 14 39.0 FE 16 14 32.0 F

Chronic Daily Cannabis Smokers• Mean age 27.4±6.6 years (19–43)• Mean BMI 23.8±3.8 (16.4-32.8)• Mean cannabis joints/day 10.6±6.3 (1–30)• Mean years cannabis use 10.6±5.8 (4-28)• 1 subject ≥2 µg/L for 18 d & ≥1 µg/L for 30 d• THC detected in 3 of 5 specimens on day 30 (up to

1.3 µg/L)

Whole Blood Detection Rates for THC, 11-OH-THC & THCCOOH (0.5 ng/mL) in Chronic Daily Cannabis Smokers During 30 Days Sustained Abstinence

Round the Clock 20 mg Oral Synthetic THC/Marinol®• Synthetic THC in sesame oil• FDA-approved medication for nausea & vomiting with cancer chemotherapy & HIV-wasting disease

Around-the-Clock 20 mg Oral THC• Investigate THC & metabolite disposition in plasma

during around-the-clock oral THC in chronic cannabis smokers– After smoked cannabis self-administration– Single-dose oral THC (dronabinol) pharmacokinetics– During continuous dosing – During monitored abstinence

• Evaluate tolerance development & model daily therapeutic & recreational THC intake

Study Design• Institutional Review Board-approved study &

written informed consent• Subjects 10• Dosing 9 days 37 oral 20 mg THC doses

Escalating 40-120 mg THC/day• # Collections 36/subject• Cannabis use 7.9 ± 8.0 (1 – 24 joints/day)• Last cannabis use 0.7 ± 0.5 days (0 – 1)• Lifetime use 10 ± 4.7 years (4 – 18)

Cannabinoid Results in Plasma & OFN = 360 Plasma OF

THCµg/L11-OH-THCµg/L THCCOOHµg/L THCµg/L

11-OH-THCµg/L THCCOOHng/L% Positive 100 99.7 100 21.1 - 98.3

Range 1.2 -67.6 0.6 - 38.9 13.3 -497.9 0.5 -399.2 - 7.5 -1087.7Median Cmax 34.6 7.3 269.1 6.5 - 361.6Median Tmax (h) 103.5 149.5 161.0 -18.0 - 161.0

Plasma & OF THC ResultsTHC Plasma µg/L OF µg/L

Median Range Median RangeAdmission n = 10 5.2 2.4 - 33.3 3.3 ND - 399.2Pre-dose n = 30 3.6 1.5 - 33.3 2.1 ND - 399.21st dose n = 50 6.8 2.3 - 27.7 0.7 ND - 6.8

Days 2 - 4 (100 mg/d)n = 90 9.7 3.3 - 44.4 0.0 ND - 8.0Days 5 - 7 (120 mg/d) n = 90 10.8 4.2 - 67.6 0.0 ND - 1.1After last dose n = 80 5.3 1.2 - 31.3 ND NDAt discharge n = 10 3.2 1.2 - 5.2 ND ND

Breath Cannabinoid Concentrations After Acute Cannabis Smoking in Occasional & Chronic Frequent Smokers

THC-Positive Breath SpecimensTime after

smoking (h)Chronic Users

N=13Occasional Users

N=11Admission 15.4% 0

-1.0 0 00.5 100% 90.9%1.0 76.9% 63.6%2.0 53.8% 03.0 0 04.0 7.7% 0

THC Excretion in Weekly Sweat Patches in Chronic Daily Cannabis Smokers During Abstinence

What Is Best THC Blood Concentration To Indicate Driving Impairment?1, 2 or 5 µg/L?

Desrosiers et al 2014 Clinical Chemistry

Median % Positive Samples Blood THC 1 µg/L

Median % Positive Samples Blood THC 5 µg/L

Legal Limits for Blood THC Concentrations & Driving • In our research, occasional use = less than daily smoking & frequent smoking as daily cannabis smoking (varies by author)• WA state uses ≥ 5 µg/L THC cutoff; CO inference of impairment at ≥ 5 µg/L THC • Only 81.2% occasional smokers ≥ 5 µg/L at 30 min; all < 5 µg/L by 2 h• <20% frequent smokers ≥ 5 µg/L by 5 h; 16.7% still ≥ 5 µg/L after 30 h

Median Time of Last Detection in BloodAnalyte Frequent Smoker (h) Occasional Smoker (h) Significant?

