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2/10/2015 Tetrahydrocannabinolic acid (THCA) – Plant Precursor to THC H OH COOH H O THCA Non‐psychoactive THC Psychoactive “THC” present in Cannabis exists mostly as THCA – assumed self‐defense role for plant Drying or heating the plant material (smoking or vaporizing) converts THCA to THC. Extensive heat and/or drying over time further converts THC to CBN (weakly psychoactive). THC, CBD and CBN – Most Extensively Studied Phytocannabinoids Tetrahydrocannabinol (THC) Cannabidiol (CBD) Cannabinol (CBN) Concentration ranges from 1 ‐ 40% of plant extract Up to 40% of plant extract (variable) Trace amounts though increases over time (THC degradation product) Pi Primary psychoactive h ti component in Cannabis Non psychoactive Non‐psychoactive, anti‐convulsant, anxiolytic activity Weakly psychoactive What is the thermodynamic driving force for conversion of THC to CBN? Which compounds are chiral? 1 2/10/2015 Endocannabinoids – Compounds Produced In Vivo That Bind to CB Receptors Anandamide most studied endocannabinoid. Sanskrit for “bliss”. O HO Anandamide Endocannabinoid that binds CB1 and CB2 receptors N H THC Phytocannabinoid that binds CB1 and CB2 receptors Compare molecular shape and polarity of anandamide and THC. THC Chemical Properties • Glassy solid / sticky solid depending on temperature • Low water solubility Low water solubility • Soluble in organic solvents – can be extracted by various methods • Boiling point 250 °C 2 2/10/2015 THC Pharmacokinetics Absorption Smoked/vaporized, oral, transdermal, sublingual, rectal suppository Effects last 2 3 hours or less if smoked longer if taken orally Effects last 2‐3 hours or less if smoked – longer if taken orally Smoking/vaporizing allows titration of desired dose Distribution Accumulates in lipophilic tissues THC Pharmacokinetics Metabolism Primarily occurs in liver – lesser extent in intestines, brain, heart, lung, other tissues Primarily occurs in liver lesser extent in intestines, brain, heart, lung, other tissues >100 metabolites formed Primary route – oxidative metabolism followed by conjugation to more water‐soluble metabolite 3 2/10/2015 THC Metabolism – Primary Route OH H OH H O 11‐OH‐THC Psychoactive metabolite THC HO O H Biphasic effects may be attributed to active metabolites. OH 11‐OH‐THC potentially causes increased appetite. H O THC‐COOH Inactive metabolite Drug screens analyze inactive metabolite THC‐COOH Excretion of THC and Its Metabolites HO O H OH H O THC COOH THC‐COOH THC COOH glucuronide THC‐COOH‐glucuronide Predominately THC‐COOH and THC‐COOH‐glucuronide excreted in urine. Trace THC excreted in urine, and some 11‐OH‐THC excreted in feces. 4 2/10/2015 Outline Mechanism for Conversion of CBD to THC (Laboratory Reaction) 5