Marijuana. Brief Recent History Late 1920s marijuana associated with crime and ethnic minorities Late 1920s marijuana associated with crime and ethnic

MarijuanaMarijuana

Brief Recent HistoryBrief Recent History Late 1920s marijuana associated with crime Late 1920s marijuana associated with crime

and ethnic minoritiesand ethnic minorities– Public concern arousedPublic concern aroused

Passage of Marijuana Tax Act of 1937Passage of Marijuana Tax Act of 1937 When 1937 tax act was passed, MJ was not When 1937 tax act was passed, MJ was not

regulated by the same system as the opioids regulated by the same system as the opioids and cocaine--intent was to eliminate its useand cocaine--intent was to eliminate its use– May 1969 ruled unconstitutionalMay 1969 ruled unconstitutional– Controlled Substance Act of 1970Controlled Substance Act of 1970

Marijuana ConstituentsMarijuana Constituents

Contains a complex mixture of over 400 Contains a complex mixture of over 400 chemicalschemicals– ~66 are cannabinoids~66 are cannabinoids– ∆∆99-THC is the primary psychoactive constituent-THC is the primary psychoactive constituent

Common Forms of CannabisCommon Forms of Cannabis Hashish - dried resin and compressed Hashish - dried resin and compressed

flowersflowers– ∆∆99-THC content ranged from 3 to 7% with rare -THC content ranged from 3 to 7% with rare

increases as high as about 20%increases as high as about 20%– Accounted for < 1% of all confiscated marijuana Accounted for < 1% of all confiscated marijuana

samples in the past ten yearssamples in the past ten years Marijuana - dried flowering tops and leavesMarijuana - dried flowering tops and leaves

– Wide range of ∆Wide range of ∆99-THC content with rare increases as -THC content with rare increases as high as about 26% high as about 26%

– most common formmost common form

Marijuana: Current Prevalence Marijuana: Current Prevalence Most widely used illicit drug in the worldMost widely used illicit drug in the world

– 150 million annual users (amphetamines ~34 million)150 million annual users (amphetamines ~34 million)

Marijuana PrevalenceMarijuana Prevalence In the U.S., 50% of young adults (18-In the U.S., 50% of young adults (18-

25 yrs old) report annual use25 yrs old) report annual use– ~15 million current users (past month use)~15 million current users (past month use)– >2 million new users (stable since mid-1990s)>2 million new users (stable since mid-1990s)– Concern about use by youthConcern about use by youth

MTF: Marijuana UseMTF: Marijuana Use

Year

USE

0

10

20

30

40

50

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 2004

% R

ep

ort

ing

Us

e in

Pa

st

30

Da

ays


Year

USE

RISK

30

40

50

60

70

80

90

0

10

20

30

40

50

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 2004

% R

ep

ort

ing

Us

e in

Pa

st

30

Da

ays %

Re

po

rting

Ris

k &

Ava

ilabilty


Year

USE

RISK

AVAILABILTY

30

40

50

60

70

80

90

0

10

20

30

40

50

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 2004

% R

ep

ort

ing

Us

e in

Pa

st

30

Da

ays %

Re

po

rting

Ris

k &

Ava

ilabilty

∆∆99-THC in U.S. Confiscated -THC in U.S. Confiscated MarijuanaMarijuana

0

1

2

3

4

5%

THC

%TH

C

70 75 80 85 90 95 00

YearYear

Significance of modest ∆Significance of modest ∆99-THC -THC increase?increase?

Public officials express concern about Public officials express concern about marijuana-related negative effectsmarijuana-related negative effects– e.g., dependence, toxicity e.g., dependence, toxicity

Similar psychoactive effects, but more Similar psychoactive effects, but more pronouncedpronounced

PharmacologyPharmacology

ReceptorsReceptors– CBCB11 (primarily in brain) (primarily in brain)– CBCB22 (immune system) (immune system)

Brain regions rich with Brain regions rich with cannabinoid receptorscannabinoid receptors

Nigrostriatal regionNigrostriatal region CerebellumCerebellum Hippocampus Hippocampus Nucleus accumbens Nucleus accumbens Cerebral cortexCerebral cortexModerate LevelsModerate Levels HypothalamusHypothalamus AmygdalaAmygdala Brain stemBrain stem Spinal cordSpinal cord

MovementMovement Fine motor movementsFine motor movements Learning and memoryLearning and memory Drug reinforcementDrug reinforcement Higher cognitive functionsHigher cognitive functions

Temperature regulationTemperature regulation EmotionalityEmotionality Sleep and arousal, nauseaSleep and arousal, nausea PainPain