THC (1 µg/L) >30 (24.0->30) 4.0 (1.0-6.0) YTHC (5 µg/L) 3.5 h (1.1->30 h) 1.0 h (0-2.1 h)* Y

11-OH-THC (1 µg/L) 12.0 (3.1->30) 3.0 (1.0-5.0) YTHCCOOH (1 µg/L) >30 >30 N

CBD (1 µg/L) 0 (0-0.5) 0 NCBN (1 µg/L) 0.6 (0-2.1) 0 (0-1.1) Y

THC-glucuronide (0.5) 0 (0-0.5) 0 (0-0.6) NTHCCOOH-glucuronide (5 µg/L) >30 27.0 (0->30) YTwo occasional smokers never had THC≥ 5µg/L

Urinary THCCOOH Excretion in Chronic Daily Cannabis Smokers

Cannabinoid Excretion Daily Use• 22 frequent cannabis users resided on closed

research unit under medical supervision• Urine cannabinoids screen >100 ng/mL on

admission• All urine specimens collected individually

ad libitum for up to 30 days• 50 ng/mL immunoassay; 15 ng/mL GCMS for

THCCOOH

Urinary THCCOOH Excretion in Chronic Daily Cannabis SmokersN AgeMeanSD

BMIMeanSDJts/DayMedian 1st Use MeanSD

YrsUsedMeanSDM 12 25.1 ±3.6 25.3 ±3.8 6.03 - 60 16.3 ±3.3 8.6 ±3.9

F 10 25.3 ±3.8 29.5 ±6.8 7.51 - 30 16.4 ±3.4 9.4 ±5.2

Urinary THCCOOH Excretion in Chronic Daily Cannabis SmokersN Days on UnitMeanSD

THCCOOH ng/mgMedianRange

Ist NegDaysMeanSD

Last PosDaysMeanSD

Last Posng/mgMeanSDM 12 26.3 ±3.9 28331 - 563 10.33.9 -17.2

20.5 ±6.3 6.53 - 26

F 10 27.6 ±3.3 17156 -793 9.1 2.2 –23.126.3 ±3.3 10.55 - 49

Daily Cannabis SmokersUrinary Excretion• 50% highest THCCOOH occurred in 1st urine• 50% Cmax up to 30 h after admission• No significant BMI difference for M or F• Mean±SD (range) time to last positive urine

– Males 491.2 ± 150.3 h (289.2 - 716.2)– Females 632.3 ± 79.6 h (498.7 - 716.0)

• Significantly longer urinary cannabinoid excretion rate in females (p<0.05)

Mean Detection Rates After 1st Negative THCCOOH in Urine

0

20

40

60

80

100

0 5 10 15 20 25 30Days After 1st Negative 50 µg/L Screen

Detec

tion Ra

te (%)

>150 ng/mg51 – 150 ng/mg0 – 50 ng/mg

Does Presence of THC &/or 11-OH-THC in Urine Suggest Recent Cannabis Use As Suggested by Kemp et al 1992, Manno et al 2001 & Brenneisen 2009

0

25

50

75

100

125

µg/L

-2 8 18 28 38 48 58 68 78 88Hours

THC11-OH-THCTHCCOOH

THC & Metabolite Urinary Excretion After One 2.74% THC Cigarette

Frequent Cannabis Exposure Study• IRB-approved; written informed consent• 33 subjects resided on closed research unit• All urine specimens individually collected for 30 days• Tandem E. coli ß-glucuronidase & alkaline hydrolysis

for THC, 11-OH-THC & THCCOOH in urine• All specimens quantified for 1st 3 days• Urinary THC <2.5 µg/L within 72 h of drug abstinence

in 26/33 (78%) daily smokers• 7 frequent users urine analyzed by 2D-GCMS• Testing stopped when THC <LOQ in 3 consecutive voids

