Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man.

Agurell, S; Halldin, M; Lindgren, J E; Ohlsson, A; Widman, M; Gillespie, H; Hollister, L

doi:10.1016/s0031-6997(25)06861-9

Cited by 409Cannabis and Cannabinoid ResearchForensic Toxicology and Drug AnalysisPharmacogenetics and Drug Metabolism

Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man.

Agurell, S, Halldin, M, Lindgren, J E, Ohlsson, A, Widman, M, Gillespie, H, Hollister, L·1986·Pharmacological Reviews

DOI 10.1016/s0031-6997(25)06861-9

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Both THC and CBD are predominantly metabolized, by the liver, through the action of the cytochrome P450 system.
“Both THC and CBD are predominantly metabolized, by the liver, through the action of the cytochrome P450 system.104,105”
From Clinical Practice Guidelines for Cannabis and Cannabinoid-Based Medicines in the Management of Chronic Pain and Co-Occurring Conditions (2024) · cites this paper as [105]
Previous investigations have not been able to confirm whether there is a direct relationship between plasma levels of cannabinoids, in particular CBD, and their clinical effects.
“however, it should be pointed out that previous investigations have not been able to confirm whether there is a direct relationship between plasma levels of cannabinoids, in particular CBD, and their clinical effects (Agurell et al, 1986).”
From Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients (2011) · cites this paper as Agurell et al, 1986