RegionRegion FunctionFunction

Abuse PotentialAbuse Potential Rats and squirrel monkeys will consistently Rats and squirrel monkeys will consistently

self-administer cannabinoidsself-administer cannabinoids Human marijuana smokers robustly self-Human marijuana smokers robustly self-

administer marijuanaadminister marijuana– Self-administration related to Self-administration related to ∆∆99--THC content of the THC content of the

cigarettescigarettes In U.S., ~7 million classified as dependent In U.S., ~7 million classified as dependent

or abuser of illicit drugs or abuser of illicit drugs – Marijuana accounted for ~4 millionMarijuana accounted for ~4 million– More people sought treatment for marijuana than any More people sought treatment for marijuana than any

other illicit drugother illicit drug

Basic Pharmacology: Review of Basic Pharmacology: Review of Acute EffectsAcute Effects

Abuse Potential (high)Abuse Potential (high) Positive subjective effects (euphoria)?Positive subjective effects (euphoria)?

Smoked Marijuana: Subjective Smoked Marijuana: Subjective EffectsEffects

.

Rat

ing

(mm

)

0

20

40

60

80

-30 7 90 140 -30 7 90 140

Time (min)

"Good Drug Effect" "High"

3.9%1.8%0%

THC Concentration

Hart et al. 2001, NeuropsychopharmacologyHart et al. 2001, Neuropsychopharmacology

Oral ∆Oral ∆99-THC: Subjective Effects-THC: Subjective Effects

0

20

40

60

80

0 45 95 140 185

Rat

ings

(mm

) (m

axim

um =

100

)

Time (min)

"Good Drug Effect"

20100

9THC Dose (mg)

Hart et al. accepted, pending revisionsHart et al. accepted, pending revisions


Abuse Potential (high)Abuse Potential (high) Positive subjective effects (increased) Positive subjective effects (increased) Some negative effects in infrequent smokersSome negative effects in infrequent smokers

– AnxietyAnxiety– Mild paranoia and hallucinationsMild paranoia and hallucinations


Abuse Potential (high)Abuse Potential (high) Positive subjective effects (increased) Positive subjective effects (increased) Heart rate?Heart rate?

Smoked Marijuana: Heart RateSmoked Marijuana: Heart Rate

60

70

80

90

100bp

m

0 10 50 105 140

Time (min)

3.9%1.8%0%

THC Concentration

Hart et al. 2001, NeuropsychopharmacologyHart et al. 2001, Neuropsychopharmacology

Oral ∆Oral ∆99-THC: Heart Rate-THC: Heart Rate

60

70

80

90

100

110bp

m

0 30 60 90 120 150 180 210 240

Time (min)

20100

9THC Dose (mg)

Hart et al. 2005, PsychopharmacologyHart et al. 2005, Psychopharmacology


Abuse Potential (high)Abuse Potential (high) Positive subjective effects (increased)Positive subjective effects (increased) Heart rate (increased)Heart rate (increased) Food intake?Food intake?

– Medical marijuana issueMedical marijuana issue

Possible Medical Uses for Possible Medical Uses for MarijuanaMarijuana

Chemotherapy-induced nauseaChemotherapy-induced nausea– Marinol® (dronabinol): ∆Marinol® (dronabinol): ∆99-THC in sesame oil in a -THC in sesame oil in a

gelatin capsulegelatin capsule– FDA-approved in 1985FDA-approved in 1985

Appetite stimulant for AIDS wastingAppetite stimulant for AIDS wasting– FDA-approved in 1992FDA-approved in 1992

Various types of painVarious types of pain GlaucomaGlaucoma AnticonvulsantAnticonvulsant Multiple Sclerosis-related spasticityMultiple Sclerosis-related spasticity


Abuse Potential (high)Abuse Potential (high) Positive subjective effects (increased)Positive subjective effects (increased) Heart rate (increased)Heart rate (increased) Food intake?Food intake?

Total Caloric intakeTotal Caloric intake

1 2 31000

2000

3000

4000

1 2 3 1 2 3

Baseline Active Placebo

kcal

MJ QID

THC QID

PboActiveBaseline* * *

** *


Individual DataIndividual Data

50040030020010000

100

200

300

400

500 Day 2

r = .95; p < .01

2016128400

4

8

12

16

20 Day 2

r = .97; p < .01

Number of Eating OccasionsRatings of "Hungry"

AUC (Oral ² 9-THC)

AU

C (S

mok

ed M

ariju

ana)



Abuse Potential (high)Abuse Potential (high) Positive subjective effects (increased)Positive subjective effects (increased) Heart rate (increased)Heart rate (increased) Food intake (increased)Food intake (increased) Cognitive effects?Cognitive effects?

