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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