, Volume 75, Issue 2, pp 158–164

Relationship between plasma delta-9-tetrahydrocannabinol concentration and pharmacologic effects in man

  • David M. Cocchetto
  • S. Michael Owens
  • Mario Perez-Reyes
  • Stephanie DiGuiseppi
  • Loren L. Miller
Original Investigations


The relationship between each of two pharmacologic effects (tachycardia and psychological “high”) of delta-9-tetrahydrocannabinol (THC) and plasma THC concentration was investigated in three male and three female experienced marihuana smokers. Each subject smoked one 1% THC cigarette on two occasions separated by 2 h. Heart rate and subjective psychological self-rating were determined frequently throughout the 4 h study period. Data were analyzed by calculating the area under the parameter versus time curves, constructing hysteresis plots, and calculating the decay rate constants from pharmacologic effect versus time plots. In both males and females, dose inhaled and psychological response were apparently equivalent for the first and second cigarettes. While all subjects exhibited marked tachycardia in response to the first cigarette, heart rate in both male and female subjects was not increased as markedly during the second cigarette. Interestingly, female subjects had less tachycardiac response than males during the second cigarette. Hysteresis plots revealed that both heart rate and subjective psychological effects were elicited in an effect compartment which was “deep” relative to the reference plasma compartment. The time courses of tachycardiac and psychological responses lagged behind the plasma THC concentration-time profile. Zero-order decay rate constants for subjective psychological rating did not change substantially from the first to second cigarette. This study suggests that plasma THC concentration is a poor predictor of simultaneously occurring physiological and psychological pharmacologic effects.

