(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 plant
Cannabis sativa
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 .511%; a typical “joint” is about 2-3%.
Therapeutic capsules, Dronabinol - Oral ingestion
Toxicokinetics
Inhalation: – – –
Oral Ingestion: – – – –
Rapidly delivered to lungs Efficient absorption into bloodstream System bioavailability ranges 10-35% 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-hydroxydelta-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 & 4953 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 recirculation Passive smoke: detection in urine??? Not at normal cut-offs
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
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
