Psychopharmacology

, Volume 226, Issue 4, pp 781–792 | Cite as

Cannabidiol enhances consolidation of explicit fear extinction in humans

  • Ravi K. Das
  • Sunjeev K. Kamboj
  • Mayurun Ramadas
  • Kishoj Yogan
  • Vivek Gupta
  • Emily Redman
  • H. Valerie Curran
  • Celia J. A. Morgan
Original Investigation

Abstract

Rationale

Whilst Cannabidiol (CBD), a non-psychotomimetic cannabinoid, has been shown to enhance extinction learning in rats, its effects on fear memory in humans have not previously been studied.

Objectives

We employed a Pavlovian fear-conditioning paradigm in order to assess the effects of CBD on extinction and consolidation.

Method

Forty-eight participants were conditioned to a coloured box (CS) with electric shocks (UCS) in one context and were extinguished in a second context. Participants received 32 mg of CBD either following before or after extinction in a double-blind, placebo-controlled design. At recall, 48 h later, participants were exposed to CSs and conditioning contexts before (recall) and after (reinstatement) exposure to the UCS. Skin conductance and shock expectancy measures of conditioned responding were recorded throughout.

Results

Successful conditioning, extinction and recall were found in all three treatment groups. CBD given post-extinction enhanced consolidation of extinction learning as assessed by shock expectancy. CBD administered at either time produced trend level reduction in reinstatement of autonomic contextual responding. No acute effects of CBD were found on extinction.

Conclusions

These findings provide the first evidence that CBD can enhance consolidation of extinction learning in humans and suggest that CBD may have potential as an adjunct to extinction-based therapies for anxiety disorders.

Keywords

Cannabidiol Cannabinoids Conditioning Extinction Consolidation Pavlovian Anxiety 

Notes

Acknowledgments

This study was supported by a grant awarded to SKK, CJAM and HVC by the Medical Research Council (UK). The authors report no conflict of interest, financial or otherwise, in this research. All data were collected in compliance with UK law.

