Hgeocities.com/cannabinoidscience/Administration.htmlgeocities.com/cannabinoidscience/Administration.htmlelayedx|J[]OKtext/html]b.HMon, 15 Sep 2003 17:17:43 GMTMozilla/4.5 (compatible; HTTrack 3.0x; Windows 98)en, *{J] Pharmacodynamics Pharmacodynamics of Cannabinoids

 Cannabinoids can be delivered in a variety of ways, the most widely used being pulmonary assimilation (smoking or vaporization) and/or oral consumption. The maximum blood plasma levels, time course and intensity of effects can vary greatly depending on the route of administration. Smoking cannabis results in peak plasma THC concentrations immediately following smoking, peak psychoactive effects about 10-20 minutes after smoking, and a cessation of acute effects within 2-3 hours (Grotenhermen, 2003). The time course of plasma concentrations and effects are basically the same for smoked and intravenous THC. Following oral consumption, on the other hand, peak THC plasma levels are acheived 90-120 minutes, peak psychoactive effects at 90-120 minutes, and a cessation of acute effects within about 8-12 hours, depending on dosage (ibid). The very slow absorption of oral THC is a major disadvantage with respect to medical efficacy.

The bioavailability of THC, i.e. the amount of THC in a given dose that makes it to general circulation, varies dramatically depending on the method of delivery. When THC is delivered intraveneously (a bioavailability of 100%), it produces effects at only 0.06mg/kg (Ohlsson et al, 1980). Intravenous doses of 5mg can produce peak plasma concentrations of greater than 400 µg/L (Kelley and Jones, 1992). The amount of THC in a cigarette is typically between about 10 and 100mg of THC. A single, high potency (10% THC by weight) cannabis cigarette weighing one gram contains 100mg of THC. Half or more of this THC is lost in sidestream smoke that is never delivered to the lungs (Perez-Reyes, 1990). Experiments using a smoking machine show that depending on puff volume and puff interval, as little as 16-19% of the THC present in the cigarette may be delivered as mainstream smoke, while as much as 69% is transferred to mainstream smoke if the cigarette is smoked in a single puff with no loss via sidestream smoke (Davis et al, 1984). About 30% of THC is assumed to be destroyed by pyrolysis. More THC is lost due to incomplete absorption of inhaled doses in the lungs. Actual bioavailability via a cigarette, i.e. the percentage of THC in the cigarette that is delivered to general circulation, ranges from 10 to 35%, and varies according to puff volume, breathhold duration, and depth of inhalation (Grotenhermen, p. 331). More experienced users tend to achieve higher levels. This appears to be due to different smoking behaviors in experienced users, since plasma levels and AUC values are about the same for heavy and light users following intravenous THC administration (Ohlsson et al, 1982). Bioavailability is higher (45% in one case) with pipes, which reduces loss via sidestream smoke (Agurell and Leander, 1971).

Bioavailability is significantly lower with oral consumption, due in part to elimination via that gastrointestinal tract, and to the first-pass effect. THC must first pass through the liver, where it is degraded by drug metablizing enzymes, before reaching the general circulation. This means that much higher oral doses of THC are needed to achieve smoking-typical plasma concentrations of THC. Bioavailability of dronabinol has been estimated to be approximately 7+/-3% (Spokart et al, 2001). Peak plasma concentrations following 20mg oral doses of THC were only 4.4-11 µg/L (Ohlsson et al, 1980). The much slower release of THC into systemic circulation also results in much lower peak plasma concentration, though the low levels are sustained for a much longer period of time. Oral THC results in a much higher proportion of the psychoactive THC metabolite 11-OH-THC, which about as psychotropically potent as THC itself (Perez-Reyes et al, 1972). With smoking, the peak plasma levels of 11-OH-THC are about 1/20th that of THC, while oral adminstration produces peak plasma ratios closer to 1:1 (Grotenhermen, p. 336). 

