Preclinically, thc, Org 28611 and Org 26828 are all cb1/cb2 agonists. This would suggest that, depending on the dose, they also show similar pharma- codynamic effects. Org 28611 and Org 26828 were studied using the same design (chapter 7 and 8), but the study in which pure thc was administered by inhalation had a completely different design (chapter 3) than the intra- venous cb1/cb2 studies. A statistical comparison was therefore not pos- sible. Nonetheless, an indication of the relationships in pharmacodynamic effects can be obtained by mutual comparisons of the pharmacodynamic effects. Compounds from a similar drug class are expected to have similar proportional effects on different cns parameters. At first sight, there were differences between the compounds. As shown in Table 1, high doses of Org 28611 and Org 26828 caused negative effects on vas mood and calm- ness and limited blood pressure reductions, which were not found with
thc. At least for the central effects, these differences seem to reflect the different side effect profiles. The other cns pharmacodynamic effects were compared using graphs as presented in Figure 1. In these graphs one aver- age pharmacodynamic effect is plotted against another pharmacodynamic effect. Compounds from the same pharmacological class are expected to produce similar effect relationships. Heart rate, body sway and vas alert- ness were determined in each study, and changed significantly after admin- istration of thc, Org 28611 and Org 26828 (Table 1). Although the size of the effect differ considerably among thc, Org 28611 and Org 26828; their effect relationships essentially run parallel to eachother. This indicates that these compounds share similar pharmacological properties and probably belong to the same cannabinoid class. This supports the view that the con- spicuous differences in subjective effects were not related to pharmacolog- ical differences. Other potential causes lie in differences in dose, subject selection and route of administration.
The doses of the three cannabinoids cannot be directly compared, but in each case they seemed to have been (close to) maximum. The effects of Org 28611 and Org 26828 were both examined during the first in human admin- istration (chapter 7 and 8). For both compounds, the maximum-tolerated dose was encountered during these studies. Above the maximum-tolerated dose of Org 28611 and Org 26828, the previously mentioned unpleasant ef- fects were observed. Although thc was also administered in an escalating dose design, the doses were expected to cause pronounced but well-known and well-tolerated effects. The administered thc doses were close to the
maximum-tolerated dose, since two out of twelve subjects experienced side effects severe enough to decide not to administer the last dose of 8 mg
thc (chapter 3). One of these subject was too sleepy to perform any test, and the other subject vomited just after administration of the third dose, but no psychiatric events occurred. In general, pure intrapulmonary thc
administration induced similar pleasant effects of relaxation and mild eu- phoria seen after recreational cannabis use. The side effect pattern of thc
differed considerably from the two novel cb1/cb2 agonists Org 28611 and Org 26828.
As mentioned above, a second reason for the observed differences in side effects may lie in differences in the subject population. Pure thc was intrapulmonary administered to mild cannabis users with an average use of twice a month (chapter 3), while Org 26828 and Org 26828 were admin- istered to subjects whose life-time use did not exceed five times (chapter 7 and 8). Literature is not consistent in reporting kinetic differences between users and non or infrequent users.16-19 This leaves pharmacodynamic sen- sitivity as a potential explanation, but a general increase in drug respon- siveness it not very likely. The pharmacodynamic effect relationships of the three compounds shown in Figure 1 actually indicate that the effects of thc
were larger than for the synthetic cannabinoids. This would indicate that
thc users were actually more sensitive, which does not agree with their lack of psychiatric side effects. It cannot be excluded that mild or limited users differed in some unknown sensitivity to the psychiatric effects of cannabi- noids, which was not measured in these studies. However, the most con- spicuous difference between the studies was the route of administration.
The route of administration might be a good explanation for the ob- served unpleasant effects after intravenous administration of Org 28611 and Org 26828. Similar undesirable effects have been observed after intra- venous administration of thc.9,10 Both intravenous and intrapulmonary administration cause a rapid onset of cannabinnoid effects. In this thesis pure thc administration was performed using a strict inhalation procedure, meaning that the volume of the balloon had to be inhaled in three to four subsequent breaths. Intrapulmonary administration allows for an effect ti- tration and consequently an avoidance of unpleasant exposure levels (and maintenance of pleasant ‘high’ effects). In contrast, subjects lose the ability to control the dose with intravenous administration. However, it is debata- ble if inhalation differences are fully responsible for the striking contrast be- tween the observed effects. An unexplained mechanism might be involved in the observed differences between intrapulmonary and intravenous ad- ministration. Nevertheless, our findings suggest that the observed unpleas- ant effects of Org 28611 and Org 26828 are related to the intravenous route of administration of these cannabinoids. Development of patient friendly (partly self-titrated) formulations are worth investigating, if cannabinoids hold their promise as medicine for various indications.
