another one of man’s oldest drugs!

medicinal uses documented back to ancient times…..

Cannabis sativa

THC – major psychoactive ingredient in the marijuana plant

cannibinol and cannbidiol also components but less present in plants

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

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

1545 – Spaniards brought marijuana to New World; English introduced it in Jamestown in 1611 where became a major commercial crop (hemp for rope)

by 1890 – cotton replaced hemp as major cash crop in southern states

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

classified marijuana with heroin and LSD as a schedule I drug (high abuse liability and no medicinal value)

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?

15

marijuana contains 500+ chemicals with 60 + 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)

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%)

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

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”

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)

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

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

Depends on route of administration◦ Smoking – smoking patterns…..

◦ oral adm

oral administration◦ 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

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

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

dose.

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

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

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

Psychological – euphoria, relaxation, sleepiness, “insight’

Perceptual – altered perception of space and time, mood changes, more introspective, more “creative”◦ primates – hallucinating?

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?

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

pulmonary◦ 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?

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

Animal models – yes Humans – less clear tolerance appears to result from

cannabinoid induced down regualtion and desensitization of brain CB1 receptors

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 (2008-2009) suggest there may be something…..

no evidence-based pharmacotherapies for managing cannabis WD or craving

behavior therapies – perhaps

medical application of MJ focus ofpublic and scientific interest for a long time

Nausea and Vomiting◦ Dronabinol (Marinol) - 1986

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

brain injury?

pain in advanced cancer (Canada)

possibility of cannabidiol instead- has beneficial effects (analgesic, antiemetic,

antitumor) but not intoxication, sedation or tachycardia

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

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

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?