1. Marijuana

2. Brief Recent History Late 1920s marijuana associated with crime and ethnic minorities Late 1920s marijuana associated with crime and ethnic minorities –Public concern aroused Passage of Marijuana Tax Act of 1937 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 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

3. Marijuana Constituents Contains a complex mixture of over 400 chemicals Contains a complex mixture of over 400 chemicals –~66 are cannabinoids –∆ 9 -THC is the primary psychoactive constituent

4. Common Forms of Cannabis Hashish - dried resin and compressed flowers Hashish - dried resin and compressed flowers –∆ 9 -THC content ranged from 3 to 7% with rare increases as high as about 20% –Accounted for < 1% of all confiscated marijuana samples in the past ten years Marijuana - dried flowering tops and leaves Marijuana - dried flowering tops and leaves –Wide range of ∆ 9 -THC content with rare increases as high as about 26% –most common form

5. Marijuana: Current Prevalence Most widely used illicit drug in the world Most widely used illicit drug in the world –150 million annual users (amphetamines ~34 million)

6. Marijuana Prevalence In the U.S., 50% of young adults (18- 25 yrs old) report annual use 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

7. MTF: Marijuana Use

10. ∆ 9 -THC in U.S. Confiscated Marijuana 0 1 2 3 4 5%THC 70758085909500 Year

11. Significance of modest ∆ 9 -THC increase? Public officials express concern about marijuana-related negative effects Public officials express concern about marijuana-related negative effects –e.g., dependence, toxicity Similar psychoactive effects, but more pronounced Similar psychoactive effects, but more pronounced

12. Pharmacology Receptors Receptors –CB 1 (primarily in brain) –CB 2 (immune system)

13. Brain regions rich with cannabinoid receptors Nigrostriatal region Nigrostriatal region Cerebellum Cerebellum Hippocampus Hippocampus Nucleus accumbens Nucleus accumbens Cerebral cortex Cerebral cortex Moderate Levels Hypothalamus Hypothalamus Amygdala Amygdala Brain stem Brain stem Spinal cord Spinal cord Movement Fine motor movements Learning and memory Drug reinforcement Higher cognitive functions Temperature regulation Emotionality Sleep and arousal, nausea Pain Region Function

14. Abuse Potential n Rats and squirrel monkeys will consistently self-administer cannabinoids n Human marijuana smokers robustly self- administer marijuana – Self-administration related to ∆ 9 -THC content of the cigarettes n 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

15. Basic Pharmacology: Review of Acute Effects Abuse Potential (high) Abuse Potential (high) Positive subjective effects (euphoria)? Positive subjective effects (euphoria)?

16. Smoked Marijuana: Subjective Effects Hart et al. 2001, Neuropsychopharmacology

17. Oral ∆ 9 -THC: Subjective Effects Hart et al. accepted, pending revisions

18. Basic Pharmacology: Review of Acute Effects Abuse Potential (high) Abuse Potential (high) Positive subjective effects (increased) Positive subjective effects (increased) Some negative effects in infrequent smokers Some negative effects in infrequent smokers –Anxiety –Mild paranoia and hallucinations

19. Basic Pharmacology: Review of Acute Effects Abuse Potential (high) Abuse Potential (high) Positive subjective effects (increased) Positive subjective effects (increased) Heart rate? Heart rate?

20. Smoked Marijuana: Heart Rate Hart et al. 2001, Neuropsychopharmacology

21. Oral ∆ 9 -THC: Heart Rate Hart et al. 2005, Psychopharmacology

22. Basic Pharmacology: Review of Acute Effects 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 issue

23. Possible Medical Uses for Marijuana Chemotherapy-induced nausea Chemotherapy-induced nausea –Marinol® (dronabinol): ∆ 9 -THC in sesame oil in a gelatin capsule –FDA-approved in 1985 Appetite stimulant for AIDS wasting Appetite stimulant for AIDS wasting –FDA-approved in 1992 Various types of pain Various types of pain Glaucoma Glaucoma Anticonvulsant Anticonvulsant Multiple Sclerosis-related spasticity Multiple Sclerosis-related spasticity

24. Basic Pharmacology: Review of Acute Effects Abuse Potential (high) Abuse Potential (high) Positive subjective effects (increased) Positive subjective effects (increased) Heart rate (increased) Heart rate (increased) Food intake? Food intake?

25. Total Caloric intake Hart et al. 2002, Psychopharmacology

26. Individual Data Hart et al. 2002, Psychopharmacology

27. Basic Pharmacology: Review of Acute Effects 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?

28. Smoked Marijuana: Acute Cognitive Effects n 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 n Cognitive effects are dose-related n Cognitive effects less dramatic in frequent smokers –Perhaps due to tolerance

29. Basic Pharmacology: Review of Acute Effects 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?

30. Driving Ability Findings have been inconsistent Findings have been inconsistent Epidemiological studies: Epidemiological studies: –L ittle evidence that drivers who use marijuana alone are more likely to be involved in an accident than non-drug using drivers Laboratory studies: Laboratory studies: –Computer-controlled driving simulator data indicate that marijuana produces significant impairments Ramaekers et al. 2004, Drug and Alcohol Dependence

31. Basic Pharmacology: Review of Acute Effects 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?

32. Psychotic illness Association between between marijuana and illness not well understood 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

33. Basic Pharmacology: Review of Acute Effects 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 mouth Dry mouth Reddened eyes Reddened eyes

34. Consequences of Chronic Marijuana Smoking Physical dependence? Physical dependence?

35. Cannabinoid Withdrawal in Laboratory Animals n SR 141716A, a CB1 cannabinoid antagonist produces a reliable withdrawal syndrome in laboratory animals undergoing chronic cannabinoid treatment n 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

36. Medication effects on precipitated cannabinoid withdrawal symptoms Hart 2005, Drug and Alcohol Dependence

37. DSM-IV-TR Substance Dependence Three or more occurring in same 12-month period 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)

38. Consequences of Chronic Marijuana Smoking Physical dependence Physical dependence –In laboratory animals (yes) –In human?

39. Marijuana Withdrawal in Humans Observed following abrupt cessation of several days of cannabis administration Observed following abrupt cessation of several days of cannabis administration –Generally, only observed in “heavy” users Symptoms include: Symptoms include: –increased anxiety, restlessness, depression, and irritability –disrupted sleep, decreased food intake Symptoms : Symptoms : –begin 1 day after cannabinoid cessation and persist from 4 to 14 days, depending on an individual’s level of dependence.

40. Medication effects on marijuana withdrawal symptoms Hart 2005, Drug and Alcohol Dependence

41. Consequences of Chronic Marijuana Smoking Physical dependence (yes) Physical dependence (yes) Cognitive impairment? Cognitive impairment?

42. Smoked Marijuana: Long-term Cognitive Effects n Data have been inconclusive Subtle deficits following brief abstinence Subtle deficits following brief abstinence – Short-term memory n 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

43. Consequences of Chronic Marijuana Smoking Physical dependence (yes) Physical dependence (yes) Cognitive impairment (inconclusive) Cognitive impairment (inconclusive) High risk groups? High risk groups?

44. Consequences of Smoking Marijuana: High Risk Groups Individuals with pre-existing diseases Individuals with pre-existing diseases –Cardiovascular –Respiratory diseases, chronic bronchitis –Schizophrenia, depression –Dependence on other substances

45. Take-home Message Much has been learned about marijuana- related effects, but much remains unknown Much has been learned about marijuana- related effects, but much remains unknown Important considerations Important considerations –Acute vs long-term effects –Account for marijuana use history –Account for co-occurring illnesses