Exogenous Cannabinoid Efficacy: Merely a Pharmacokinetic Interaction?

Abstract

Endocannabinoid pharmacology is now relatively well understood with a number of endocannabinoids and endogenous cannabinoid neurotransmitters identified and the pharmacokinetics relatively well ascertained. Further, the cannabinoid receptors are now molecularly and pharmacologically characterised and the cell processes involved in endocannabinoid transcription, synthesis, post-translational modification and protein expression are reported. Endogenous cannabinoids have been shown to have key roles in immune and pain pathways and neuro-behavioural signalling including appetite regulation. Significant recent interest has thus been shown in understanding these pathways to guide the development of agents that inhibit the natural catabolism of endogenous cannabinoids to modify pain and appetite, and to synthesise antagonists for the treatment of disease such as obesity. This research is concurrent with the renewed clinical interest in exogenous cannabinoids and their use in disease. However, the complex pharmacology and physiological effects of exogenous cannabinoids, either as individual components or in combination, as extracts or via administration of the whole plant in humans, are less well known. Yet as with all other therapeutics, including those derived from plants, knowledge of the pharmacokinetics and dynamics of the complete plant, the individual chemical molecules and their synthetic versions, including formulations and excipients is a standard part of drug development. This article covers the key pharmacological knowledge required to guide further exploration of the toxicity and efficacy of different cannabinoids and their formulations in blinded placebo-controlled studies.

This is a preview of subscription content, log in to check access.

Change history

  • 21 February 2018

    In the original publication, Page 3, Sect. 4.3, the first sentence was incorrectly published.

References

  1. 1.

    Andreasson S, Allebeck P, Rydberg U. Schizophrenia in users and nonusers of cannabis: a longitudinal study in Stockholm County. Acta Psychiatr Scand. 1989;79:505–10.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Beecher HK. The powerful placebo. J Am Med Assoc. 1955;159:1602–6.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Citti C, Ciccarella G, Braghiroli D, Parenti C, Vandelli MA, Cannazza G. Medicinal cannabis: principal cannabinoids concentration and their stability evaluated by a high performance liquid chromatography coupled to diode array and quadrupole time of flight mass spectrometry method. J Pharm Biomed Anal. 2016;128:201–9. doi:10.1016/j.jpba.2016.05.033.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Claussen U, Korte F. Concerning the behavior of hemp and of delta-9-6a, 10a-trans-tetrahydrocannabinol in smoking. Justus Liebigs Ann Chem. 1968;713:162–5.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–20. doi:10.1056/NEJMoa1611618.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Diaz GJ. Toxicosis by plant alkaloids in humans and animals in Colombia. Toxins (Basel). 2015;7:5408–16. doi:10.3390/toxins7124892.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Drost L, et al. Efficacy of different varieties of medical cannabis in relieving symptoms in PTSD patients. Supp Care Cancer. 2017;25:S223–4.

    Google Scholar 

  8. 8.

    Drug Enforcement Administration Museum and Visitors Centre. Cannabis, coca and poppy: nature’s addictive plants. http://www.deamuseum.org/ccp/resources/index.html. Accessed 11 July 2017.

  9. 9.

    European Medicines Agency. Public statement on Acomplia (rimonabant): withdrawal of the marketing authorisation in the European Union. EMEA 7 Westferry Circus, Canary Wharf, UK. 2009. http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/11/WC500012189.pdf. Accessed 1 Sept 2017.

  10. 10.

    Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–51. doi:10.1111/epi.13060.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Gieringer D. Cannabis vaporization: a promising strategy for smoke harm reduction. J Cannabis Ther. 2001;3(4):153–70.

    Article  Google Scholar 

  12. 12.

    Gieringer D, St. Laurent S, Goodrich S. Cannabis vaporizer combines efficient delivery of THC with effective suppression of pyrolytic compounds. J Cannabis Ther. 2004;1:7–27.

  13. 13.

    Gunasekaran N, Long LE, Dawson BL, et al. Reintoxication: the release of fat-stored delta(9)-tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure. Br J Pharmacol. 2009;158:1330–7. doi:10.1111/j.1476-5381.2009.00399.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4:1770–804. doi:10.1002/cbdv.200790152.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Harmonised Tripartite Guideline. Nonclinical Evaluation for Anticancer Pharmaceuticals S9. 2009. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S9/Step4/S9_Step4_Guideline.pdf. Accessed 1 Sept 2017.