References

  1. Akirav I (2011) The role of cannabinoids in modulating emotional and non-emotional memory processes in the hippocampus. Front Behav Neurosci 5:34PubMedGoogle Scholar
  2. Atsak P, Roozendaal B, Campolongo P (2011) Role of the endocannabinoid system in regulating glucocorticoid effects on memory for emotional experiences. Neuroscience 204:104–116PubMedCrossRefGoogle Scholar
  3. Baddeley A, Emslie H, Nimmo-Smith I (1993) The spot-the word test: a robust estimate of verbal intelligence based on lexical decision. Br J Clin Psychol 32:55–65PubMedCrossRefGoogle Scholar
  4. Bechara A, Tranel D, Damasio H, Adophs R, Rockland C, Damasio AR (1995) Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 269:1115–1118PubMedCrossRefGoogle Scholar
  5. Beck AT, Steer RA, Brown GK (1996) Manual for the Beck Depression Inventory-II. Psychological Corporation, San AntonioGoogle Scholar
  6. Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:1094–1097PubMedCrossRefGoogle Scholar
  7. Bergamaschi MM, Quieroz RHC, Crippa JAS, Zuardi AW (2011) Safety and side effects of cannabidiol, a Cannabis sativa constituent. Current Drug Safety 6(4):237–49Google Scholar
  8. Bitencourt RM, Pamplona FA, Takahashi RN (2008) Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats. Eur Neuropsychopharmacol 18:849–859PubMedCrossRefGoogle Scholar
  9. Boddez Y, Baeyens F, Luyten L, Vanteenwegen D, Hermans D, Beckers T (2012) Rating data are underrated: validity of US expectancy in human fear conditioning. J Behav Ther Exp Psychiatry 44:201–206PubMedCrossRefGoogle Scholar
  10. Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218CrossRefGoogle Scholar
  11. Campolongo P, Roozendaal B, Trezza V, Hauer D, Schelling G, McGaugh JL, Cuomo V (2009) Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory. PNAS 106:4888–4893PubMedCrossRefGoogle Scholar
  12. Campolongo P, Ratano P, Manduca A, Scattoni ML, Palmery M, Trezza V, Cuomo V (2012) The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness. Front Behav Neurosci 6:11PubMedGoogle Scholar
  13. Chhatwal JP, Davis M, Maguschak KA, Ressler KJ (2005) Role of endogenous cannabinoids in cognition and emotionality. Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology 30(3):516–524PubMedCrossRefGoogle Scholar
  14. de Bitencourt RM, Pamplona FA, Takahashi RN (2013) A current overview of cannabinoids and glucocorticoids in facilitating extinction of aversive memories: potential extinction enhancers. Neuropharmacology 64:389–395PubMedCrossRefGoogle Scholar
  15. DeHouwer J (2009) The propositional approach to associative learning as an alternative for association formation models. Learn Behav 37:1–20CrossRefGoogle Scholar
  16. Dudai Y (2004) The neurobiology of consolidation, or, how stable is the engram? Annu Rev Psychol 55:51–86PubMedCrossRefGoogle Scholar
  17. Fowler CJ, Tiger G, Ligresti A, López-Rodriguez ML, Di Marzo V (2004) Selective inhibition of anandamide cellular uptake versus enzymatic hydrolysis – a difficult issue to handle. European Journal of Pharmacology 492:1–11Google Scholar
  18. Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signalling. Physiol Rev 83:1017–1066PubMedGoogle Scholar
  19. Grillon C (2009) D-Cycloserine facilitation of fear extinction and exposure-based therapy might rely on lower-level, automatic mechanisms. Biol Psychiatry 66:636–641PubMedCrossRefGoogle Scholar
  20. Hill MN, McEwen BS (2009) Endocannabinoids: the silent partner of glucocorticoids in the synapse. PNAS 106:4579–4580PubMedCrossRefGoogle Scholar
  21. Hill MN, Froese LM, Morrish AC, Sun JC, Floresco SB (2006) Alterations in behavioral flexibility by cannabinoid CB1 receptor agonists and antagonists. Psychopharmacology 187:245–259PubMedCrossRefGoogle Scholar
  22. Kaplan GB, Moore KA (2011) The use of cognitive enhancers in animal models of fear extinction. Pharmacol Biochem Behav 99(2):217–228PubMedCrossRefGoogle Scholar
  23. Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M, Koethe D (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2:e94PubMedCrossRefGoogle Scholar
  24. Lovibond PF, Shanks DR (2002) The role of awareness in Pavlovian conditioning: empirical evidence and theoretical implications. J Exp Psychol 28:3–26Google Scholar
  25. Lutz B (2007) The endocannabinoid system and extinction learning. Mol Neurobiol 36:92–101PubMedCrossRefGoogle Scholar
  26. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534PubMedCrossRefGoogle Scholar
  27. Mineka S (1979) The role of fear in theories of avoidance learning, flooding and extinction. Psychol Bull 86:985–1010CrossRefGoogle Scholar
  28. Mineka S, Zinbarg R (1996) Conditioning and ethological models of anxiety disorders: stress-in-dynamic-context anxiety models. In: Hope DA (ed) Nebraska symposium on motivation, vol 43. Perspectives on anxiety, panic, and fear. University of Nebraska Press, LincolnGoogle Scholar
  29. Morgan CJA, Schafer G, Freeman TP, Curran HV (2010) Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study. Br J Psychiatry 197:285–290PubMedCrossRefGoogle Scholar
  30. Müller GE, Pilzecker A (1900) Experimentelle Beiträge zur Lehre vom Gedächtnis. Z Psychol Ergänzungsband 1:1–300Google Scholar
  31. Niyuhire F, Varvel SA, Thorpe AJ, Stokes RJ, Wiley JL, Lichtman AH (2007) The disruptive effects of the CB(1) receptor antagonist rimonabant on extinction learning in mice are task-specific. Psychopharmacology 191:223–231PubMedCrossRefGoogle Scholar
  32. Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D (2007) Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo controlled clinical trial. Pain 133:210–220PubMedCrossRefGoogle Scholar
  33. Ohman A, Minkea S (2001) Fears, phobias and preparedness: toward an evolved module of fear and fear learning. Psychol Rev 108:483–522PubMedCrossRefGoogle Scholar
  34. Osan R, Tort ABL, Amaral OB (2011) A mismatch-based model for memory reconsolidation and extinction in attractor networks. PLoS One 6(8):e23113PubMedCrossRefGoogle Scholar
  35. Pamplona FA, Prediger RD, Pandolfo P, Takahashi RN (2006) The cannabinoid receptor agonist WIN-55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats. Psychopharmacology 188:641–649PubMedCrossRefGoogle Scholar
  36. Pamplona FA, Bitencourt RM, Takahashi RN (2008) Short- and long-term effects of cannabinoids on the extinction of contextual fear memory in rats. Neurobiol Learn Mem 90:290–293PubMedCrossRefGoogle Scholar
  37. Pavlov IP (1927) Conditioned reflexes. Oxford, LondonGoogle Scholar
  38. Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol 153(2):199–215PubMedCrossRefGoogle Scholar
  39. Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC (1998) Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci 63:PL1–PL6PubMedCrossRefGoogle Scholar
  40. Rachman S, Radomsky AS, Shafran R (2008) Safety behaviour: a reconsideration. Behav Res Ther 46:163–173PubMedCrossRefGoogle Scholar
  41. Reiss S (1991) Expectancy model of fear, anxiety and panic. Clin Psychol Rev 11(92):141–153CrossRefGoogle Scholar
  42. Sevenster D, Beckers T, Kindt M (2012) Retrieval per se is not sufficient to trigger reconsolidation of human fear memory. Neurobiol Learn Mem 97:338–345PubMedCrossRefGoogle Scholar
  43. Spielberger CD, Gorssuch RL, Lushene PR, Vagg PR, Jacobs GA (1983) Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press, Inc., Palo AltoGoogle Scholar
  44. Stern CAJ, Gazarini L, Takahashi RN, Guimaraes FS, Bertogliuo LJ (2012) On disruption of fear memory by reconsolidation blockade: evidence from cannabidiol treatment. Neuropsychopharmacology 37:2132–2142PubMedCrossRefGoogle Scholar
  45. Suzuki A, Josselyn SA, Frankland PW, Massuhige S, Silva AJ, Kida S (2004) Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 24:4787–4795PubMedCrossRefGoogle Scholar
  46. Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150(5):613–623PubMedCrossRefGoogle Scholar
  47. Varvel SA, Lichtman AH (2002) Evaluation of CB1 receptor knockout mice in the Morris water maze. J Pharmacol Exp Ther 301:915–924PubMedCrossRefGoogle Scholar
  48. Watson JB, Rayner R (1920) Conditioned emotional reactions. J Exp Psychol 3:1–14CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Ravi K. Das
    • 1
  • Sunjeev K. Kamboj
    • 1
  • Mayurun Ramadas
    • 2
  • Kishoj Yogan
    • 2
  • Vivek Gupta
    • 2
  • Emily Redman
    • 1
  • H. Valerie Curran
    • 1
  • Celia J. A. Morgan
    • 1
  1. 1.Clinical Psychopharmacology UnitUniversity College LondonLondonUK
  2. 2.UCL Medical SchoolUniversity College LondonLondonUK

Personalised recommendations