, Volume 210, Issue 1, pp 97–106 | Cite as

Cannabis constituents modulate ∆9-tetrahydrocannabinol-induced hyperphagia in rats

  • Jonathan A. Farrimond
  • Andrew J. Hill
  • Benjamin J. Whalley
  • Claire M. WilliamsEmail author
Original Investigation



The hyperphagic effect of ∆9-tetrahydrocannabinol (∆9THC) in humans and rodents is well known. However, no studies have investigated the importance of ∆9THC composition and any influence other non-∆9THC cannabinoids present in Cannabis sativa may have. We therefore compared the effects of purified ∆9THC, synthetic ∆9THC (dronabinol), and ∆9THC botanical drug substance (∆9THC-BDS), a ∆9THC-rich standardized extract comparable in composition to recreationally used cannabis.


Adult male rats were orally dosed with purified ∆9THC, synthetic ∆9THC, or ∆9THC-BDS, matched for ∆9THC content (0.34–2.68 mg/kg). Prior to dosing, subjects were satiated, and food intake was recorded following ∆9THC administration. Data were then analyzed in terms of hourly intake and meal patterns.


All three ∆9THC substances tested induced significant hyperphagic effects at doses ≥0.67 mg/kg. These effects included increased intake during hour one, a shorter latency to onset of feeding and a greater duration and consumption in the first meal. However, while some differences in vehicle control intakes were observed, there were significant, albeit subtle, differences in pattern of effects between the purified ∆9THC and ∆9THC-BDS.


All ∆9THC compounds displayed classical ∆9THC effects on feeding, significantly increasing short-term intake whilst decreasing latency to the first meal. We propose that the subtle adjustment to the meal patterns seen between the purified ∆9THC and ∆9THC-BDS are due to non-∆9THC cannabinoids present in ∆9THC-BDS. These compounds and other non-cannabinoids have an emerging and diverse pharmacology and can modulate ∆9THC-induced hyperphagia, making them worth further investigation for their therapeutic potential.


Cannabis Phytocannabinoids Feeding 9THC Dronabinol Behavior 







9-Tetrahydrocannabinol botanical drug substance


9-Tetrahydrocannabinolic acid






Analysis of variance


Cannabinoid type 1 receptor


Cannabinoid type 2 receptor












Central nervous system




G-protein coupled receptor


Transient receptor potential A1


Transient receptor potential vanilloid 1



This research was supported in part by the University of Reading Research Endowment Trust Fund (to JAF). The authors thank Mr. Trevor Jenkinson and his team for technical assistance and GW Pharmaceuticals for the kind gifts of purified ∆9THC and ∆9THC-BDS.


