Marijuana

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Marijuana

• Carl L. Hart, Ph.D.
• Division on Substance Abuse, New York State
  Psychiatric Institute, Department of Psychiatry,
  College of Physicians and Surgeons, and
  Department of Psychology, Columbia University

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ASAMs 2008 Review Course in Addiction Medicine

• ACCME required disclosure of
• relevant commercial relationships
• Dr. Hart discloses that he has received honoraria
  from Shire, Inc.,
• for consulting services .

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Brief Recent History

• Late 1920s marijuana associated with crime and
  ethnic minorities
• Public concern aroused
• Passage of Marijuana Tax Act of 1937
• When 1937 tax act was passed, MJ was not
  regulated by the same system as the opioids and
  cocaine--intent was to eliminate its use
• May 1969 ruled unconstitutional
• Controlled Substance Act of 1970

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Marijuana Constituents

• Contains a complex mixture of over 400 chemicals
• 66 are cannabinoids
• ?9-THC is the primary psychoactive constituent

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Common Forms of Cannabis

• Hashish - dried resin and compressed flowers
• ?9-THC content ranged from 3 to 7 with rare
  increases as high as about 20
• Accounted for samples in the past ten years
• Marijuana - dried flowering tops and leaves
• Wide range of ?9-THC content with rare increases
  as high as about 26
• most common form

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Marijuana Current Prevalence

• Most widely used illicit drug in the world
• 150 million annual users (amphetamines 34
  million)

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Marijuana Prevalence

• In the U.S., 50 of young adults (18-25 yrs old)
  report annual use
• 15 million current users (past month use)
• 2 million new users (stable since mid-1990s)
• Concern about use by youth

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MTF Marijuana Use
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MTF Marijuana Use
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MTF Marijuana Use
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?9-THC in U.S. Confiscated Marijuana
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Significance of modest ?9-THC increase?

• Public officials express concern about
  marijuana-related negative effects
• e.g., dependence, toxicity
• Similar psychoactive effects, but more pronounced

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Pharmacology

• Receptors
• CB1 (primarily in brain)
• CB2 (immune system)

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Brain regions rich with cannabinoid receptors
Function
Region

• Nigrostriatal region
• Cerebellum
• Hippocampus
• Nucleus accumbens
• Cerebral cortex
• Moderate Levels
• Hypothalamus
• Amygdala
• Brain stem
• Spinal cord

• Movement
• Fine motor movements
• Learning and memory
• Drug reinforcement
• Higher cognitive functions
• Temperature regulation
• Emotionality
• Sleep and arousal, nausea
• Pain

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Abuse Potential

• Rats and squirrel monkeys will consistently
  self-administer cannabinoids
• Human marijuana smokers robustly self-administer
  marijuana
• Self-administration related to ?9-THC content of
  the cigarettes
• In U.S., 7 million classified as dependent or
  abuser of illicit drugs
• Marijuana accounted for 4 million
• More people sought treatment for marijuana than
  any other illicit drug

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Basic Pharmacology Review of Acute Effects

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

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Smoked Marijuana Subjective Effects
Hart et al. 2001, Neuropsychopharmacology
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Oral ?9-THC Subjective Effects
Hart et al. accepted, pending revisions
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Basic Pharmacology Review of Acute Effects

• Abuse Potential (high)
• Positive subjective effects (increased)
• Some negative effects in infrequent smokers
• Anxiety
• Mild paranoia and hallucinations

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Basic Pharmacology Review of Acute Effects

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

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Smoked Marijuana Heart Rate
Hart et al. 2001, Neuropsychopharmacology
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Oral ?9-THC Heart Rate
Hart et al. 2005, Psychopharmacology
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Basic Pharmacology Review of Acute Effects

• Abuse Potential (high)
• Positive subjective effects (increased)
• Heart rate (increased)
• Food intake?
• Medical marijuana issue

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Possible Medical Uses for Marijuana