Smoked Marijuana: Acute Smoked Marijuana: Acute Cognitive Effects Cognitive Effects

Cognitive performance is disrupted Cognitive performance is disrupted temporarily in several domains:temporarily in several domains: – slowed cognitive processingslowed cognitive processing– impaired short-term memoryimpaired short-term memory– impaired inhibitory controlimpaired inhibitory control– loss of sustained concentration or vigilanceloss of sustained concentration or vigilance– impaired visuospatial processingimpaired visuospatial processing

Cognitive effects are dose-relatedCognitive effects are dose-related Cognitive effects less dramatic in Cognitive effects less dramatic in

frequent smokersfrequent smokers– Perhaps due to tolerancePerhaps due to tolerance


Abuse Potential (high)Abuse Potential (high) Positive subjective effects (increased)Positive subjective effects (increased) Heart rate (increased)Heart rate (increased) Food intake (increased)Food intake (increased) Cognitive effects (variable)Cognitive effects (variable) Driving ability?Driving ability?

Driving AbilityDriving Ability Findings have been inconsistentFindings have been inconsistent Epidemiological studies:Epidemiological studies:

– LLittle evidence that drivers who use marijuana alone ittle evidence that drivers who use marijuana alone are more likely to be involved in an accident than are more likely to be involved in an accident than non-drug using driversnon-drug using drivers

Laboratory studies:Laboratory studies:– Computer-controlled driving simulator data indicate Computer-controlled driving simulator data indicate

that marijuana produces significant impairmentsthat marijuana produces significant impairments

Ramaekers et al. 2004, Ramaekers et al. 2004, Drug and Alcohol DependenceDrug and Alcohol Dependence


Abuse Potential (high)Abuse Potential (high) Positive subjective effects (increased)Positive subjective effects (increased) Heart rate (increased)Heart rate (increased) Food intake (increased)Food intake (increased) Cognitive effects (variable)Cognitive effects (variable) Driving ability (depends on model used)Driving ability (depends on model used) Does marijuana cause psychotic illness?Does marijuana cause psychotic illness?

Psychotic illnessPsychotic illness

Association between between marijuana Association between between marijuana and illness not well understoodand illness not well understood– Marijuana use can precipitate psychotic episodesMarijuana use can precipitate psychotic episodes– No evidence that marijuana can cause the underlying No evidence that marijuana can cause the underlying

psychotic disorderpsychotic disorder


Abuse Potential (high)Abuse Potential (high) Positive subjective effects (increased)Positive subjective effects (increased) Heart rate (increased)Heart rate (increased) Food intake (increased)Food intake (increased) Cognitive effects (variable)Cognitive effects (variable) Driving ability (depends on model used)Driving ability (depends on model used) Does marijuana cause psychotic illness (unclear)Does marijuana cause psychotic illness (unclear) Verbal Behavior (decreased)Verbal Behavior (decreased) Dry mouthDry mouth Reddened eyes Reddened eyes

Consequences of Chronic Consequences of Chronic Marijuana SmokingMarijuana Smoking

Physical dependence?Physical dependence?

Cannabinoid Withdrawal in Cannabinoid Withdrawal in Laboratory AnimalsLaboratory Animals

SR 141716A, a CB1 cannabinoid SR 141716A, a CB1 cannabinoid antagonist produces a reliable withdrawal antagonist produces a reliable withdrawal syndrome in laboratory animals syndrome in laboratory animals undergoing chronic cannabinoid treatmentundergoing chronic cannabinoid treatment

Symptoms:Symptoms:– wet-dog shakes, paw tremors, piloerection, and wet-dog shakes, paw tremors, piloerection, and

increased groomingincreased grooming– reduced DAergic activity in the VTA-NAc pathway, and reduced DAergic activity in the VTA-NAc pathway, and

upregulated expression and release of CRH in the upregulated expression and release of CRH in the central nucleus of the amygdalacentral nucleus of the amygdala

Medication effects on Medication effects on precipitated cannabinoid precipitated cannabinoid

withdrawal symptomswithdrawal symptomsInvestigators Species Medication OutcomeVerberne et al. 1981 Rat ² 9-THC ² 9-THC reduced withdrawal symptoms.

Lichtman et al. 2001 Mouse ² 9-THC ² 9-THC reversed withdrawal-related paw

tremors.

Lichtman et al. 2001 Mouse Clonidine Clonidine reversed withdrawal-related

paw tremors.