Urine THC Concentrations

Relevance1st data on extended urinary excretion of THC,

11-OH-THC & THCCOOH in frequent cannabis users during monitored abstinenceTHC was detected in urine for up to 25 days after

tandem enzymatic & alkaline hydrolysisNeither THC or 11-OH-THC in urine are definitive

markers of recent cannabis use

Predicting New Cannabis Use in Urine Chronic Daily Cannabis Smokers

Model Development & Validation• Develop & validate a model to differentiate new cannabis use from residual urinary drug excretion in chronic daily cannabis smokers• Significance

– Extended excretion of cannabinoids in urine after chronic usage– No models developed or validated for chronic cannabis smokers

• All urine collected, cannabinoids quantified & normalized to creatinine concentrations

Model Development• 48 Participants resided on closed research unit throughout to preclude cannabis use• 2,377 urine specimens collected• For each subject, every specimen compared with every other specimen collected ≥48h later• 123,513 Specimen 2/Specimen 1 ratios• Ratios sorted into Specimen 1 groups: 6-15, 15-25, 25-50, 50-100, 100-200, 200-400, 400-600, >600 ng/mg

Model Development• Unique model for each Specimen 1 group• Prediction probabilities 80, 90, 95, 99%• Models developed for creatinine-normalized concentration ratios• Non-normalized ratio models abandoned

– Large variability– Less accurate predictions than creatinine-normalized models

Model Development

80% PI90% PI95% PI99% PI

7203600

Ratio

ΔT (≥48 H)

Single Specimen 1 GroupUpper PI Limit = Ae-kt + Z1-/2 S2Model + RMS√

Decision Rules: Rule 1• Increasing THCCOOH after admission

– Peak concentrations up to 40 h after admission– Represents cannabis use close to admission– Occurred in 6 participants (9%)– Ratios expected to be high

• Rule 1: Cannabis re-use predicted from 1st & 2nd specimens = do not use 1st specimen for predictions

Decision Rules: Rule 2• Admission specimen >800 ng/mg, remaining >200 ng/mg for up to 14 days• Occurred in 4 participants (6%)• Rule 2: If 1st specimen ≥800 ng/mg, & ≥200 ng/mg on day 5, false re-use predictions may occur up to 14 days

Decision Tree

New use predicted:False prediction possible for 14 days (Rule 2). Collect again after 15 days

Collect 2nd specimen on 5th dayCollect 2nd specimen ≥48h later

1st Specimen <800 ng/mg

Collect 1st Specimen

No new use predicted:Use 1st specimen for all comparisonsNew use predicted:Do not use 1stspecimen (Rule 1). Collect 3rdspecimen at least 48h later.

1st Specimen ≥800 ng/mg

<200 ng/mg:Model prediction accurate

≥200 ng/mg:

No new use predicted:Model prediction accurate

Suspected Cannabis Re-use

00.20.40.60.8

11.21.41.6

0 100 200 300 400 500 600

New use participant

Days

NN (ng/mL)CN (ng/mg)

Concen

tration

Ratio

ΔT

Specimen 1 group 200-400 ng/mg0

500100015002000

0 5 10 15 20 25 30

0

0.5

1

0 200 400 600

Ratio

Specimen 1 group 200-400 ng/mg

ΔT hours

Remaining 67 Participants

Model of Recent Cannabis Smoking Based on Urine THC-glucuronide (Desrosiers 2014 Clin Chem)• If urinary THC-glucuronide increase

– Absolute % difference ≥50% between 2 consecutive THC-glucuronide-positive samples – Creatinine-normalized concentration ≥ 2 µg/g in 1st

sample • Predicted cannabis smoking within 6 h of 1st urine sample with high efficiencies

– 93.1% in frequent smokers– 76.9% in occasional smokers

Subjective “High”