Key words

Tetrahydrocannabinol Pharmacodynamics Hysteresis plots Tachycardia Intoxication 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agurell S, Levander S, Binder M, Bader-Bartfai A, Gustafsson B, Leander K, Lindgren J, Ohlsson A, Tobisson B (1976) Pharmacokinetics of Δ 8-tetrahydrocannabinol(Δ 6-tetrahydrocannabinol) in man after smoking — relations to physiological and psychological effects. In: Braude MC, Szara S (eds) The pharmacology of marihuana. Raven Press, New YorkGoogle Scholar
  2. Alván G, Ericsson O, Levander S, Lindgren JE (1974) Plasma concentrations and effects of methaqualone after single and multiple oral doses in man. Eur J Clin Pharmacol 7:499–454Google Scholar
  3. Babor TF, Mendelson JH, Greenberg I, Kuehule JC (1975) Marihuana consumption and tolerance to physiological and subjective effects. Arch Gen Psychiatry 32:1548–1552Google Scholar
  4. Bernstein JG, Becker D, Babor TF, Mendelson JH (1974) Physiological assessments: cardiopulmonary function. In: Mendelson JH, Rossi AM, Meyer RE (eds) The use of marijuana. A psychological and physiological inquiry. Plenum Press, New YorkGoogle Scholar
  5. Clark SC (1975) Marihuana and the cardiovascular system. Pharmacol Biochem Behav 3:299–306Google Scholar
  6. Galeazzi RL, Benet LZ, Sheiner LB (1976) Relationship between the pharmacokinetics and pharmacodynamics of procainamide. Clin Pharmacol Ther 20:278–289Google Scholar
  7. Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active component of hashish. J Am Chem Soc 86:1646–1647Google Scholar
  8. Garrett ER (1975) The pharmacokinetic bases of biological response quantification in toxicology, pharmacology, and pharmacodynamics. In: Jucker E (ed) Progress in Drug research. Vol 21, Birkhäuser, BaselGoogle Scholar
  9. Gibaldi M, Perrier D (1975) Pharmacokinetics. Marcel Dekker, New YorkGoogle Scholar
  10. Hinderling PH, Garrett ER (1976) Pharmacodynamics of the antiarrhythmic disopyramide in healthy humans: correlation of the kinetics of the drug and its effects. J Pharmacokinet Biopharm 4:231–242Google Scholar
  11. Hinderling PH, Garrett ER (1977) Pharmacokinetics of β-methyl digoxin in healthy humans III: pharmacodynamic correlations. J Pharm Sci 66:326–329Google Scholar
  12. Hunt CA, Jones RT (1980) Tolerance and disposition of tetrahydrocannabinol in man. J Pharmacol Exp Ther 215:35–44Google Scholar
  13. Isbell H, Gorodetzsky CW, Jasinski D, Claussen U, Spulak FV, Korte F (1967) Effects of 1-delta-9-trans-tetrahydrocannabinol in man. Psychopharmacologia 11:184–188Google Scholar
  14. Johnson S, Domino EF (1971) Some cardiovascular effects of marihuana smoking in normal volunteers. Clin Pharmacol Ther 12:762–768Google Scholar
  15. Jones R, Benowitz N, Bachman J (1976) Clinical studies of cannabis tolerance and dependence. Ann NY Acad Sci 282:221–239Google Scholar
  16. Kelman AJ, Whiting B (1980) Modeling of drug response in individual subjects. J Pharmacokinet Biopharm 8:115–130Google Scholar
  17. Kiplinger GF, Manno JE, Rodda BE, Forney RB (1971) Dose-response analysis of the effects of tetrahydrocannabinol in man. Clin Pharmacol Ther 12:650–657Google Scholar
  18. Kramer WG, Kolibash AJ, Lewis RP, Bathala MS, Visconti JA, Reuning RH (1979) Pharmacokinetics of digoxin: relationship between response intensity and predicted compartmental drug levels in man. J Pharmacokinet Biopharm 7:47–61Google Scholar
  19. Lemberger L, Silberstein SD, Axelrod J, Kopin IJ (1970) Marihuana: studies on the disposition and metabolism of delta-9-tetrahydrocannabinol in man. Science 170:1320–1322Google Scholar
  20. Lemberger L, Weiss JL, Watanabe AM, Galanter IM, Wyatt RJ, Cardon PV (1972) Delta-9-tetrahydrocannabinol: temporal correlation of the psychologic effects and blood levels after various routes of administration. N Engl J Med 286:685–688Google Scholar
  21. Levander S, Binder M, Agurell S, Bader-Bartfai A, Gustafsson B, Leander K, Lindgren JE, Olsson A, Tobisson B (1974) Pharmacokinetics in relation to physiological and psychological effects of Δ-8-THC (Δ-8-thiocarbanidin). Acta Pharm Suec 11:662–663Google Scholar
  22. Levy G (1966) Kinetics of pharmacologic effects. Clin Pharmacol Ther 7:362–372Google Scholar
  23. Levy G (1969) Pharmacokinetics of LSD effects. Clin Pharmacol Ther 10:134–135Google Scholar