Anggadiredja et al.

2003

Mouse Prostaglandin E2 Prostaglandin E2 lessened withdrawal

symptoms.

Cui et al. 2001 Rat Lithium Lithium blocked symptoms of

withdrawal symptoms.

Hart 2005, Drug and Alcohol DependenceHart 2005, Drug and Alcohol Dependence

DSM-IV-TR Substance DependenceDSM-IV-TR Substance Dependence Three or more occurring in same 12-month Three or more occurring in same 12-month

periodperiod– 1)1) tolerance; tolerance; – 2)2) withdrawal; withdrawal; – 3)3) uses more or over longer period than intended; uses more or over longer period than intended; – 4)4) persistent desire or unsuccessful efforts to cut persistent desire or unsuccessful efforts to cut

down or control use; down or control use; – 5)5) a great deal of time spent in activities necessary to a great deal of time spent in activities necessary to

obtain substance; obtain substance; – 6)6) important social, occupational, recreational important social, occupational, recreational

activities reduced or given up because of the activities reduced or given up because of the substance;substance;

– 7)7) continued use despite continued use despite recurrentrecurrent substance-related substance-related physical or psychological problem(s) physical or psychological problem(s)


Physical dependencePhysical dependence– In laboratory animals (yes)In laboratory animals (yes)– In human?In human?

Marijuana Withdrawal in Marijuana Withdrawal in HumansHumans

Observed following abrupt cessation of Observed following abrupt cessation of several days of cannabis administrationseveral days of cannabis administration– Generally, only observed in “heavy” usersGenerally, only observed in “heavy” users

Symptoms include:Symptoms include:– increased anxiety, restlessness, depression, and irritabilityincreased anxiety, restlessness, depression, and irritability– disrupted sleep, decreased food intakedisrupted sleep, decreased food intake

SymptomsSymptoms::– begin 1 day after cannabinoid cessation and persist from 4 begin 1 day after cannabinoid cessation and persist from 4

to 14 days, depending on an individual’s level of to 14 days, depending on an individual’s level of dependence.dependence.

Medication effects Medication effects on marijuana on marijuana

withdrawal symptomswithdrawal symptomsInvestigators Medication OutcomeHaney et al. 2001 Bupropion Bupropion worsened symptoms during

withdrawal.

Haney et al. 2003a Nefazodone Nefazodone decreased some withdrawal

symptoms, but it had no effect on most

symptoms.

Haney et al. 2004 Divalproex Divalproex worsened mood and psychomotor

performance during marijuana consumption

and during marijuana withdrawal.

Haney et al. 2004 ² 9-THC ² 9-THC reduced marijuana withdrawal

symptoms and reversed the withdrawal-

associated psychomotor performance

decrements and weight loss associated with

marijuana withdrawal.

Hart 2005, Drug and Alcohol DependenceHart 2005, Drug and Alcohol Dependence


Physical dependence (yes)Physical dependence (yes) Cognitive impairment?Cognitive impairment?

Smoked Marijuana: Long-term Smoked Marijuana: Long-term Cognitive Effects Cognitive Effects

Data have been inconclusiveData have been inconclusive Subtle Subtle deficitsdeficits following brief abstinence following brief abstinence

– Short-term memoryShort-term memory In general, following a sufficient abstinent In general, following a sufficient abstinent

period (> 1 month), regular marijuana use period (> 1 month), regular marijuana use appears to produce minimal effects on appears to produce minimal effects on cognition as measured by standard cognition as measured by standard neuropsychological testsneuropsychological tests


Physical dependence (yes)Physical dependence (yes) Cognitive impairment (inconclusive)Cognitive impairment (inconclusive) High risk groups?High risk groups?

Consequences of Smoking Consequences of Smoking Marijuana: High Risk GroupsMarijuana: High Risk Groups

Individuals with pre-existing diseasesIndividuals with pre-existing diseases– CardiovascularCardiovascular– Respiratory diseases, chronic bronchitisRespiratory diseases, chronic bronchitis– Schizophrenia, depression Schizophrenia, depression – Dependence on other substancesDependence on other substances

Take-home MessageTake-home Message Much has been learned about marijuana-Much has been learned about marijuana-

related effects, but much remains related effects, but much remains unknownunknown

Important considerationsImportant considerations– Acute vs long-term effectsAcute vs long-term effects– Account for marijuana use historyAccount for marijuana use history– Account for co-occurring illnesses Account for co-occurring illnesses

Documents

Marijuana. Brief Recent History Late 1920s marijuana associated with crime and ethnic minorities Late 1920s marijuana associated with crime and ethnic