Pharmacokinetics is the term we use to describe the absorption of cannabinoids, their distribution throughout the body, their metabolism, and their elimination from the body. Pharmacokinetics is key to understanding many of the issues related to the medical use of cannabis. For example, differences in the time of analgesic onset between the different methods of administration and duration of cannabinoid presence in the blood, potentially impact driving and other high concentration activities. What makes understanding of the pharmacokinetics of cannabis very challenging, is that cannabis herbs contains hundreds of chemical compounds including over a sixty cannabinoids. One compound, which has been extensively studied is THC, one of the two principal components in the cannabis herb. The other is CBD. We will take a closer look into the pharmacokinetics of THC in this talk. Smoking, the principal means of cannabis consumption provides almost immediate delivery of THC from the lungs to the brain. This contributes significantly to the sensation reported by recreational users as high, and therefore, bolsters the substance addictive potential. Bioavailability is a common term used in medicine. It refers to the percentage of compounds found in the body from the total amount administered. The bioavailability of smoked THC ranges from two percent to as high as 56 percent. This tremendous range can be explained by patient variability in smoking characteristics, the number of inhalations, the volume, the duration, the interval between puffs, and hold time in the lungs all influence the degree of drug exposure. This variability contributes to uncertainty in dose delivery, and makes it very difficult to conduct clinical trials on the effectiveness and safety of smoked cannabis. Let's look for a minute at blood concentrations of THC after smoking a single cannabis cigarette. THC can be detected in the plasma immediately after the first puff. Within a few minutes, it reaches a peak and rapidly declines in the following 15 to 30 minutes, almost totally disappearing two hours later. This figure shows the huge difference in peak THC plasma concentrations among six individuals, and these difference can be noted despite the fact that they all smoked one cigarette with equal THC concentrations, and were all exposed to the same computer-paced smoking procedure that controlled the number of puffs, lengths of inhalation, hold time, and time between puffs. Compared to smoking, oral absorption of cannabis is lower with lower and delayed peak THC concentration. Factors such as dose, vehicle of ingestion, and physiological factors can influence drug concentrations in plasma. Vehicles of ingestion include capsules, oil drops, cookies, et cetera. Between subject bioavailability in plasma concentrations following oral ingestion is also large with a range of as little as five percent to a maximum of 20 percent. Studies show that, for the ingestion of 20 milligrams of THC in a chocolate cookie or 10 milligram of Marinol capsule, peak plasma concentrations are typically low, and appears somewhere following one and five hours after administration. Foil preparations seem to improve the bioavailability of oral THC. The pharmacokinetics of the oromucosal spray, Sativex, is well known. The spray was developed to take advantage of the relative permeable oral mucosal. The oral mucosa permits quick systemic absorption, and offers a delivery pathways allowing the patients to ingest the squeezed doses. It's important to note that with this method, a certain unknown portion of the dose gets swallowed, and undergoes alimentary tract absorption. Plasma concentrations show a high degree of inter-subject variability. Peak plasma concentration appears one and a half to four hours following administration and blood THC nearly disappears within 12 to 24 hours after dosing. There is no data on the pharmacokinetics of sublingual cannabinoid oil drops. Following topical application of cannabis patches, low blood concentrations of THC can be detected. One advantage of the topical application of cannabis over oral use, is that it bypasses the liver rendering it potentially more efficient. On the other hand, it delivers THC to the blood and from there to the brain more slowly when compared to smoking which naturally reduces its abuse potential. Shortly after smoking cannabis, THC concentrations decrease rapidly. This occurs because of the distribution of the cannabinoids from the blood into the lungs, heart, liver, and brain. Less highly perfused tissues including fat accumulate THC more slowly. THC is highly fat soluble, and therefore, tends to accumulate in fatty tissues where it may be retained for extended periods of time. It is later slowly release back from lipids storage to the blood. So, low concentrations of THC can be detected in the blood of chronic users as many as four days after smoking. The metabolism of the major cannabis constituents, THC and CBD, has already been reviewed by Professor Myrie. Briefly, the liver converts THC into two major metabolites, 11-hydroxy-THC which is biologically active and 9-carboxy-THC, a non-active metabolite. This is done primarily in the liver by the enzyme CYP 4502C9. In the case of smoked cannabis, the active metabolite appears approximately 10 minutes after smoking, whereas the inactive metabolites can be found in increasing blood concentrations some 30 to 45 minutes after smoking. So, both the absorption of THC into tissues and its metabolism contribute to its quick disappearance from the blood after smoking. Importantly CYP 4502C9 is responsible for the metabolism of many other drugs and substances. If this enzyme becomes less active for any reason, the rate of THC metabolism may decreases and cause THC accumulation. Reduced activity can be induced by medications, toxins, liver disease, and so on. Elimination of THC occurs mainly through the urine with a total of 80 to 90 percent eliminated within five days mostly as THC metabolites. Traces of cannabinoids can be detected in the urine as long as two to four weeks after last intake. Hence, positive urine test for cannabinoids indicates only the drug exposure has occurred. It does not provide any information on the how and when it was used, the dose taken, or the degree of cognitive impairment it may have caused. Lastly, cannabinoids can also be detected in sweat and in oral fluids. This probably does not have any biological significance but may be important for roadside cannabis use detection. I'll elaborate on this topic in our class on cannabis and driving.