HPH115 SPR2018_Lecture 2_THC.pdf - THC, , (phytocannabinoids arepartoftheen

HPH115 SPR2018_Lecture 2_THC.pdf - THC, ,...

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Unformatted text preview: THC, Other Phytocannabinoids and Some Synthetic Cannabinoids Types of Cannabinoids by Origin Depending on their origin, cannabinoids can be classified as: • • • Molecules that can be found in the plant (phytocannabinoids) Endogenous substances found in the animal organism that are part of the endocannabinoid system (endocannabinoids) Molecules that are synthesized in the laboratory (synthetic cannabinoids) *THC = major psychoactive drug in cannabis 1. Phytocannabinoids (phyto=plants): so comes from plants 2. Endocannabinoids: made by humans/ animals 3. Synthetic: man-made chemicals that mimic effects of phytocannabinoids that make it more specific and targeted/stronger function Chemical Structure of THC This is the structure of the THC compound Really hard to isolate pure compound of THC Method of separation (column chromatography): mass spectroscopy allowed for the full separation of chemicals inside the cannabis plants— defined the compound of THC and exactly what the structure looked like *know the scientists name* Method of separation: Column chromatography. Mass spectrometry, infrared spectroscopy, and NMR were also employed to identify chemicals separated by chromatography THC was first isolated, characterized and synthesized by Raphael Mechoulam & Yehiel Gaoni (1964) Tetrahydrocannabinol Numbering System The actual name of THC is delta 9- tetrahydrocannabinol Earlier work by Roger Adams and Alexander Todd in 1940s had shown that the natural material had a basic tricyclic benzopyran structure with a double bond either at the 9‐ or 8‐position in the alicyclic ring The Cannabinoid Receptors, by Patricia H. Reggio (ed.), 2009. Ch. 1 Key Structural Elements Contributing to Biological Activity in THC and Synthetic Cannabinoids (the C‐11 position in the alicyclic ring) The incorporation of a hydroxyl group at C‐11 increases the binding affinity to CB1 receptors (the hydroxyl at C‐1) The presence of a phenolic hydroxyl is very important for eliciting CB1 affinity (aliphatic side chain at C‐3) Cannabinoid activity is retained if the alkyl chain has minimum 3 to 8 carbon atoms the 4 places on the compound that are important in the biological effect of the THC on humans 1. Phenolic hydroxyl: critical position that is critical for THC effects—without it there will be no effect 2. Side chain: if you increase from 3 to 8 carbon atoms (optimal number is 7) then the biological effects of THC are greatly increased 3.Northern Aliphatic Hydroxyl: if you change this you can change the affinity of the compound to the target proteins in the animals—greater or lower 4. Soouthern Aliphatic Hydroxyl: if you change this then the potency of the THC will increase or decrease The Sciences of Marijuana, by L. L. Iversen, 1st ed., 2000. Ch. 2 People tested on small animals for different kinds of THC compounds—looked at several aspects to measure the potency of each type -do they show you reduced locomotor activity (are they slower in movement—reaction time) - hypothermia (is there a reduction in body temperature) - catalepsy (if put on a rod does the mouse freeze-up or become rigid —the skeletal muscle will become more stiff and rigid) - reduced sensitivity to pain (the mouse tail would be put on a plate with increasing temp and the tail flicks—under the influence the sensitivity will be reduced) THC Induces a Tetrad of Effects Behavior tests (tetrad) used to measure potency of the synthetic THC compounds made in the lab Administration of THC to mice leads to a classical “tetrad” of effects: • • • • Reduced locomotor activity Hypothermia (a decrease in core body temperature), Catalepsy as indicated by immobility in the ring test (a test that measures the animal’s behavior after it is placed on a horizontal wire ring) Hypoalgesia (reduced pain sensitivity) measured using the hot‐plate or tail‐flick test Catalepsy: a medical condition characterized by a trance or seizure with a loss of sensation and consciousness accompanied by rigidity of the body Psychopharmacology: Drugs, the Brain, and Behavior. 