171 summary and conclusions
Summarizing, this thesis describes useful cannabinoid biomarkers, which can be of value in early drug development. A reproducible, practical and well-tolerated mode of intrapulmonary thc administration with reliable pharmacokinetic and pharmacodynamic time profiles was described. Ac- curate pharmacokinetic/pharmacodynamic models were composed, which allow quantitative assessments of endogenous cb1/cb2 systems, and opti- mization of thc-based study designs. These results were used to confirm the pharmacological effects of a selective cb1 antagonist ave1625, which led to a reduction of the anticipated therapeutically active dose. In addi- tion, sedative and amnestic properties of two similar, but not identical novel intravenous cb1 agonists, Org 28611 and Org 26828, were evaluated. These compounds did not produce the expected sedation and relaxation that would make them suitable for development in anaesthesia. The com- pounds are now in development for other indications. Comparisons with
thc suggested that the route of administration is a decisive factor in caus- ing unpleasant central nervous system effects. This could have an impact on the desirable galenic and pharmacokinetic properties of new cannabi- noid agonists. The studies in healthy volunteers and the models presented in this thesis have been very useful for the early development of different cannabinoids as medicines.
Figure 1 The different relationships of heart rate versus body sway, heart rate versus vas alertness and body sway versus vas alertness for the dif- ferent compounds (thc, Org 28611 and Org 26828).
Table 1 Pharmacodynamic measurements performed after thc, Org 28611 and Org 26828 administration. Blue cells indicate statistically significant changes. Dark cells indicate parameter not measured.
TEST THC Org 28611 (µg/kg) Org 26828(µg/kg)
1 3 6 10 0.3 1 3 6
Heart rate Systolic Blood pressure Diastolic Blood pressure EEG
Saccadic peak velocity Body sway VAS alertness VAS calmness VAS mood VAS external perception VAS internal perception VAS feeling high
173 introduction
references
1 Grotenhermen F. Pharmacokinetics and phar- macodynamics of cannabinoids. Clin. Pharma- cokinet. 2003; 42: 327-360.
2 Huestis MA, Gorelick DA, Heishman SJ, Pres- ton KL, Nelson RA, Moolchan ET, Frank RA. Blockade of effects of smoked marijuana by the cb1-selective cannabinoid receptor an- tagonist sr141716. Arch. Gen. Psychiatry 2001; 58: 322-328.
3 Wall ME, Sadler BM, Brine D, Taylor H, Perez- Reyes M. Metabolism, disposition, and kinet- ics of delta-9-tetrahydrocannabinol in men and women. Clin. Pharmacol. Ther. 1983; 34: 352-363.
4 Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK. Plasma delta-9 tet- rahydrocannabinol concentrations and clinical effects after oral and intravenous administra- tion and smoking. Clin. Pharmacol. Ther. 1980; 28: 409-416.
5 Hollister LE, Gillespie HK, Ohlsson A, Lindgren JE, Wahlen A, Agurell S. Do plasma concentra- tions of delta 9-tetrahydrocannabinol reflect the degree of intoxication? J. Clin. Pharmacol. 1981; 21: 171S-177S.
6 Zeidenberg P, Clark WC, Jaffe J, Anderson SW, Chin S, Malitz S. Effect of oral administration of delta9 tetrahydrocannabinol on memory, speech, and perception of thermal stimula- tion: results with four normal human volunteer subjects. Preliminary report. Compr. Psychia- try 1973; 14: 549-556.
7 Ameri A. The effects of cannabinoids on the brain. Prog. Neurobiol. 1999; 58: 315-348. 8 Tramer MR, Carroll D, Campbell FA, Reynolds
DJ, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001; 323: 16-21.
9 D’Souza DC, Perry E, MacDougall L, Am- merman Y, Cooper T, Wu YT, Braley G, Gue- orguieva R, Krystal JH. The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocan- nabinol in Healthy Individuals: Implications for Psychosis. Neuropsychopharmacology 2004; 29: 1558-1572.
10 Naef M, Russmann S, Petersen-Felix S, Bren- neisen R. Development and pharmacokinetic characterization of pulmonal and intravenous delta-9-tetrahydrocannabinol (thc) in hu- mans. J. Pharm. Sci. 2004; 93: 1176-1184. 11 Win NN, Fukayama H, Kohase H, Umino M.
The different effects of intravenous propofol
and midazolam sedation on hemodynamic and heart rate variability. Anesth. Analg. 2005; 101: 97-102.
12 Jones RT. Cardiovascular system effects of marijuana. J. Clin. Pharmacol. 2002; 42: 58S- 63S.
13 Hall W, Solowij N. Adverse effects of cannabis. Lancet 1998; 352: 1611-1616.
14 Sidney S. Cardiovascular consequences of marijuana use. J. Clin. Pharmacol. 2002; 42: 64S-70S.
15 Randall MD, Harris D, Kendall DA, Ralevic V. Cardiovascular effects of cannabinoids. Phar- macol. Ther. 2002; 95: 191-202.
16 Hunt CA, Jones RT. Tolerance and disposition of tetrahydrocannabinol in man. J. Pharmacol. Exp. Ther. 1980; 215: 35-44.
17 Lemberger L, Weiss JL, Watanabe AM, Galanter IM, Wyatt RJ, Cardon PV. Delta-9-tetrahydro- cannabinol. Temporal correlation of the psy- chologic effects and blood levels after various routes of administration. N. Engl. J. Med. 1972; 286: 685-688.
18 Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK. Single dose kinetics of deuterium labelled delta 1-tetrahydrocan- nabinol in heavy and light cannabis users. Biomed. Mass Spectrom. 1982; 9: 6-10. 19 Casswell S, Marks D. Cannabis induced im-
pairment of performance of a divided atten- tion task. Nature 1973; 241: 60-61.