Though smoking is the most efficient and most widely used method of cannabinoid delivery, it is also probably the least healthy. Fortunately, there are other methods of delivery that give the benefits of smoking, including rapid onset of effects, easy dose titration, and lack of first-pass effect, while dramatically reducing the respiratory concerns associated with smoking. For instance, cannabinoids can be administered sublingually (under the tongue). Preliminary reports sublingual cannabis extracts indicates that it produces the desired effects, and that that the effects develop relatively quickly (Guy and Flint, 2000; Wade et al, 2003). Another promising technology is the vaporizer. Vaporizers heat cannabis to a temperature above to the boiling point of THC, but below the temperature at which combustion occurs, producing a THC-rich vapor lacking tar and combustion-created carcinogens. Preliminary reports indicate that vaporizers can produce vapor that is greater than 90% cannabinoids, with no benzene, toluene, and naphthalene (Gieringer, 2001). Polycyclic aromatic hydrocarbons (PAH) can also probably be greatly reduced if not eliminated by vaporization, since they form at temperatures higher than those needed for vaporization.


References

Agurell and Leander, 1971. Stability, transfer and absorption of cannabinoid constituents of cannabis (hashish) during smoking. Acta Pharmaceutica Suecica 8 (4): 391-402.

Azorlosa et al, 1995. Marijuana smoking: effects of varying puff volume and breathhold duration. Journal of Pharmacology and Experimental Therapeutics 272(2), 560-569.
Two studies were conducted to quantify biological and behavioral effects resulting from exposure to controlled doses of marijuana smoke. In one study, puff volume (30, 60 and 90 ml) and in a second study, breathhold duration (0, 10 and 20 sec) were systematically varied while holding constant other smoking topography parameters (number of puffs = 10, interpuff interval = 60 sec and inhalation volume = 25% of vital capacity). Each study also varied levels of delta 9-tetrahydro-cannabinol marijuana cigarette content (1.75% and 3.55%). Regular marijuana users served as subjects (n = 7 in each experiment). Subjects smoked 10 puffs in each of six sessions; a seventh, nonsmoking session (all measures recorded at the same times as in active smoking sessions) served as a control. Variations in puff volume produced significant dose-related changes in postsmoking plasma delta 9-tetrahydro-cannabinol levels, carbon monoxide boost and subjective effects (e.g., "high"). In contrast, breathholding for 10 or 20 sec versus 0 sec increased plasma delta 9-tetrahydro-cannabinol levels but not CO boost or subjective effects. Task performance measures were not reliably influenced by marijuana smoke exposure within the dosing ranges examined. These findings confirm the utility of the controlled smoking technology, support the notion that cumulative puff volume systematically influences biological exposure and subjective effects, but cast doubt on the common belief that prolonged breathholding of marijuana smoke enhances classical subjective effects associated with its reinforcing value in humans.
Block et al, 1998. Sedative, stimulant, and other subjective effects of marijuana: relationships to smoking techniques. Pharmacology Biochemistry and Behavior 59(2), 405-412.
A double-blind, placebo-controlled study assessed subjective effects of smoking marijuana with either a long or short breath-holding duration. During eight test sessions, 55 male volunteers made repeated ratings of subjective "high," sedation, and stimulation, as well as rating their perceptions of motivation and performance on cognitive tests. The major finding of the study was that the long, relative to the short, breath-holding duration increased "high" ratings after smoking marijuana, but not placebo. Marijuana smoking increased sedation and a perception of worsened test performance, and decreased motivation with respect to test performance. Paradoxical subjective effects were observed in that subjects reported some stimulation as well as sedation after smoking marijuana, particularly with the long breath-holding duration. Breath-holding duration did not produce any subjective effects that were independent of the drug treatment, i.e.. occurred equally after smoking of marijuana and placebo, such as we previously observed with respect to test performance.
Davis et al, 1984. Some smoking characteristics of marijuana cigarettes. In: Agurell S, Dewey WL, Willette RE, editors. The cannabinoids: chemical, pharmacologic and therapeutic aspects. New York: Academic Press, 245-261.

Guy and Flint, 2000. A phase one study of sublingual Cannabis based medicinal extracts. 2000 Symposium on the Cannabinoids. Burlington (VT): International Cannabinoid Research Society: 2000, 115.