  1. Akbas F, Gasteyger C, Sjödin A, Astrup A, Larsen TM (2008) A critical review of the cannabinoid receptor as a drug target for obesity management. Obes Rev 10:58–67CrossRefPubMedGoogle Scholar
  2. Beal JA (1994) Appetite effect of dronabinol. J Clin Oncol 12:1524–1525PubMedGoogle Scholar
  3. Ben Amar M (2006) Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol 105:1–25CrossRefPubMedGoogle Scholar
  4. Blundell JE, McArthur RA (1978) Behavioural flux and feeding: continuous monitoring of food intake and food selection, and the video-recording of appetitive and satiety sequences for the analysis of drug action. Anorectic agents: mechanism of action and tolerance. Raven Press, New York, pp 19–43Google Scholar
  5. Brown AJ (2007) Novel cannabinoid receptors. Brit J Pharmacol 152:567–575CrossRefGoogle Scholar
  6. Burkey TH, Quock RM, Consroe P, Roeske WR, Yamamura HI (1997) ∆9-Tetrahydrocannabinol is a partial agonist of cannabinoid receptors in mouse brain. Eur J Pharmacol 323:R3–R4CrossRefPubMedGoogle Scholar
  7. Carr TP, Jesch ED, Brown AW (2008) Endocannabinoids, metabolic regulation, and the role of diet. Nutr Res 28:641–650CrossRefPubMedGoogle Scholar
  8. Dennis I, Whalley BJ, Stephens GJ (2008) Effects of ∆9-tetrahydrocannabivarin on [35S] GTPγS binding in mouse brain cerebellum and piriform cortex membranes. Brit J Pharmacol 154:1349–1358CrossRefGoogle Scholar
  9. De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P, Di Marzo V (2008) Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther 325: 1007–1015CrossRefPubMedGoogle Scholar
  10. Dewey WL, Martin BR, May EL (1984) Cannabinoid stereoisomers: pharmacological effects. Handbook of stereoisomers: drugs in psychopharmacology. CPC Press, Boca Raton, pp 317–326Google Scholar
  11. Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784CrossRefPubMedGoogle Scholar
  12. Di Patrizio NV, Simansky KJ (2008) Activating parabrachial cannabinoid CB1 receptors selectively stimulates feeding of palatable foods in rats. J Neurosci 28:9702–9709CrossRefGoogle Scholar
  13. Elsohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78:539–548CrossRefPubMedGoogle Scholar
  14. Evans AT, Formukong E, Evans FJ (1987) Activation of phospholipase A2 by cannabinoids. Lack of correlation with CNS effects. FEBS Lett 211: 119–122CrossRefPubMedGoogle Scholar
  15. Gallate JE, McGregor IS (1999) The motivation for beer in rats: effects of ritanserin, naloxone and SR141716. Psychopharmacology 142:302–308CrossRefPubMedGoogle Scholar
  16. Gallate JE, Saharov T, Mallet PE, McGregor IS (1999) Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist. Eur J Pharmacol 370:233–240CrossRefPubMedGoogle Scholar
  17. Grotenhermen F (2006) Cannabinoids and the endocannabinoid system. Cannabinoids 1:10–14Google Scholar
  18. Haney M, Rabkin J, Gunderson E, Foltin RW (2005) Dronabinol and marijuana in HIV + marijuana smokers: acute effects on caloric intake and mood. Psychopharmacology 181:170–178CrossRefPubMedGoogle Scholar
  19. Hao S, Avraham Y, Mechoulam R, Berry EM (2000) Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur J Pharmacol 392:147–156CrossRefPubMedGoogle Scholar
  20. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583PubMedGoogle Scholar
  21. Holland ML, Allen JD, Arnold JC (2008) Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1). Eur J Pharmacol 591:128–131CrossRefPubMedGoogle Scholar
  22. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30:515–527CrossRefPubMedGoogle Scholar
  23. Jones D (2008) End of the line for cannabinoid receptor 1 as an anti-obesity target? Nat Rev Drug Discov 7:961–962CrossRefPubMedGoogle Scholar
  24. Kirkham TC, Blundell JE (1984) Dual action of naloxone on feeding revealed by behavioural analysis: separate effects on initiation and termination of eating. Appetite 5:45PubMedGoogle Scholar
  25. Kirkham TC, Williams CM (2001) Endogenous cannabinoids and appetite. Nutr Res 14:65–86CrossRefGoogle Scholar
  26. Lozovaya N, Min R, Tsintsadze V, Burnashev N (2009) Dual modulation of CNS voltage-gated calcium channels by cannabinoids: focus on CB1 receptor-independent effects. Cell Calcium 46:154–162CrossRefPubMedGoogle Scholar