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“The primary step is hydroxylation on C-7, leading to (7)-7-hydroxy-CBD, followed by further oxidation to (7)-7- carboxy-CBD (Agurell et al., 1986).”
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Influential
Comparison of Cannabinoid Pharmacokinetic Properties in Occasional and Heavy Users Smoking a Marijuana or Placebo Joint
Toennes, S. W., Ramaekers, J. G., Theunissen, E. L., Moeller, M. R., & Kauert, G. F. (2008) · Journal of Analytical Toxicology · doi:10.1093/jat/32.7.470 · Cited by 121 · see citing works
Cannabis for migraine treatment: the once and future prescription? An historical and scientific review
Russo, E. B. (1998) · Pain · doi:10.1016/s0304-3959(98)00033-5 · Cited by 117 · see citing works
“Another article examined pharmacokinetics (Agurell et al., 1986).”
Background
Effect of Dronabinol on Nutritional Status in HIV Infection
Struwe, M. C. W., Kaempfer, S., Geiger, C. J., Pavia, A. T., Plasse, T. F., Shepard, K. V., Ries, K., & Evans, T. G. (1993) · Annals of Pharmacotherapy · doi:10.1177/106002809302700701 · Cited by 117 · see citing works
Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous High-Dose Oral THC
Schwilke, E. W., Schwope, D. M., Karschner, E. L., Lowe, R. H., Darwin, W. D., Kelly, D. L., Goodwin, R. S., Gorelick, D. A., & Huestis, M. A. (2009) · Clinical Chemistry · doi:10.1373/clinchem.2008.122119 · Cited by 117 · see citing works
Cannabinoids and Multiple Sclerosis
Pertwee, R. G. (2007) · Molecular Neurobiology · doi:10.1007/s12035-007-0005-2 · Cited by 110 · see citing works
“In addition, cannabinoid elimination from the body is rather slow (Agurell et al., 1986), necessitating lengthy wash-out periods between treatments if a cross-over design is used.”
Background
Cannabis and Cannabinoids for Chronic Pain
Romero-Sandoval, E. A., Kolano, A. L., & Alvarado-Vazquez, P. A. (2017) · Current Rheumatology Reports · doi:10.1007/s11926-017-0693-1 · Cited by 115 · see citing works
Medical Marijuana and Chronic Pain: a Review of Basic Science and Clinical Evidence
Jensen, B., Chen, J. L., Furnish, T. J., & Wallace, M. S. (2015) · Current Pain and Headache Reports · doi:10.1007/s11916-015-0524-x · Cited by 111 · see citing works
Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon-gamma and suppress interleukin-1 alpha in vitro
Watzl, B., Scuderi, P., & WATSON, R. R. (1991) · International Journal of Immunopharmacology · doi:10.1016/0192-0561(91)90160-9 · Cited by 111 · see citing works
A review of the published literature into cannabis withdrawal symptoms in human users
Smith, N. T. (2002) · Addiction · doi:10.1046/j.1360-0443.2002.00026.x · Cited by 111 · see citing works
“They also note that individual differences may affect absorption rates; the experienced cannabis user may receive less THC in their plasma, but compensates by altering their smoking technique (Agurell et al. 1986).”
BackgroundInfluential
Inhibition of FAAH and activation of PPAR: New approaches to the treatment of cognitive dysfunction and drug addiction
Panlilio, L. V., Justinová, Z., & Goldberg, S. R. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.01.003 · Cited by 106 · see citing works
“The dose range of THC that maintained self-administration behavior in these studies (1–16 βg/kg per injection) was lower than that used in previous studies and comparable to that received from smoking a marijuana cigarette (Agurell et al., 1986; Tanda et al., 2000).”
Method
The Cannabinoid Acids
BURSTEIN, S. H. (1999) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(98)00069-2 · Cited by 107 · see citing works
“Pathways of Metabolism D 9 -THC is rapidly metabolized in the body to a number of oxygenated products (for reviews, see Agurell et al. , 1986; Burstein, 1985; Harvey and Paton, 1984); however, the most important route in most species involves oxidation of the allylic methyl group, and is outlined…”
Background
Interindividual Variation in the Pharmacokinetics of Δ9-Tetrahydrocannabinol as Related to Genetic Polymorphisms in CYP2C9
Sachse-Seeboth, C., Pfeil, J., Sehrt, D. B., Meineke, I., Tzvetkov, M. V., Bruns, E., Poser, W., Vormfelde, S. V., & Brockmöller, J. (2008) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2008.213 · Cited by 105 · see citing works
Use of cannabidiol (CBD) for the treatment of chronic pain
Urits, I., Gress, K. L., Charipova, K., Habib, K., Lee, D. M., Lee, C. S., Jung, J. W., Kassem, H., Cornett, E. M., Paladini, A., et al. (2020) · Best practice & research. Clinical anaesthesiology · doi:10.1016/j.bpa.2020.06.004 · Cited by 104 · see citing works
ASRA Pain Medicine consensus guidelines on the management of the perioperative patient on cannabis and cannabinoids
Shah, S., Schwenk, E. S., Sondekoppam, R. V., Clarke, H. A., Zakowski, M. I., Lynn, R. R., Yeung, B., Nicholson, K., Schwartz, G. S., Hooten, W. M., et al. (2023) · Regional Anesthesia & Pain Medicine · doi:10.1136/rapm-2022-104013 · Cited by 110 · see citing works
Acute effects of THC on time perception in frequent and infrequent cannabis users
Sewell, R. A., Martin, A. M. S., Elander, J., Radhakrishnan, R., Williams, A. H., Skosnik, P. D., Pittman, B. P., Ranganathan, M., & D’Souza, D. C. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2915-6 · Cited by 101 · see citing works
“THC was administered IV via automated infusion pump in order to reduce inter- and intraindividual variability in plasma THC levels and to mimic the time course of plasma THC levels associated with subjective “high” (Ohlsson et al. 1980; Lindgren et al. 1981; Agurell et al. 1986).”
Method
Two cases of "cannabis acute psychosis" following the administration of oral cannabis
Favrat, B., Ménétrey, A., Augsburger, M. P., Rothuizen, L. E., Appenzeller, M., Buclin, T., Pin, M. A., Mangin, P. J., & Giroud, C. (2005) · BMC Psychiatry · doi:10.1186/1471-244x-5-17 · Cited by 100 · see citing works
“the percent delivery to the respiratory tree) strongly depends on the smoking technique; it has been reported to reach approximately 50% [23].”
Background
