1. another one of man’s oldest drugs!
medicinal uses documented back to
ancient times…..
Cannabis sativa

3. THC – major psychoactive ingredient in the marijuana plant
cannibinol and cannbidiol also components but less present in plants

4. THC mimics action of endogenous cannabinoid (anandamide)
until ~ 1990 – classified as a mild sedative- hypnotic agent with effects similar to low doses of alcohol
since early 1990’s – evidence that THC binds to specific cannabinoid receptors in brain (CB-1) and PNS (CB-2).
THC mimics action of endogenous cannabinoid (anandamide)
exist in brain in quantities that exceed more NT

5. a bit of history first known written record
China - Emperor Shen-Nung (2737 B.C.E),
beriberi, constipation, "female weakness," gout, malaria, rheumatism and absentmindedness
Egypt (20th century B.C.E)
cannabis was used to treat sore eyes

6. Marijuana in America
1545 – Spaniards brought marijuana to New World; English introduced it in Jamestown in where became a major commercial crop (hemp for rope)
by 1890 – cotton replaced hemp as major cash crop in southern states

7. Marijuana in America (2)
some medications contained marijuana ingredients but % very small in comparison with cocaine and heroin
1920’s – some historians claim its emergence due to prohibition
use mostly restricted to jazz muscians and people in show business
known as an evil and menace

8. Controlled Substance Act of 1970
classified marijuana with heroin and LSD as a schedule I drug (high abuse liability and no medicinal value)

9. Some current facts
most widely used illicit drug in US and western hemisphere
15 million illicit users
2009 – 25% teenage Americans had smoked marijuana in past month (Partnership for a Drug-Free America)
Early onset of heavy use (daily) (by about 12 years of age) – is associated with more severe psychopathology in later life
gateway drug?

10. 15

11. Primary psychoactive ingredient in marijuana
marijuana contains 500+ chemicals with unique to the plant
66 chemicals called cannabinoids – unique to cannabis plant
1964 – principle psychoactive agent identified
most abundant psychoactive agent is ∆9 THC (isolated in 1964)

12. Names for cannabis products
marijuana, hashish, charas, bhang, ganja, sinsemilla
Hashish and charas – dried resinous exudates of female flowers – most potent (THC 10 – 20%)
Ganja and Sinsemilla – dried material found in tops of female plants (5 – 8%)
marijuana – lower grade preps taken from dried remainder of plant (2 – 5%)

13. potency can also differ based on
where plant is grown
times (higher potency now than 20 years ago)

14. So where does ∆9 THC work?
currently know about two cannabinoid receptors
CB1 – found primarily in brain
Highest quantity in basal ganglia, hippocampus, cerebellum, cortex and spinal cord
CB2 – found primarily in periphery
Immune system; heart, and body tissues involved in inflamation and pain responses
endogenous agent – endocannabinoids
Anadamide -
sanskrit for “internal bliss”

15. What does the CB1 receptor do?
THC receptor is a specific G-protein-coupled receptor
CB-1 receptors are primarily found on presynaptic terminals and inhibit calcium ion flux and facilitate potassium channels
(inhibits release of other nt – primarily GLU)

16. Anandamide first isolated in 1992
weaker agonist than THC (also shorter ½ life)
partial agonist at hippocampal GLU releasing neurons
produces behavioral, hypothermic, and analgesic effects similar to cannabinoids
anandamide – activates only ~ 50% of available receptors (THC only ~ 20%)
structurally- unlike THC

17. Routes of administration
can be smoked or ingested (oral)
effects after smoking lasts 2 – 4 hours
cannot be injected because resin is not water soluble
highly lipid soluble and so regular use can result in storage in fats for weeks – shows up in urine tests

18. Pharmacokinetics Depends on route of administration
Smoking – smoking patterns…..
oral adm

19. pharmacokinetics oral administration smoking
THC preparation – dronabinol (Marinol)
available since mid 1980’s
onset is delayed and 1st pass metabolism quite high
taken for appetite stimulation
smoking
effects almost immediately after smoking begins; Peak blood about 10 min after initiation
within 2 hrs levels fall

20. absorption, metabolism, excretion
distribution particlarly to organs with fatty material;
readily crosses brain, placenta,
Metabolized by p450 enzymes to active metabolite which is then converted to inactive metabolite and excreted
much of THC stored in body fat and slowly released

21. Metabolism Clearing metabolites
Can be as short as 2 days (for the one time user)
6 weeks (for the chronic user) following the last dose.