  24. Lovering EG, McGilveray IJ, McMillan I, Tostowarky W (1975) Comparative bioavailabilities form truncated blood level curves. J Pharm Sci 64:1521–1524Google Scholar
  25. Manno JE, Kiplinger GF, Scholz NE, Forney RB (1971) Influence of alcohol and marihuana on motor and mental performance of volunteer subjects. Clin Pharmacol Ther 12:202–211Google Scholar
  26. Mayersohn M, Perrier D (1978) Kinetic of pharmacologic response to cocaine. Res Commun Chem Pathol Pharmacol 22:465–474Google Scholar
  27. Meffin PJ, Winkle RA, Blaschke TF, Fitzgerald J, Harrison DC (1977) Response optimization of drug dosage: antiarrythmic studies with tocainide. Clin Pharmacol Ther 22:42–57Google Scholar
  28. Metzler CM (1969) A mathematical model for the pharmacokinetics of LSD effect. Clin Pharmacol Ther 10:737–740Google Scholar
  29. Miller L, Cornett T, Drew W, McFarland D, Brightwell D, Wikler A (1977) Marijuana: dose-response effects on pulse rate, subjective estimates of potency, pleasantness, and recognition memory. Pharmacology 15:268–275Google Scholar
  30. Nowlan R, Cohen S (1977) Tolerance to marijuana: heart rate and subjective “high”. Clin Pharmacol Ther 22:550–556Google Scholar
  31. Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK (1980) Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther 28:409–416Google Scholar
  32. Owens SM (1981) Marihuana use among drivers in fatal single vehicle accidents. Dissertation Abstracts (in press)Google Scholar
  33. Owens SM, McBay AJ, Reisner HM, Perez-Reyes M (1981) 125I Radioimmunoassay of Δ 9-tetrahydrocannabinol in blood and plasma with a solid phase second antibody separation method. Clin Chem 27: 619–624Google Scholar
  34. Perez-Reyes M, Lipton MA, Timmons MC, Wall ME, Brine DR, Davis KH (1973) Pharmacology of orally administered Δ 9-tetrahydrocannabinol. Clin Pharmacol Ther 14:48–55Google Scholar
  35. Perez-Reyes M, Timmons MC, Wall ME (1974) Long-term use of marihuana and the development of tolerance or sensitivity to Pharmacology of orally administered Δ 9-tetrahydrocannabinol. Arch Gen Psychiatry 31:89–91Google Scholar
  36. Reuning RH, Sams RA, Notari RE (1973) Role of pharmacokinetics in drug dosage adjustment. 1. Pharmacologic effect kinetics and apparent volume of distribution of digoxin. J Clin Pharmacol 13:127–141Google Scholar
  37. Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J (1979) Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 25:358–371Google Scholar
  38. Stanski DR, Sheiner LB (1979) Pharmacokinetics and dynamics of muscle relaxants. A nesthesiology 51:103–105Google Scholar
  39. Thomas GB (1968) Calculus and analytic geometry. 4 edn. Addison-Wesley, ReadingGoogle Scholar
  40. Wagner JG (1968) Kinetics of pharmacologic response. I. Proposed relationships between response and drug concentration in the intact animal and man. J Theor Biol 20:173–201Google Scholar
  41. Wagner JG, Aghajanian GK, Bing OHL (1968) Correlation of performance test scores with “tissue concentration” of lysergic acid diethylamide in human subjects. Clin Pharmacol Ther 9:635–638Google Scholar
  42. Waskow IE, Olsson JE, Salzman C, Katz MM (1970) Psychological effects of tetrahydrocannabinol. Arch Gen Psychiatry 22:97–107Google Scholar
  43. Weil AT, Zinberg NE, Nelsen JM (1968) Clinical and psychological effects of marijuana in man. Science 162:1234–1242Google Scholar
  44. Weiss JL, Watanabe AM, Lemberger L, Tamarkin NR, Cardon PV (1972) Cardiovascular effects of delta-9-tetrahydrocannabinol in man. Clin Pharmacol Ther 13:671–684Google Scholar
  45. Whiting B, Holford NHG, Sheiner LB (1980) Quantitative analysis of the disopyramide concentration-effect relationship. Br J Clin Pharmacol 9:67–75Google Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • David M. Cocchetto
    • 1
  • S. Michael Owens
    • 2
  • Mario Perez-Reyes
    • 3
  • Stephanie DiGuiseppi
    • 3
  • Loren L. Miller
    • 4
  1. 1.Division of Pharmaceutics, School of PharmacyUniversity of North CarolinaChapel HillUSA
  2. 2.Department of Phathology, School of MedicineUniversity of North CarolinaChapel HillUSA
  3. 3.Department of Psychiatry, School of MedicineUniversity of North CarolinaChapel HillUSA
  4. 4.Department of Clinical ResearchBurroughs Wellcome CompanyResearch Triangle ParkUSA
  5. 5.Department of Pharmaceutical Sciences, College of PharmacyUniversity of ArizonaTucsonUSA

Personalised recommendations