2nd ed., by Meyer JS & Quenzer LF, 2013 Cannabis High • A typical Cannabis high starts with tingling of the body and head, progresses to dizziness and a quickening of mental associations with sharpened senses, heightened perception, increased appetite, and a distortion of the sense of time, causing it to go faster, and ends with calm, drowsiness, and eventually sleep. (Iversen, Brain 126: 1252– 1270, 2003) • The pharmacokinetics (i.e., the movement of drugs within the body) of Δ9‐THC depends on the method of its administration. The “typical” effects of a cannabis high: individual starts with tingling of head and body individual becomes more sensitive to sensory stimulus and heightened perception individual has increased appetite to sugary and fatty food individual has distortion of time —feels longer than normal ends with calm, drowsiness and sleepiness Pharmacokinetics: research to understand the movement of a drug inside the human or animal body -starting with absorption, distribution, then metabolism, and excretion from the body the way a person takes/consumes the drug effects the pharmacokinetics Pharmacokinetics (Absorption, distribution, metabolism and elimination of a drug in the body over time) Routes of Administrations and the Subjective High Temporal relationship to the subjective high of people with different methods of consumption *by mouth: takes about 6 hours for the high to go away and gradually increases *by smoking: starts experiencing high feeling much faster (peak at 30 minutes) and dexreases very quickly with the high being over by 4 hours *THC does not dissolve very well in water—it dissolves in lipids but experimentally tested intravenously to see how the most effective method is compared to smoking and oral consumption (oral) (smoking) (i.v.) Time course of the subjective "high" after administering THC by different routes. Smoking gives as rapid an effect as an intravenous injection, whereas taking the drug by mouth produces a delayed and prolonged "high." The subjective experience somewhat outlasts the presence of THC in blood because THC persists longer in the brain. Temporal relationship again and this method of experimentally the testers know that smoking is the most effective method for temporal response (because really fast onset) and also that the THC presence in the blood/plasma is so fast Mean Time Course of Plasma THC Concentrations even before they are done with the joint/blunt the concentration of THC in the blood is already at the peak of absorption—THC is absorbed into the blood VERY quickly!! Summary: by inhalation there is a very fast and efficient delivery of THC to the blood—almost immediate effects Cannabinoids and THC are lipophilic—loves lipids and so by the second time around it is slower—the previously deposited compounds in fat cells/plasma membranes of cells are released and this prolongs the presence of THC in the blood (Smoking) Average blood levels of THC in human volunteers who smoked two identical marijuana cigarettes, each containing about 9 mg of THC, 2 hours apart. Insets show the rapid absorption of the drug during the period of smoking. The Sciences of Marijuana, by L. L. Iversen, 2nd ed., 2008. Ch. 2 Metabolic Transformation of 9‐THC (Note: Analogous pathways exist for 8‐THC and cannabichromanon) When THC comes into the body—orally -digestive system and degraded by digestive enxymes (dilutes so effects of THC) Marijuana and the Cannabinoids, M.A. ElSohly (ed.), 2007. Ch. 7 -carried by the blood to the liver—after liver degradation it is 11-delta9-THC which is more potent than the original compound of the THC (11-delta9-THC is a new metabolized compound which has higher affinity for target proteins in the body -further metabolized to 11-delta9-THC-carboxylic acid and this has no psychoactive effects and the body wants to get rid of it and excretes from the body in the urine Principal Route of THC Metabolism 11‐hydroxy‐THC: a psychoactive metabolite formed in the liver which is equipotent and longer‐ lasting compared with THC higher affinity for target proteins in the human body increasing the effects of the drug in the body= more potent (at the least it is equipotent/ equal) and longer lasting If you consume by smoking—you lose alot of THC by combustion (the burning) you can absorb quickly because of transfer from lungs to brain) the receptors in brain cells detect the THC compound quickly and are absorbed and put into blood stream non-psychoactive part of the compound that is excreted from the body The Sciences of Marijuana, by L. L. Iversen, 2nd ed., 2008. Ch. 2 Time Course of Plasma Concentrations of THC & Metabolites ( 9‐tetrahydrocannabinol) (11‐hydroxy‐ 9‐THC) (11‐nor‐9‐carboxy‐ 9‐THC) So little hydroxy-thc is made by the smoking process because only a portion is going through the liver for degradation as compared to oral consumption (which would have much more hydroxy-thc because all of it goes through the liver for degradation) Mean plasma concentrations of 9‐tetrahydrocannabinol (THC), 11‐hydroxy‐ 9‐THC (11‐OH‐THC), and 11‐nor‐9‐carboxy‐ 9‐THC (THCCOOH) by gas chromatography/mass spectrometry during smoking of a single 3.55% THC cigarette. Each arrow represents one inhalation or puff on the cannabis cigarette. (N = 6) Marijuana and the Cannabinoids, M.A. ElSohly (ed.), 2007, Ch. 9 Time Course of Plasma Concentrations of THC & Metabolites (Compressed Time Course) Clicker Q’s: 1. Cannabinoids are odorless! It is the turpenes that give the plant the odor and not the cannabinids 2. Male plant has clusters of flowers and is obvious ( 9‐tetrahydrocannabinol) (11‐hydroxy‐ 9‐THC) (11‐nor‐9‐carboxy‐ 9‐THC) the carboxy-thc plateaus and continues on which accumulates in