22. Pharmacological Effects
Effects on the CNS
analgesic – in rodents THC is analgesic (and blocked by CB1 antagonists)
Sativex – used for relieving pain associated with MS
used in UK, Canada, in Phase III clinical trials in US
cannibas based pharmaceutical product containing THC and cannabidiol delivered in an oromucosal spray
decreases body temperature
calms aggressive behavior
potentiates the effects of barbiturates and other sedatives
blocks convulsions
depresses reflexes

23. Other effects Primate studies decreases complex behavior
increase social interactions
increase feeding behavior
(CB 1 receptors in hypothalamus and limbic system)
increase intake of sweet and fatty foods

24. CNS effects of THC vary with dose, route of administration, experience of user, vulnerability to psychoactive effects and setting

25. Behavioral effects (1)
Psychological – euphoria, relaxation, sleepiness, “insight’
Perceptual – altered perception of space and time, mood changes, more introspective, more “creative”
primates – hallucinating?

26. Behavioral effects of ∆9 THC
Cognitive Effects – impairment of short term memory (little doubt about acute – long term is more controversial)
Attentional issues
divided attention – easily distracted
increased risk for accident correlated with blood concentrations
Psychosis?

27. Peripheral Manifestations of Marijuana
fairly minimal
main manifestations of acute marijuana intoxication
tachycardia (heart rate)
no association with MJ use w cardiovascular disease
peripheral CB2 receptors may be defense of heart against ischemic attack
conjunctival reddening of eyes (vasodilation)
possible headache

28. pulmonary reproduction
Marijuana smoke contains many of the same tars and carcinogenic compounds as cigarettes but in greater quantity (more benzopyrene
single mj may be more harmful then because……
reproduction
controversial; some data suggest reduced T
alterations in female cycling
offspring?

29. immune system CB2 receptors play regulatory role in immune function
long-term MJ use associated with some immunosuppression; significance??
other depressant drugs do the same
seem to exert antitumor effects

30. Tolerance Animal models – yes Humans – less clear
tolerance appears to result from cannabinoid induced down regualtion and desensitization of brain CB1 receptors

31. Dependence? Primarily psychological dependence
Physical? - maybe with very very high doses…..
studies in late 1970’s – early 1980’s
210 mg THC (10 – 20 joints/day) – can precipitate an abstinence syndrome that may include irritability, restlessness, reduced appetite, etc.
more recent – 1999 study with 4 days – 4 joints/day
no participants requested to stop the study
Some recent studies ( ) suggest there may be something…..

32. Treatment?
no evidence-based pharmacotherapies for managing cannabis WD or craving
behavior therapies – perhaps

33. Possible Therapeutic value of cannabinoid agonists
medical application of MJ focus ofpublic and scientific interest for a long time
Nausea and Vomiting
Dronabinol (Marinol)
synthetic cannabinol
available for medical use (Schedule III) for chemotherapy-induced nausea
approved in 1993 for AIDS patients –
data not compelling that this is the best drug
Increasing appetite
Aids-related wasting disease

34. Other therapeutic uses
brain injury?
pain in advanced cancer (Canada)
possibility of cannabidiol instead-
has beneficial effects (analgesic, antiemetic, antitumor) but not intoxication, sedation or tachycardia

35. synthetic cannabinoid agonists of abuse
2007 –
“spice”, K2, “kind”
labeled as “incense” not intended for human consumption
widely sold on internet
herbals in the prep do not activate the CB receptors but synthetic drugs added to mix do
so far these are undetectable in chemical analysis fur MJ and other drugs of abuse

36. some of these compounds are currently illegal in numerous countries (and some states in the US including KY)

37. Interesting final points
overactive CB system may contribute to numerous diseases including
obesity, nicotine dependence, obesity-related cardiovascular disorders, etc
would cannabinoid antagonists work?
rimonabant (Acomplia)
concern in the US about safety?
other agents?