Tempering aversive/traumatic memories with cannabinoids: a review of evidence from animal and human studies
Aversive learning and memory are essential to cope with dangerous and stressful stimuli present in an ever-changing environment. When this process is dysfunctional, however, it is associated with posttraumatic stress disorder (PTSD). The endocannabinoid (eCB) system has been implicated in synaptic plasticity associated with physiological and pathological aversive learning and memory.
Objective and methods
The objective of this study was to review and discuss evidence on how and where in the brain genetic or pharmacological interventions targeting the eCB system would attenuate aversive/traumatic memories through extinction facilitation in laboratory animals and humans. The effect size of the experimental intervention under investigation was also calculated.
Currently available data indicate that direct or indirect activation of cannabinoid type-1 (CB1) receptor facilitates the extinction of aversive/traumatic memories. Activating CB1 receptors around the formation of aversive/traumatic memories or their reminders can potentiate their subsequent extinction. In most cases, the effect size has been large (Cohen’s d ≥ 1.0). The brain areas responsible for the abovementioned effects include the medial prefrontal cortex, amygdala, and/or hippocampus. The potential role of cannabinoid type-2 (CB2) receptors in extinction learning is now under investigation.
Drugs augmenting the brain eCB activity can temper the impact of aversive/traumatic experiences by diverse mechanisms depending on the moment of their administration. Considering the pivotal role the extinction process plays in PTSD, the therapeutic potential of these drugs is evident. The sparse number of clinical trials testing these compounds in stress-related disorders is a gap in the literature that needs to be addressed.
KeywordsStress Anxiety Endocannabinoid Cannabidiol Extinction
This work was supported by grants from the National Council for Scientific and Technological Development (CNPq), São Paulo Research Foundation (FAPESP), and the National Institute of Science and Translational Medicine (INCT, 465458/2014-9). Figures were created in the Mind the Graph platform (www.mindthegraph.com).
This work was supported by grants from the National Council for Scientific and Technological Development (CNPq), São Paulo Research Foundation (FAPESP), and the National Institute of Science and Translational Medicine (INCT, 465458/2014-9).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Bluett RJ, Baldi R, Haymer A, Gaulden AD, Hartley ND, Parrish WP, Baechle J, Marcus DJ, Mardam-Bey R, Shonesy BC, Uddin MJ, Marnett LJ, Mackie K, Colbran RJ, Winder DG, Patel S (2017) Endocannabinoid signalling modulates susceptibility to traumatic stress exposure. Nat Commun 8:14782PubMedPubMedCentralCrossRefGoogle Scholar
- Bremner JD, Vermetten E, Schmahl C, Vaccarino V, Vythilingam M, Afzal N, Grillon C, Charney DS (2005) Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychol Med 35:791–806PubMedPubMedCentralCrossRefGoogle Scholar
- Bremner JD, Vythilingam M, Vermetten E, Southwick SM, McGlashan T, Nazeer A, Khan S, Vaccarino LV, Soufer R, Garg PK, Ng CK, Staib LH, Duncan JS, Charney DS (2003) MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am J Psychiatry 160:924–932PubMedCrossRefGoogle Scholar
- Cohen J (1989) Statistical power analysis for the behavioral sciences, 2nd edn. Lawrence Erlbaum Associates, New YorkGoogle Scholar
- Dincheva I, Drysdale AT, Hartley CA, Johnson DC, Jing D, King EC, Ra S, Gray JM, Yang R, DeGruccio AM, Huang C, Cravatt BF, Glatt CE, Hill MN, Casey BJ, Lee FS (2015) FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nat Commun 6:6395PubMedPubMedCentralCrossRefGoogle Scholar
- Fidelman S, Mizrachi Zer-Aviv T, Lange R, Hillard CJ, Akirav I (2018) Chronic treatment with URB597 ameliorates post-stress symptoms in a rat model of PTSD. Eur Neuropsychopharmacol 28(5):630–642.Google Scholar
- Fonzo GA, Simmons AN, Thorp SR, Norman SB, Paulus MP, Stein MB (2010) Exaggerated and disconnected insular-amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorder. Biol Psychiatry 68:433–441PubMedPubMedCentralCrossRefGoogle Scholar
- Gold AL, Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, Metzger LJ, Dougherty DD, Alpert NM, Fischman AJ, Pitman RK (2011) Decreased regional cerebral blood flow in medial prefrontal cortex during trauma-unrelated stressful imagery in Vietnam veterans with post-traumatic stress disorder. Psychol Med 41:2563–2572PubMedCrossRefGoogle Scholar
- Green MK, Rani CS, Joshi A, Soto-Pina AE, Martinez PA, Frazer A, Strong R, Morilak DA (2011) Prenatal stress induces long term stress vulnerability, compromising stress response systems in the brain and impairing extinction of conditioned fear after adult stress. Neuroscience 192:438–451PubMedCrossRefGoogle Scholar