Dose & Tolerance Effects

D’Souza, Neuropsychopharmacology, 2008

Placebo NonabuserPlacebo Abuser

2.5 mg Nonabuser2.5 mg Abuser

5 mg Nonabuser5 mg Abuser

Total Immediate Recall Delayed Free Recall

Total Co

rrect Ite

ms Rec

alled

Hysteresis• Acute cannabis effects have counter-clockwise hysteresis indicating prominent distribution phase• After blood/tissue equilibrium (~ 45min), correlation of THCconcentrations & effects, e.g., tracking up to 7 h• Rarely is blood sampled in accident or DUID prior to distribution

Concentration Effect Curves

100

THC µg/L

BPM120

140

80

20015010050060

.15 h.25 h

.05 h

.10 h.79 h

12 h

6 h

VAS Feel Drug

20015010050001020304050

.20 h.38 h

.07 h

.15 h.79 h

Heart Rate

Hysteresis in Subjective “High”

Long-term Neurocognitive Impairment in

Chronic Cannabis Smokers?

Public Health & Safety Implications• Some states have zero tolerance or per se

legislation for cannabinoids in blood, plasma/serum or urine for driving under the influence of drugs

• Long-term cannabinoid excretion makes interpretation of cannabinoid involvement in accidents or crimes difficult

• Is there residual cognitive &/or psychomotor impairment with residual THC concentrations?

[18F]FMPEP-d2: inverse agonist radioligand for cannabinoid CB1 receptors, collaboration with NIMH, Bob Innes & Jussi Hirvonen

Reversible & Regionally Selective Downregulation of Brain Cannabinoid CB1Receptors in Chronic Daily Cannabis Smokers

Study Design & Subjects• [18F]FMPEP-d2 PET in cannabis users & healthy male subjects• Repeat [18F]FMPEP-d2 PET in cannabis users after 28 days monitored abstinence

Healthy Subjects Cannabis SmokersN 26 26

Age (yrs) 22 ± 10 29 ± 8BMI (kg/m2 27 ± 5 24 ± 4

Cannabis use <10X life 12 ± 8 yrs; 10 ± 7 jts/d

CB1-Cannabinoid Receptors Specifically Downregulated in Cortical Regions of Chronic Daily Cannabis Smokers (N=30) as Compared to Controls (N=28)Healthy subjects Chronic cannabis smokers

Group × region interaction: F=6.5, p=0.0001 * p < 0.05 ** p < 0.005Brain Region

CB1 Receptor DownregulationCorrelated with Years of Cannabis AbuseControl subjects: no correlation with age

CB1 Receptors Increase after Abstinence in Specific Brain Regions

Repetition × region interaction: F=3.3, p=0.037* p < 0.05

Does Cognitive Impairment Accompany Low Residual THC Concentrations in Chronic Frequent Cannabis Smokers?

Public Health & Safety Implications• Frequent cannabis exposure can produce neurocognitive impairment

– Solowij et al 1995: irreversible loss of cognitive performance in heaviest cannabis users– Pope et al 2001: impairment at least 7 but less than 28 days of abstinence in heavy users– Bolla et al 2002: dose-related cannabis impairment >28 days of abstinence

• Frequent cannabis smokers store THC in tissues, with increasing body burden with frequency & duration of use

Dunedin NZ Study• 1037 individuals followed from age 13 to 38• Cannabis use evaluated by interviews at 18, 21, 26, 32 & 38 years• Neuropsychological testing conducted at ages 13 & 38, before & after a pattern of persistent cannabis use developed• # occasions cannabis smoking ages 14-21 documented from never to >400 times• Later life outcomes dose-dependently varied withcannabis use frequency & age of 1st drug use

0 20 40 60 80Welfare

Unemployed

Income

Degree

Never1-99100-199200-299300-399400+

Cannabis Use & Later Life Outcomes Are Dose-Dependent

# occasions smokingcannabis

ages 14-21

% University degree age 25Personal income NZ $age 25%Unemployed (ages 21-25)% Welfare dependent(ages 21-25)

(Fergusson & Boden Addiction 2008)

Neuropsychological Decline from Childhood to Midlife with Persistent Cannabis Use• Meier et al 2012 Proc Nat Acad Sci