  16. 16.

    International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Harmonised Guideline Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). 2016. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Addendum_Step2.pdf. Accessed 1 Sept 2017.

  17. 17.

    Kim PS, Fishman MA. Cannabis for pain and headaches. Primer Curr Pain Headache Rep. 2017;21:19. doi:10.1007/s11916-017-0619-7.

    Article  PubMed  Google Scholar 

  18. 18.

    Klumpers LE, Beumer TL, van Hasselt JG, et al. Novel delta(9)-tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects. Br J Clin Pharmacol. 2012;74:42–53. doi:10.1111/j.1365-2125.2012.04164.x.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Martin JH, Lucas CJ, Reuter SE, Galettis P. Cannabinoid toxicity post therapeutic intraperitoneal injection. Clin Ther. 2017;39:abstract e80.

  20. 20.

    Nahtigal I, Blake A, Hand A, Florentinus-Mefailoski A, Hashemi H. The pharmacological properties of cannabis. J Pain Manage. 2016;9:481–91.

    Google Scholar 

  21. 21.

    National Academies of Sciences. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. National Academies Press, 2017. doi:10.17226/24625.

  22. 22.

    Naumann RK, Ondracek JM, Reiter S, Shein-Idelson M, Tosches MA, Yamawaki TM, Laurent G. The reptilian brain. Curr Biol. 2015;25:R317–21. doi:10.1016/j.cub.2015.02.049.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Perez-Reyes M, Wall ME. Presence of delta9-tetrahydrocannabinol in human milk. N Engl J Med. 1982;307:819–20. doi:10.1056/NEJM198209233071311.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Peschel W. Quality control of traditional cannabis tinctures: pattern, markers, and stability. Sci Pharm. 2016;84:567–84. doi:10.3390/scipharm84030567.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Pomahacova B, Van der Kooy F, Verpoorte R. Cannabis smoke condensate III: the cannabinoid content of vaporised Cannabis sativa. Inhal Toxicol. 2009;21:1108–12. doi:10.3109/08958370902748559.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163:1344–64. doi:10.1111/j.1476-5381.2011.01238.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Schoeler T, Monk A, Sami MB, et al. Continued versus discontinued cannabis use in patients with psychosis: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:215–25. doi:10.1016/S2215-0366(15)00363-6.

    Article  PubMed  Google Scholar 

  28. 28.

    Temporary Specialist Scientific Committee. Report by the Temporary Specialist Scientific Committee (TSSC), “FAAH (fatty acid amide hydrolase),” on the causes of the accident during a phase 1 clinical trial in Rennes in January 2016. 2016. http://ansm.sante.fr/var/ansm_site/storage/original/application/744c7c6daf96b141bc9509e2f85c227e.pdf. Accessed July 2017.

  29. 29.

    Therapeutic Goods Administration. Australian public assessment report for nabiximols. Australian Government, Department of Health, Therapeutic Goods Administration, Canberra, Australia. 2013.

  30. 30.

    Therapeutic Goods Administration. Medicinal cannabis products: overview of regulation. 2017. http://www.tga.gov.au/medicinal-cannabis-products-overview-regulation. Accessed 10 July 2017.

  31. 31.

    Thomas G, Kloner RA, Rezkalla S. Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know. Am J Cardiol. 2014;113:187–90. doi:10.1016/j.amjcard.2013.09.042.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Turner CE, Elsohly MA, Boeren EG. Constituents of Cannabis sativa L. XVII. A review of the natural constituents. J Nat Prod. 1980;43:169–234.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    US Food and Drug Administration. Marinol® (dronabinol) capsules. FDA, White Oak, 2004.

  34. 34.

    Zgair A, Wong JC, Lee JB, et al. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines. Am J Transl Res. 2016;8:3448–59.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jennifer H. Martin.

Ethics declarations

Funding

No funding was received in the preparation of this article.

Conflict of interest

Jennifer H. Martin, Jennifer Schneider, Catherine J. Lucas and Peter Galettis have no conflicts of interest directly relevant to the content of this article.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Martin, J.H., Schneider, J., Lucas, C.J. et al. Exogenous Cannabinoid Efficacy: Merely a Pharmacokinetic Interaction?. Clin Pharmacokinet 57, 539–545 (2018). https://doi.org/10.1007/s40262-017-0599-0

Download citation