Marijuana Use among HIV-positive and High-risk Adolescents: A Comparison of Self-report through Audio Computer-assisted Self-administered Interviewing and Urinalysis
Murphy, D. A. (2000) · American Journal of Epidemiology · doi:10.1093/aje/152.9.805 · Cited by 99 · see citing works
“Detection beyond 24 hours depends on the amount of usage, the potency of inhaled or ingested marijuana, and general smoking/inhalation behaviors (18).”
Background
Marijuana Poisoning
Fitzgerald, K. T., Bronstein, A. C., & Newquist, K. L. (2013) · Topics in companion animal medicine · doi:10.1053/j.tcam.2013.03.004 · Cited by 99 · see citing works
Sex difference in the oxidative metabolism of Δ9-tetrahydrocannabinol in the rat
Narimatsu, S., Watanabe, K., Yamamoto, I., & Yoshimura, H. (1991) · Biochemical Pharmacology · doi:10.1016/0006-2952(91)90657-q · Cited by 99 · see citing works
Sex Differences in Δ9-Tetrahydrocannabinol Metabolism and In Vivo Pharmacology Following Acute and Repeated Dosing in Adolescent Rats
Wiley, J., & Burston, J. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.05.057 · Cited by 93 · see citing works
Cannabinoids and Psychosis
D’Souza, D. C. (2007) · International review of neurobiology · doi:10.1016/s0074-7742(06)78010-2 · Cited by 96 · see citing works
Modulation by fluoxetine of striatal dopamine release following Δ9‐tetrahydrocannabinol: a microdialysis study in conscious rats
Malone, D. T., & TAYLOR, D. A. H. B. (1999) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0702753 · Cited by 97 · see citing works
“The studies described above used the i.p. route of administration but in the present experiment, the i.v. route was chosen, which provides a faster absorption to D9-THC's sites of action in the brain (Agurell et al, 1986).”
BackgroundMethod
Survey of cannabis use in patients with amyotrophic lateral sclerosis
Amtmann, D., Weydt, P., Johnson, K. L., Jensen, M. P., & Carter, G. T. (2004) · American Journal of Hospice and Palliative Medicine® · doi:10.1177/104990910402100206 · Cited by 95 · see citing works
The molecular mechanisms that underpin the biological benefits of full-spectrum cannabis extract in the treatment of neuropathic pain and inflammation
Maayah, Z. H., Takahara, S., Ferdaoussi, M., & Dyck, J. R. B. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165771 · Cited by 97 · see citing works
Medical cannabis ‒ the Canadian perspective
Ramkellawan, S., Bober, S., Mindra, S., Moreau, J. M., & Ko, G. D. (2016) · Journal of Pain Research · doi:10.2147/jpr.s98182 · Cited by 91 · see citing works
“Pharmacokinetics To date, most pharmacokinetic studies of cannabinoids have focused on the bioavailability of inhaled THC, which varies substantially in the literature, likely due to differences in factors such as breath-hold length, source of cannabis material, and method of inhalation.(53,54) In general, 25%–27% of…”
A marijuana-drug interaction primer: Precipitants, pharmacology, and pharmacokinetics
Cox, E. J., Maharao, N. V., Patilea-Vrana, G., Unadkat, J. D., Rettie, A. E., McCune, J. S., & Paine, M. F. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.05.001 · Cited by 91 · see citing works
“The pharmacokinetics of primary phytocannabinoids have been reviewed extensively (Agurell et al., 1986; Grant et al., 2017; Grotenhermen, 2003; Huestis, 2007; Lucas et al., 2018; Stout and Cimino, 2014).”
Background
Simultaneous GC-EI-MS Determination of 9-Tetrahydrocannabinol, 11-Hydroxy- 9-Tetrahydrocannabinol, and 11-nor-9-Carboxy- 9-Tetrahydrocannabinol in Human Urine Following Tandem Enzyme-Alkaline Hydrolysis
Abraham, T. T., Lowe, R. H., Pirnay, S., Darwin, W. D., & Huestis, M. A. (2007) · Journal of Analytical Toxicology · doi:10.1093/jat/31.8.477 · Cited by 89 · see citing works
Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction
Rodríguez-Muñoz, M., Sánchez‐Blázquez, P., Merlos, M., & Garzón-Niño, J. (2016) · Oncotarget · doi:10.18632/oncotarget.10095 · Cited by 87 · see citing works
“Like most cannabinoids, CBD is metabolized extensively by the liver, where it is hydroxylated to 7-hydroxyl-CBD by cytochrome P450 (CYP) enzymes, predominantly isozymes of the CYP3A (2/4) and CYP2C (8/9/19) families [181].”
Background
Delta-9-tetrahydrocannabinol (THC) serum concentrations and pharmacological effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg THC
Hunault, C. C., Mensinga, T. T., de Vries, I., et al. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1260-2 · Cited by 89 · see citing works
“The main physical effects reported in previous reports are an increase in heart rate, a conjunctival injection, a subjective ‘high’ feeling and an impairment of cognitive and psychomotor functions (Agurell et al. 1986).”
Background
Medicinal cannabis: is Δ9–tetrahydrocannabinol necessary for all its effects?
Wilkinson, J. D., Whalley, B. J., Baker, D., Pryce, G., Constanti, A., Gibbons, S., & Williamson, E. M. (2003) · Journal of Pharmacy and Pharmacology · doi:10.1211/0022357022304 · Cited by 89 · see citing works
“…of ¢9THC causes pharmacokinetic problems for dose-titration, as it is variably absorbed and undergoes varied and significant first-pass metabolism (Agurell et al 1986; Grotenhermen 2003), and in at least one case, oral cannabis standardized according to ¢9THC content was found to be ineffective…”
Background
Frontal lobe dysfunction in long-term cannabis users
Lundqvist, T., Jönsson, S., & Warkentin, S. (2001) · Neurotoxicology and Teratology · doi:10.1016/s0892-0362(01)00165-9 · Cited by 88 · see citing works
“This difference in time of assessment after cessation may be an important factor because the terminal half-life of THC is between 1 and 7 days with an average of 2–5 days [1].”
Background
Medicinal Cannabis: In Vitro Validation of Vaporizers for the Smoke-Free Inhalation of Cannabis
Lanz, C., Mattsson, J., Soydaner, U., & Brenneisen, R. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147286 · Cited by 88 · see citing works
“Furthermore, the bioavailability after oral administration was reported to be inter-individually very variable, thus showing an unreliable onset of action [13,20,21].”
Background

Delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate exposures reported to America’s Poison Centers
Burgess, A., Hays, H. L., Badeti, J., Spiller, H. A., Rine, N. I., Gaw, C. E., Ding, K., & Smith, G. A. (2024) · Clinical Toxicology · doi:10.1080/15563650.2024.2340115 · Cited by 13 · see citing works
An efficient new cannabinoid antiemetic in pediatric oncology
Abrahamov, A., Abrahamov, A., & Mechoulam, R. (1995) · Life Sciences · doi:10.1016/0024-3205(95)00194-b · Cited by 183 · see citing works
Comparison between delta-9-tetrahydrocannabinol and cannabis extract on resorption rate in mice.
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Pharmacological specificity of the discriminative stimulus effects of Δ9-tetrahydrocannabinol in rhesus monkeys
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Effects of delta-9-tetrahydrocannabinol on social behaviour in the laboratory mouse and rat
Cutler, M. G., & Mackintosh, J. H. (1975) · Psychopharmacology · doi:10.1007/bf00428908 · Cited by 24 · see citing works

Authors: Agurell, S., Halldin, M., Lindgren, J. E., Ohlsson, A., Widman, M., Gillespie, H., & Hollister, L.
ORCID: Halldin, M
Ohlsson, A
Venue: Pharmacological Reviews
Publisher: Elsevier BV
Published: 1986-03
Volume: 38
Issue: 1
Pages: 21-43
ISSN: 0031-6997 (ISSN-L)
DOI: 10.1016/s0031-6997(25)06861-9
OpenAlex: W2107684761
Cited by: 406
References: 0
Citations by year: 2026: 4 · 2025: 6 · 2024: 10 · 2023: 7 · 2022: 5 · 2021: 8 · 2020: 45 · 2019: 17 · 2018: 12 · 2017: 11 · 2016: 21 · 2015: 14 · 2014: 14 · 2013: 8 · 2012: 10
FWCI: 7.34
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Pharmacological Reviews (publishedVersion)
PubMed (publishedVersion)
PubMed
Topics: Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords: delta-1-tetrahydrocannabinol, cannabinoids, pharmacokinetics, drug metabolism, human metabolism
MeSH terms: Animals, Biotransformation, Cannabidiol, Cannabinoids, Drug Tolerance, Feces, Humans, Kinetics, Dronabinol, Tissue Distribution

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Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man.

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