• Chemotherapy-induced nausea
• Marinol (dronabinol) ?9-THC in sesame oil in a
  gelatin capsule
• FDA-approved in 1985
• Appetite stimulant for AIDS wasting
• FDA-approved in 1992
• Various types of pain
• Glaucoma
• Anticonvulsant
• Multiple Sclerosis-related spasticity

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Basic Pharmacology Review of Acute Effects

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

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Total Caloric intake
Hart et al. 2002, Psychopharmacology
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Individual Data
Hart et al. 2002, Psychopharmacology
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Basic Pharmacology Review of Acute Effects

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

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Smoked Marijuana Acute Cognitive Effects

• Cognitive performance is disrupted temporarily in
  several domains
• slowed cognitive processing
• impaired short-term memory
• impaired inhibitory control
• loss of sustained concentration or vigilance
• impaired visuospatial processing
• Cognitive effects are dose-related
• Cognitive effects less dramatic in frequent
  smokers
• Perhaps due to tolerance

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Basic Pharmacology Review of Acute Effects

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

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Driving Ability

• Findings have been inconsistent
• Epidemiological studies
• Little evidence that drivers who use marijuana
  alone are more likely to be involved in an
  accident than non-drug using drivers
• Laboratory studies
• Computer-controlled driving simulator data
  indicate that marijuana produces significant
  impairments

Ramaekers et al. 2004, Drug and Alcohol Dependence
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Basic Pharmacology Review of Acute Effects

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

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Psychotic illness

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

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Basic Pharmacology Review of Acute Effects

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

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Consequences of Chronic Marijuana Smoking

• Physical dependence?

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Cannabinoid Withdrawal in Laboratory Animals

• SR 141716A, a CB1 cannabinoid antagonist produces
  a reliable withdrawal syndrome in laboratory
  animals undergoing chronic cannabinoid treatment
• Symptoms
• wet-dog shakes, paw tremors, piloerection, and
  increased grooming
• reduced DAergic activity in the VTA-NAc pathway,
  and upregulated expression and release of CRH in
  the central nucleus of the amygdala

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Medication effects on precipitated cannabinoid
withdrawal symptoms
Hart 2005, Drug and Alcohol Dependence
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DSM-IV-TR Substance Dependence

• Three or more occurring in same 12-month period
• 1) tolerance
• 2) withdrawal
• 3) uses more or over longer period than intended
  
• 4) persistent desire or unsuccessful efforts to
  cut down or control use
• 5) a great deal of time spent in activities
  necessary to obtain substance
• 6) important social, occupational, recreational
  activities reduced or given up because of the
  substance
• 7) continued use despite recurrent
  substance-related physical or psychological
  problem(s)

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Consequences of Chronic Marijuana Smoking

• Physical dependence
• In laboratory animals (yes)
• In human?

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Marijuana Withdrawal in Humans

• Observed following abrupt cessation of several
  days of cannabis administration
• Generally, only observed in heavy users
• Symptoms include
• increased anxiety, restlessness, depression, and
  irritability
• disrupted sleep, decreased food intake
• Symptoms
• begin 1 day after cannabinoid cessation and
  persist from 4 to 14 days, depending on an
  individuals level of dependence.

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Medication effects on marijuana withdrawal
symptoms
Hart 2005, Drug and Alcohol Dependence
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Consequences of Chronic Marijuana Smoking

• Physical dependence (yes)
• Cognitive impairment?

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Smoked Marijuana Long-term Cognitive Effects

• Data have been inconclusive
• Subtle deficits following brief abstinence
• Short-term memory
• In general, following a sufficient abstinent
  period ( 1 month), regular marijuana use appears
  to produce minimal effects on cognition as
  measured by standard neuropsychological tests

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Consequences of Chronic Marijuana Smoking

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

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Consequences of Smoking Marijuana High Risk
Groups

• Individuals with pre-existing diseases
• Cardiovascular
• Respiratory diseases, chronic bronchitis
• Schizophrenia, depression
• Dependence on other substances

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Take-home Message

• Much has been learned about marijuana-related
  effects, but much remains unknown
• Important considerations
• Acute vs long-term effects
• Account for marijuana use history
• Account for co-occurring illnesses