  27. Ma YL, Weston SE, Whalley BJ, Stephens GJ (2008) The phytocannabinoid ∆9-tetrahydrocannabivarin modulates inhibitory neurotransmission in the cerebellum. Brit J Pharmacol 154:204–215CrossRefGoogle Scholar
  28. McHugh D, Tanner C, Mechoulam R, Pertwee RG, Ross RA (2008) Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. Mol Pharmacol 73:441–450CrossRefPubMedGoogle Scholar
  29. Mechoulam R, Gaoni Y (1967) The absolute configuration of ∆1-tetrahydrocannabinol, the major active constituent of hashish. Tetrahedron Lett 12:1109–1111CrossRefPubMedGoogle Scholar
  30. Moore THM, Zammit S, Lingford-Hughes A, Barnes TRE, Jones PB, Burke M, Lewis G (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370:319–328CrossRefPubMedGoogle Scholar
  31. Neovius M, Teixeira-Pinto A, Rasmussen F (2007) Shift in the composition of obesity in young adult men in Sweden over a third of a century. Int J Obes 32:832–836CrossRefGoogle Scholar
  32. Pertwee RG (2007) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: ∆9-tetrahydrocannabinol, cannabidiol and ∆9-tetrahydrocannabivarin. Brit J Pharmacol 153:199–215CrossRefGoogle Scholar
  33. Pertwee RG (2008a) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: ∆9-tetrahydrocannabinol, cannabidiol and ∆9-tetrahydrocannabivarin. Brit J Pharmacol 153:199–215CrossRefGoogle Scholar
  34. Pertwee RG (2008b) Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond. Addict Biol 13:147–159CrossRefPubMedGoogle Scholar
  35. Rao GK, Kaminski NE (2006) Cannabinoid-mediated elevation of intracellular calcium: a structure-activity relationship. J Pharmacol Exp Ther 317:820–829CrossRefPubMedGoogle Scholar
  36. Riedel G, Fadda P, McKillop-Smith PRG, Platt B, Robinson L (2009) Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Brit J Pharmacol 156:1154–1166CrossRefGoogle Scholar
  37. Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29:2053CrossRefPubMedGoogle Scholar
  38. Takeda S, Misawa K, Yamamoto I, Watanabe K (2008) Cannabidiolic acid as a selective cyclooxygenase-2 inhibitory component in cannabis. Drug Metab Dispos 36:1917–1921CrossRefPubMedGoogle Scholar
  39. Thomas A, Stevenson LA, Wease KN, Price MR, Baillie G, Ross RA, Pertwee RG (2005) Evidence that the plant cannabinoid ∆9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Brit J Pharmacol 7:917–926CrossRefGoogle Scholar
  40. Weston SE, Williamson EM, Constanti A, Stephens GJ, Whalley BJ (2006) Tetrahydrocannabivarin exhibits anticonvulsant effects in a piriform cortical brain slice model of epileptiform activity. Proceedings of the BPS at
  41. Whalley BJ, Wilkinson JD, Williamson EM, Constanti A (2004) A novel component of cannabis extract potentiates excitatory synaptic transmission in rat olfactory cortex in vitro. Neurosci Lett 365:58–63CrossRefPubMedGoogle Scholar
  42. Williams CM, Kirkham TC (1999) Anandamide induces overeating: mediation by central cannabinoid CB1 receptors. Psychopharmacology 143:315–317CrossRefPubMedGoogle Scholar
  43. Williams CM, Kirkham TC (2002) Observational analysis of feeding induced by ∆9-THC and anandamide. Physiol Behav 76:241–250CrossRefPubMedGoogle Scholar
  44. Williams CM, Kirkham TC (in press) Accumbens shell infusion of the endocannabinoid 2-AG increases food intake by advancing meal-onset in free-feeding rats. PsychopharmacologyGoogle Scholar
  45. Williams CM, Rogers PJ, Kirkham TC (1998) Hyperphagia in pre-fed rats following oral ∆9-THC. Physiol Behav 65:343–346CrossRefPubMedGoogle Scholar
  46. Williamson EM, Evans FJ (2000) Cannabinoids in clinical practice. Drugs 60:1303–1314CrossRefPubMedGoogle Scholar
  47. Wirth PW, Watson ES, ElSohly M, Turner CE, Murphy JC (1980) Anti-inflammatory properties of cannabichromene. Life Sci 26:1991–1995CrossRefPubMedGoogle Scholar
  48. Zhu HJ, Wang JS, Markowitz JS, Donovan JL, Gibson BB, Gefroh HA, Devane CL (2006) Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana. J Pharmacol Exp Ther 317:850–857CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jonathan A. Farrimond
    • 1
    • 2
  • Andrew J. Hill
    • 1
    • 2
  • Benjamin J. Whalley
    • 2
  • Claire M. Williams
    • 1
    Email author
  1. 1.School of Psychology and Clinical Language SciencesUniversity of ReadingReadingUK
  2. 2.School of PharmacyUniversity of ReadingReadingUK

Personalised recommendations