the blood and keeps being produced even after smoking Mean plasma concentrations of 9‐tetrahydrocannabinol (THC), 11‐ hydroxy‐ 9‐THC (11‐OH‐THC), and 11‐nor‐9‐carboxy‐ 9‐THC (THCCOOH) by gas chromatography/mass spectrometry following smoking of a single 3.55% THC cigarette. (N = 6) Marijuana and the Cannabinoids, M.A. ElSohly (ed.), 2007. Ch. 9 blood stream—this results in an elongated time of THC being present in your body) -the carboxy-THC is not psychoactive and is one of the maor metabolites and can be detected for weeks after consumption - test for the carboxy-thc and measure the ratios present to beable to tell how long ago THC was consumed - absorption in oral liquid and saliva happens because of direct contact of the THC whether through oral or smoing consumption can determine if the person is under the influence (good for car accidents) Elimination of THC from the Body • Although THC disappears quite rapidly from the circulation, • • • • • elimination of the drug from the body takes several days. THC and its metabolites are gradually excreted: 1/3 in urine, 2/3 in feces; those in the fat tissues slowly leak back into the bloodstream and are eventually eliminated. Overall elimination half‐time of 3‐5 days (some metabolites may persist for weeks). 11‐nor‐carboxy‐THC (one of the major metabolites): positive urine or blood test results for days or even weeks after a single (cannabis) exposure. Carboxy metabolite/unchanged THC ratios can indicate fairly accurately how long ago cannabis was consumed. Measurement of THC in samples of saliva: acutely reflects cannabis use within the past few hours; is more relevant for roadside traffic accident. Urinary Excretion Profile (11‐nor‐9‐carboxy‐ 9‐THC) Urine detection for the THC is good Urinary excretion profile of 11‐nor‐9‐carboxy‐ 9‐THC (THCCOOH) as measured by gas chromatography/mass spectrometry (GC/MS) in one subject following smoking of a single 3.55% THC cigarette. The horizontal line at 15 ng/mL represents the current GC/MS cutoff used in most testing programs. The urinary THC‐COOH concentrations (ng/mL) normalized to urine creatinine concentrations (mg/mL) are illustrated with closed triangles. Marijuana and the Cannabinoids, M.A. ElSohly (ed.), 2007. Ch. 9 General Drug Effects and Detection Time Ranges blood and oral fluid (saliva) is detectable for hours- few days urine is detectable is better with a longer window for detection which is days to weeks sweat is detectable for weeks to months and it can be detectabe in hair for months-years for medical question or biological question the BEST method for testing for detection becuase if is present in the blood it can be effecting the brain cells which effects your perception of the world and actions in your boy General drug effects and detection time ranges in various matrices following occasional cannabinoid use. Marijuana and the Cannabinoids, M.A. ElSohly (ed.), 2007. Ch. 9 Cannabis is an annual, dioecious, flowering herb belonging to the Cannabaceae family. It contains 66 psychotropic principles and more than 400 substances Constituents of Cannabis by chemical class (as of the end of 2012) Cannabinoids (104): cannabinoids can be psychoactive or non-psychoactive but all psychoactive other than THC are in much lower concentration and potency 9‐THC type; 8‐THC type; Cannabigeriol (CBG)‐type; Cannabichromene (CBC)‐type; Cannabidiol (CBD)‐type; Cannabinodiol (CBND)‐type; Cannabielsoin (CBE)‐type; Cannabicyclol (CBL)‐type; Cannabinol (CBN)‐type; Cannabitriol (CBT)‐type; Miscellaneous‐type cannabinoids There are also non-cannabinoids compounds in cannabis also Noncannbinoid Constituents (441): Flavonoids; Steroids; Phenanthrenes; Fatty acids; Spiroindans; Nitrogenous compounds; Xanthones; Biphenyls Handbook of Cannabis, by R. Pertwee (ed.), 2014. Ch. 1 Constituents of Cannabis major psychoactive compound in cannabis precursor of THC and CBD major nonpsychoactive compound made up of mostly non-cannabinoids This table represents a simple breakdown of compounds found in Cannabis. There are several isomers of each class or type, as well as hundreds of non‐CB components, including terpenes, flavonoids, vitamin K, fatty acids, nitrogenous compounds, etc. Neuropathology of Drug Addictions and Substance Misuse, Volume 1, 1st ed., by Preedy (ed.), 2016. Ch. 62 Primary Cannabinoids from Cannabis Plants KNOW CBD, THC, CBN, CBG if you have little CBN you know they are being stored well which is a good and if you have a lot floating around it can determine that they do not store well These compounds are the secondary metabolites of Cannabis. They are synthesized as acidic versions and decarboxylate over time or when heat is applied. Neuropathology of Drug Addictions and Substance Misuse, Volume 1, 1st ed., by Preedy (ed.), 2016. Ch. 62 Biosynthesis Biosynthesis of the Main Cannabinoids phytocannabinoids biosynthesis shown here (the cannabinoids in plants) THCA—THC acid synthesis CBDA—CBD acid synthesis in the