Heishman et al, 1989. Effects of tetrahydrocannabinol content on marijuana smoking behavior, subjective reports, and performance. Pharmacology Biochemistry and Behavior 34(1), 173-179. 
This study investigated the smoking topography of marijuana and its effect on heart rate, subjective reports, and cognitive/psychomotor task performance. Male subjects (N = 12) with histories of moderate marijuana use smoked ad lib one cigarette containing 0, 1.3, or 2.7% delta 9-THC on separate days. Smoking topography measures revealed smaller puff and inhalation volumes and shorter puff duration for the high marijuana dose compared to the low dose. No other smoking behavior differed between the active doses. Heart rate was increased dose dependently over placebo levels. Active marijuana also increased subjective reports of drug effect over placebo, but not dose dependently. Significant memory impairment was observed on a forward and reverse digit span task, and performance was impaired on the digit symbol substitution task by the high, but not low, dose of marijuana. Performance on a divided attention task was not affected by marijuana. Thus, although subjects adjusted their smoking of cigarettes varying in THC content, dose-related effects of marijuana were obtained on several measures. The observed differences and individual variation in smoking topography measures suggest that precise control of smoking behavior would improve the accuracy of marijuana dose delivery.
Hollister et al, 1981. Do plasma concentrations of delta 9-tetrahydrocannabinol reflect the degree of intoxication? Journal of Clinical Pharmacology 21 (8-9 Suppl.), 171S-177S.

Huestis et al, 1992. Blood cannabinoids: I. absorption of THC and formation of 11-OH-THC and THC-COOH during and after smoking marijuana. Journal of Analytic Toxicology 16, 276-282.

Huestis, 1999. Pharamacokinetics of THC in inhaled and oral preparations. In: Marijuana and Medicine, Nahas et al (eds), Humana Press, Totowa, pp. 105-116.