- Gunduz-Cinar O, MacPherson KP, Cinar R, Gamble-George J, Sugden K, Williams B, Godlewski G, Ramikie TS, Gorka AX, Alapafuja SO, Nikas SP, Makriyannis A, Poulton R, Patel S, Hariri AR, Caspi A, Moffitt TE, Kunos G, Holmes A (2013) Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry 18:813–823PubMedCrossRefGoogle Scholar
- Gurvits TV, Shenton ME, Hokama H, Ohta H, Lasko NB, Gilbertson MW, Orr SP, Kikinis R, Jolesz FA, McCarley RW, Pitman RK (1996) Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 40:1091–1099PubMedPubMedCentralCrossRefGoogle Scholar
- Kishimoto Y, Cagniard B, Yamazaki M, Nakayama J, Sakimura K, Kirino Y, Kano M (2015) Task-specific enhancement of hippocampus-dependent learning in mice deficient in monoacylglycerol lipase, the major hydrolyzing enzyme of the endocannabinoid 2-arachidonoylglycerol. Front Behav Neurosci 9:134PubMedPubMedCentralCrossRefGoogle Scholar
- Lisboa SF, Gomes FV, Silva AL, Uliana DL, Camargo LH, Guimaraes FS, Cunha FQ, Joca SR, Resstel LB (2015) Increased contextual fear conditioning in iNOS knockout mice: additional evidence for the involvement of nitric oxide in stress-related disorders and contribution of the endocannabinoid system. Int J Neuropsychopharmacol 18(8). https://doi.org/10.1093/ijnp/pyv005
- Lisboa SF, Niraula A, Resstel LB, Guimaraes FS, Godbout JP, Sheridan JF (2018) Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2. Neuropsychopharmacology 43:1924–1933PubMedCrossRefGoogle Scholar
- Lu AT, Ogdie MN, Jarvelin MR, Moilanen IK, Loo SK, McCracken JT, McGough JJ, Yang MH, Peltonen L, Nelson SF, Cantor RM, Smalley SL (2008) Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder. Am J Med Gen Part B, Neuropsychiatr Genet 147B:1488–1494CrossRefGoogle Scholar
- Manwell LA, Satvat E, Lang ST, Allen CP, Leri F, Parker LA (2009) FAAH inhibitor, URB-597, promotes extinction and CB(1) antagonist, SR141716, inhibits extinction of conditioned aversion produced by naloxone-precipitated morphine withdrawal, but not - extinction of conditioned preference produced by morphine in rats. Pharmacol Biochem Behav 94:154–162PubMedCrossRefGoogle Scholar
- Marsch R, Foeller E, Rammes G, Bunck M, Kössl M, Holsboer F, Zieglgänsberger W, Landgraf R, Lutz B, Wotjak CT (2007) Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J Neurosci 27:832–839PubMedCrossRefGoogle Scholar
- Mayo LM, Asratian A, Linde J, Holm L, Natt D, Augier G, Stensson N, Vecchiarelli HA, Balsevich G, Aukema RJ, Ghafouri B, Spagnolo PA, Lee FS, Hill MN, Heilig M (2018) Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice. Mol Psychiatry. https://doi.org/10.1038/s41380-018-0215-1
- Morena M, Berardi A, Colucci P, Palmery M, Trezza V, Hill MN, Campolongo P (2018) Enhancing endocannabinoid neurotransmission augments the efficacy of extinction training and ameliorates traumatic stress-induced behavioral alterations in rats. Neuropsychopharmacology 43:1284–1296PubMedCrossRefGoogle Scholar
- Ruehle S, Remmers F, Romo-Parra H, Massa F, Wickert M, Wortge S, Haring M, Kaiser N, Marsicano G, Pape HC, Lutz B (2013) Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons: distinctive sufficiency for hippocampus-dependent and amygdala-dependent synaptic and behavioral functions. J Neurosci 33:10264–10277PubMedCrossRefGoogle Scholar
- Sbarski B, Akirav I (2018) Chronic exposure to cannabinoids before an emotional trauma may have negative effects on emotional function. Eur Neuropsychopharmacol 28(8):955–969Google Scholar
- Shin LM, Bush G, Milad MR, Lasko NB, Brohawn KH, Hughes KC, Macklin ML, Gold AL, Karpf RD, Orr SP, Rauch SL, Pitman RK (2011) Exaggerated activation of dorsal anterior cingulate cortex during cognitive interference: a monozygotic twin study of posttraumatic stress disorder. Am J Psychiatry 168:979–985PubMedPubMedCentralCrossRefGoogle Scholar
- Spagnolo PA, Ramchandani VA, Schwandt ML, Kwako LE, George DT, Mayo LM, Hillard CJ, Heilig M (2016) FAAH gene variation moderates stress response and symptom severity in patients with posttraumatic stress disorder and comorbid alcohol dependence. Alcohol Clin Exp Res 40:2426–2434PubMedPubMedCentralCrossRefGoogle Scholar
- Vila-Verde C, Lisboa SF, Uliana DL, Resstel LB, Guimarães FS (2018) F050 - cannabidiol prevents stress-induced impairment of conditioned fear in rats: involvement of serotonergic, cannabinoid and nitrergic systems 11th FENS Forum of Neuroscience, Berlin, GermanyGoogle Scholar
- Yarnell S (2015) The use of medicinal marijuana for posttraumatic stress disorder: a review of the current literature. Prim Care Companion CNS Disord 17(3). https://doi.org/10.4088/PCC.15r01786