– Dunedin Study: 1037 individuals birth to 38 yrs– Reported neurotoxic cannabis effects on adolescent brain with persistent cannabis intake– Decline in function in multiple domains– Impairment strongest in adolescent-onset cannabis users, more persistent use greater decline in IQ– Cannabis cessation did not fully restore functioning among adolescent-onset cannabis users– Prevention & policy efforts should target adolescents

IQ tested ages 13 & 38; Meier MH et al., PNAS 2012

Neuropsychological Decline from Childhood to Midlife with Persistent Cannabis Use1 Diagnosis 2 Diagnoses 3+ Diagnoses

-0.8

-0.6

-0.4

-0.2

0

0.2

Change

in Full-

Scale IQ

(in

standar

d devia

tion un

its)

p = 0.44 p = 0.09 p = 0.02

Cannabis dependent before age 18Not cannabisdependent before age 18

Psychomotor Impairment & Chronic Frequent Cannabis Smoking

PLoS One 2012

Public Health & Safety Implications• Some states have zero tolerance or per se

legislation for cannabinoids in blood, plasma/serum or urine for driving under the influence of drugs

• Long-term cannabinoid excretion makes interpretation of cannabinoid involvement in accidents or crimes difficult

• Is there residual cognitive &/or psychomotor impairment with residual THC concentrations?

Psychomotor Impairment in Chronic Daily Cannabis Smokers • What is duration of psychomotor impairment in

chronic frequent cannabis smokers?• Compared psychomotor performance on tasks

validated by Jan Ramaekers at University of Maastricht to predict impaired on the road driving

• Compared performance of chronic frequent smokers to occasional cannabis & ecstasy users over 22 days

Psychomotor Tasks• Critical tracking

– Measures ability to control a displayed error signal in a 1st-order compensatory tracking task

– Primary dependent measure is frequency of control losses or critical frequency (λc)

• Tracking error during divided attention– Ability to divide attention between two tasks performed

simultaneously– Primary dependent measure is control losses & tracking

Divided Attention Task (DAT)• Control Losses

– # times cursor hits side marker• Mean Tracking Error

– Distance between cursor’s position & center of scale• “Hits”

– # of correct “2” detections• False alarms

– # of incorrect “2” detections• Reaction time

– Time to “2” detection (in msec)

Mean SE Critical Tracking Task in Chronic Cannabis Smokers During Sustained Abstinence

012345

BL D 8 D 14-16 D 21-23 Control

* * **

Mean±SE Tracking Error (mm) in Chronic Daily Cannabis Smokers During Sustained Abstinence

05

10152025

BL D 8 D 14-16 D 21-23 Control

* * ** # #

Mean±SE DAT Control Losses in Chronic Cannabis Smokers During Sustained Cannabis Abstinence

05

101520253035

BL D 8 D 14-16 D 21-23 Control

*

**

*#

Psychomotor Impairment in Chronic Cannabis Smokers• Psychomotor performance in critical tracking &

divided attention tasks in 19 male chronic, daily cannabis smokers impaired at baseline relative to occasional drug users

• Sustained cannabis abstinence moderately improved critical tracking & divided attention performance, but impairment still observable after 3 weeks of abstinence

Psychomotor Impairment in Chronic Cannabis Smokers• We reported significant increases in CB-1

cannabinoid receptors in specific brain areas during improvement in psychomotor performance

• Chronic daily cannabis smokers had impaired psychomotor function compared to occasional drug users for at least 3 weeks of sustained cannabis abstinence

KarlScheidweiler, PhD MadelineSwortwood, PhD

Xingxing Daio, PhD

Osama Abulseoud, MD

Maria Andersson, PhD Jeremy Charlier, PhD

Allan Barnes, BS

Rebecca Hartman, PhD

Matt Newmeyer, BS

Megan Taylor, BS Caitlin House, BS

Kayla Ellefson, MS Alex San Nicolas, MS CristinaSempio, MS

Maria LauraZuccoli, MD Jackie Highland, BS