Nahas, 2001. The pharmacokinetics of THC in fat and brain: resulting functional responses to marijuana smoking. Human Psychopharmacology: Clinical and Experimental 16, 247-255.
A pleasant sensory perception (PSP), the high of THC or of marihuana consumption, is a consistent functional response to this drug only manifested by man, and which occurs concurrently with an increased heart rate. However, it has not been possible to relate consistently magnitude and duration of these functional markers to THC plasma concentration, whatever the route of administration. A re-analysis of all the available clinical and experimental data reporting the pharmacokinetics and storage of THC in tissues in function of time, have indicated that the discrepancies between functional responses and plasma molecular THC concentration may be accounted for by the pharmacokinetics of THC. The instant uptake and unlimited storage of THC by neutral fat limits the molecular concentration of the drug present in the plasma to a level which does not exceed 6 x 10(14) molecules/ml. The physicochemical nature of the membrane lipid bilayer (of the blood-brain barrier) will restrict the access of THC into the bilayer receptors and its: reactive enzymes. The PSP and increased heart rate of marihuana is correlated with the molecular concentration of THC in the bilayer (blood-brain barrier) of the order of 10(12)-10(14) molecules/ml. This number in turn would be related to the number of functional THC receptor sites in the lipid bilayer. THC would exert its functional properties on PSP and heart rate through a molecular transmission to specific receptor site and bilipid layer physicochemical interations. Rapid uptake and slow release of THC in fat associated with a rate-limited uptake into brain may be a general philogenetic mechanism which would protect brain function from prolonged exposure to xenobiotics like THC and other fat soluble drugs.
Ohlsson et al., 1980. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clinical Pharmacology and Therapeutics 28, 409-416.
Delta-9-tetrahydrocannabinol (THC) was given intravenously, by smoking, and by mouth to 11 healthy subjects. Plasma profiles of THC after smoking and intravenous injection were similar whereas plasma levels after oral doses were low and irregular, indicating slow and erratic absorption. Based on AUC0-360 min systemic availability of THC after smoking was estimated to be 18 +/- 6%. Oral THC in a chocolate cookie provided systemic availability of 6 +/- 3%. Of the two major clinical signs of cannabis intoxication, reddened conjunctivae persisted for as long as THC levels were above 5 ng/ml, and tachycardia was a less reliable measurement of prevailing THC levels or "high." The time courses of plasma concentrations and clinical "high" were of the same order for intravenous injection and smoking, with prompt onset and steady decline over a 4-hr period. The appearance of "high" lagged behind the increase in plasma concentrations, suggesting that brain concentrations were increasing as plasma concentrations decreased. After oral THC, the onset of clinical effects was much slower and lasted longer, but effects occurred at much lower plasma concentrations than after the other two methods of administration.
Ohlsson et al, 1982. Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users. Biomedical Mass Spectrometry 9(1), 6-10.
Deuterium labelled delta 1-tetrahydrocannabinol was administered intravenously (5.0 mg) and by smoking (10.0 mg) to five heavy and four light marihuana users. All subjects smoked an estimated amount of 8.6-9.9 mg delta 1-tetrahydrocannabinol. The plasma levels of delta 1-tetrahydrocannabinol were followed for 48 hours and in two subjects fof 72 hours after administration. The systemic availability after inhalation calculated from the area under curve values was in the range of 27 +/- 10% for the heavy users and 14 +/- 1% for the light users. There was little difference between the groups with regard to the amount of smoked delta 1-tetrahydrocannabinol or plasma levels and area under curve values obtained after i.v. administration. Thus, it seems likely that the statistically significant difference in systemic availability of smoked delta 1-tetrahydrocannabinol was due to a more efficient smoking by the heavy users. It is also indicated that heavy users prefer slightly higher delta 1-tetrahydrocannabinol plasma levels than light users. Based on the area under curve values after i.v. administration, a plasma clearance of 760-1190 ml min-1 was calculated. The elimination half-life of delta 1-tetrahydrocannabinol is more than 20 hours. The present results do not suggest that tolerance or sensitivity to delta 1-tetrahydrocannabinol in heavy users is readily achieved.
Perez-Reyes et al, 1972. Intravenous injection in man of delta-9- tetrahydrocannabinol and 11-OH delta-9-tetrahydrocannabinol. Science 177, 633-635.
A microsuspension of delta-9-tetrahydrocannabinol and its metabolic derivative 11-OH-delta-9-tetrahydrocannabinol has been prepared with 25 percent human serum albumin as the vehicle. Intravenosu infusion of this preperation to humans indicates that both tetrahydrocannabinols are equally potent in producing the typical marijuana-like psychological and physiological effects.
Perez-Reyes et al, 1982. Comparison of effects of marihuana cigarettes to three different potencies. Clinical Pharmacology and Therapeutics 31(5),617-24.

Perez-Reyes, 1990. Marijuana Smoking: Factors that Influence the Bioavailability of Tetrahydrocannabinol, in Chiang and Hawks, eds., Research Findings on Smoking of Abused Substances, NIDA Research Monograph 99.

Sporkert  et al., 2001. Pharmacokinetic investigation of delta-9-tetrahydrocannabinol and its metabolites after single administration of 10mg Marinol in attendance of a psychiatric study with 17 volunteers. Poster at the 39th Annual International Meeting, International Association of Forensic Toxicologists; 2001 Aug 26-30; Prague, Czech Republic.

Zacny and Chait, 1989. Breathhold duration and response to marijuana smoke. Pharmacology Biochemistry and Behavior 33(2), 481-484. 
Marijuana smokers are frequently observed to hold the smoke in their lungs for prolonged periods (10-15 sec) apparently in the belief that prolonged breathholding intensifies the effects of the drug. The actual influence of breathhold duration on response to marijuana smoke has not been studied. The present study examined the effects of systematic manipulation of breathhold duration on the physiological, cognitive and subjective response to marijuana smoke in a group of eight regular marijuana smokers. Subjects were exposed to each of three breathhold duration conditions (0, 10 and 20 sec) on three occasions, scheduled according to a randomized block design. A controlled smoking procedure was used in which the number of puffs, puff volume and postpuff inhalation volume were held constant. Expired air carbon monoxide levels were measured before and after smoking to monitor smoke intake. Typical marijuana effects (increased heart rate, increased ratings of "high" and impaired memory performance) were observed under each of the breathhold conditions, but there was little evidence that response to marijuana was a function of breathhold duration.