plants the production of the cannabinoids are not in neutral form they are in acidic form and there are no psychoactive function in culture (intravenously) or high heat situation or combustion (by smoking), there is a nonenzymatic decarboxylation synthesis happening and the compounds are now neutral and have the psychoactive activity National Academies Report, 1/2017 Products of Biosynthesis and Decarboxylation From plant the THCA and CBDA are not bioactive forms of the compounds only after combustion, high heat, etc and decarboxylation process is the THC and CBD bioactive • • • Phytocannabinoids are biosynthesized as acidic precursors, such as THCA. Acidic phytocannabinoids are decarboxylated to form neutral cannabinoids. The conversion of acidic to neutral cannabinoid can occur from prolonged storage and when heat is applied, generating carbon dioxide and water. (CBDA, cannabidiolic acid; THC, 9‐tetrahydrocannabinol; CBD, cannabidiol; CBG, cannabigerol) Neuropathology of Drug Addictions and Substance Misuse, Volume 1, 1st Edition, by Preedy (ed.), 2016. Ch. 62 Is Cannabidiol (CBD) Psychoactive? • Cannabidiol (CBD) is one of the major constituents of the plant and does not possess any of the psychotropic effects of 9‐THC but has several pharmacological effects which have been confirmed in vitro assays and in animal and human tests. • Although CBD is commonly thought of as being non‐ psychoactive, researchers have now demonstrated that CBD exhibits antipsychotic, anxiolytic (anxiety‐ reducing) and antidepressant effects. Therefore, CBD is technically “psychoactive” because it does affect the mind. The more appropriate answer is CBD is “not psychoactive like THC”. CBD does have psychoactive effects just not like THC, it effects human’s minds by reducing depression and anxiety but does not contribute to the “subjective high” for instance Reduces cocaine dependence in animals and is not a traditional cannabinoid but can bind to the cannabinoid receptor (this a not a caanabinoid but it is a compound produced in plants) Structure and Key Facts about Beta‐Caryophyllene, a Non‐Cannabinoid (BCP) BCP is a volatile terpene that activates CB2 receptors and may be a useful therapeutic compound. Neuropathology of Drug Addictions and Substance Misuse, Volume 1, 1st ed., by Preedy (ed.), 2016. Ch. 62 Synthetic: made in a laboratory —not produced naturally in plants of animals Synthetic Cannabinoids • Synthetic cannabinoids include a variety of distinct chemical structures and can be divided into two main classes: the classical cannabinoids, structurally related to THCs, and the nonclassical cannabinoids (cannabimimetics) structurally unrelated to THCs. • Many hundreds of new THC derivatives were made during 1950s and 1960s. It proved impossible to separate the desired properties of THC (antinausea, pain relieving) from the intoxicating effects. • Nevertheless, the chemical research provided a detailed insight into the structure activity of the THC molecule. • Several derivatives proved to be even more active than THC. Examples of Synthetic Cannabinoids Cannabinoid Agonists Nantradol: the first potent synthetic THC analog; found to have analgesic properties Levonantradol: the active isomer in Nantradol; more water soluble and thus easier to formulate and deliver as a potential medicine; project dropped due to psychoactive side effects Nabilone: the only synthetic THC analog developed and approved as a medicine, sold under the trade name Cesamet CP 55,940: possessing only 2 of the 3 rings of THC; widely used as a valuable research compound Nantradol—compounds made from a mixture of a few isomers levonantradol— made from a specific isolated isomer of nantradol and is more absorbable but taken offf research because of side effects of the psychoactive aspect nabilone—very useful for medicinal use of easing nausea and sickness in patients Cannabinoid Antagonist—THC antagonist so works opposite of THC appetitie increase for salty and fatty foods—reduces patients appetite and works to reduce obesity but also dropped from the market (in european countries) patients complaine dof thoughts of depression, anxiety, and suicide Cannabinoid Antagonists SR141716A: The first cannabinoid antagonist (for CB1 receptors) to be described, now called rimonabant; a valuable research tool Some Known Physiological Effects of Synthetic Cannabinoids measured many categories to measure the effect of the cannabinoids List of different physiological effects synthetic compounds were not made for human consumption but for research tool • Synthetic cannabinoids were developed as research tools to explore the function of the endocanabinoid system and as potential therapeutic agents. • Many synthetic cannabinoids are now classified as Schedule I drugs under the US Controlled Substance Act. Neuropathology of Drug Addictions and Substance Misuse, Volume 1, 1st ed., by Preedy (ed.), 2016. Ch. 71 ...
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