Delta 9-tetrahydrocannabinol

(THC)

Diane Gubernot
PubH 242, Fall 2003
Dr. Guidotti
What is Delta-9-tetrahydrocannabinol?

„ Delta-9-tetrahydrocannabinol is also
called cannabinol, cannabis, and THC
„ THC is the chemical responsible for
most of the pharmocological and
pyschological effects in marijuana
„ It is derived from the Cannabis sativa
plant
Where THC is Encountered

„ Historically: used as a medicine in the

19th century, in the form of marijuana
„ Marijuana became a Schedule I
controlled substance in 1970.
„ Currently, THC found in:
– Marijuana (Widely used)
– Synthetic therapeutics (Dronabinol)
Chemical & Physical Properties

„ Solid
„ Highly lipophilic and water insoluable
„ Molecular formula: C12H30O2
„ Molecular Weight: 314.45
Exposure
„ Exposure is primarily deliberate
„ Marijuana
– Inhalation (including second-hand smoke)
– Oral ingestion (e.g. marijuana brownies)
– THC content in marijuana varies from .5-
11%; a typical “joint” is about 2-3%.
„ Therapeutic capsules, Dronabinol
- Oral ingestion
Toxicokinetics
„ Inhalation:
– Rapidly delivered to lungs
– Efficient absorption into bloodstream
– System bioavailability ranges 10-35%
„ Oral Ingestion:
– Absorption is low and erratic
– Degraded by stomach acid
– Liver metabolism also reduces the bioavailability
– Bioavailability ranges 4-14%
„ Multi-compartment toxicokinetic model
Dose-Response
„ When smoked: Maximum plasma
concentration achieved within minutes
– Psychotropic effects start in seconds or minutes,
reach a maximum at 15-30 min. and taper off
within 2-3 hours
„ Orally: psychotropic effects set in with a delay
of 30-90 min., reach maximum after 2-3 hours
and last for 4-12 hours
„ Dose dependent
„ Acts on cannabinoid receptors in the brain
Distribution
„ THC in blood: 90% plasma, 10% Red Blood
Cells (RBCs)
„ Almost 99% of THC in plasma is bound to
proteins
„ THC rapidly penetrates highly vascularized
tissue
„ Low concentrations in the brain probably due
to rate of moving in and out
„ Stored in fatty tissues
Metabolism

„ Mainly metabolized in the liver via

cytochrome P450 enzyme
„ Some metabolism in heart and lung
„ THC is rapidly converted to 11-hydroxy-
delta-9-THC, which produces the same
effects as the parent compound
„ 11-OH-THC stays in the brain, which
contributes to the effects of THC
Elimination

„ Slow due to re-diffusion from fat

„ Half-life reported at 20-30 hours & 49-
53 hours
„ Metabolites bound in plasma and slowly
excreted
 Excretion
„ THC excreted mainly as acid metabolites
„ 15-30% in urine
„ 30-65% in feces
„ Also detected in breast-milk
„ Urine detection: 2 to 19 days, depending on
the dosage
„ Excretion delayed by enterohepatic re-
circulation
„ Passive smoke: detection in urine???
Not at normal cut-offs
 THC
Metabolism,
Serum protein- Hepatic
binding Lung, intestine Extra-hepatic

metabolites
Tissue
Shortage [THC] in extracellular water Biliary
fat Excretion,
Enterohepatic
Hair [THC] at site of action recirculation
saliva
sweat Renal excretion
Cannabinol receptors
Glomerular filtration
.
Tubular secretion
THC effects Passive reabsorption
Toxicity & Carcinogenicity
„ There is no defined toxic threshold
„ “High” effects require a dose of about 5ug/kg
„ LD50 in rats/mice is extremely high
– 800-1900 mg/kg in rats
– CNS depression Death
– LD50 in monkeys and dogs unattainable at very
high doses
„ non-fatal consumption by the dog and monkey is
equal to a human eating 46 pounds of 1% marijuana
or 10lbs of 5% hashish at one time
„ No acute toxicity at usual doses consumed by
humans
„ No reports of fatalities due to “overdose” of marijuana
Toxicity & Carcinogenicity
„ Unlikely that there is a teratogenic risk
(birth defects)
„ Potential for high doses triggering a
myocardial infarction in susceptible
individuals
„ No reports of THC being carcinogenic
„ Mixed reports about marijuana causing
cancer
Health Outcomes: Immediate Effects
„ Impaired short-term memory
„ Dry mouth
„ Distorted perception
„ Euphoric feeling
„ Impaired judgment and complex motor
skills
„ Tachycardia (increased heart rate)
„ Anxiety, panic attacks, paranoia, and
lethargy at higher doses
Health Outcomes: Long-term Effects

„ Possible adverse effects on:

– Reproductive system
– Endocrine system
– Immune system
– Synthesis of nucleic acids and proteins
„ Respiratory
illnesses (associated with
smoking marijuana)
Health Outcomes - Marijuana

„ Deposits 4x as much tar in the lungs as

one tobacco cigarette
„ Cellular changes in lung are possible
pre-cursors of lung cancer
„ No evidence that smoking while
pregnant effects the fetus
„ Marijuana use produces a profound
tolerance, and possible dependence
Other Outcomes – Marijuana Use
„ Societal costs:
– Drug-related auto wrecks
– Property damage
– Truancy and school failure
– Drug-related crimes
„ Occupational Issues:
– Drug-related accidents
– Increased absences & tardiness
– Worker Compensation claims
– Lost productivity
Treatment

„ No antidote for THC

„ Therapy for Marijuana Use:
– Counseling
– Support-groups
– Drug-Rehab
„ Drug Use Prevention
 Biomarkers
„ THC metabolites can be detected in the
plasma, urine, hair and saliva
„ Plasma and saliva screen detect only very
recent use ( 4-12 hours)
„ Urine screens most widely used
– Detects recent use (approx. one week)
– Enzyme-linked Immunosorbant Assay
– 50ng/mL cut-off
„ Very unlikely that second-hand smoke be
detected in a urine screening test
 Special Issues – The Medical Debate
„ Studies show marijuana is an effective:
– Antiemetic
– Anticonvulsant
– Appetite stimulant
– Analgesic
– Muscle relaxant
– Also useful for treating: glaucoma, asthma, migraines
– Potentially useful for chronic pain
„ Effects the Central Nervous System by
suppressing neural impulses
„ Long-term medical use shows no physical or
cognitive effects
 Regulation
„ FDA Approved Dronabinol (brand name
Marinol) prescribed to chemotherapy
patients
– 1999 IOM Report states patients prefer smoking
marijuana to dronabinol since it is faster acting
and the dose is easier to control
„ Marijuana: Controlled Substance Act Schedule I
drug
– Considered to have no medical use
„ THC: Schedule I and II drug
– Has a medical use
.