Abstract
Rationale
Preclinical research suggests that pharmacologically elevating cannabinoid levels may attenuate fear memory expression and enhance fear extinction.
Objectives
We studied the effects of cannabidiol (CBD) on fear memory expression and fear re-extinction in 69 patients with panic disorder with agoraphobia or with social anxiety disorder. Moderation by sex, diagnosis, and serotonergic antidepressant (AD) use was explored.
Methods
A cued fear conditioning paradigm was applied before the first treatment session with 300 mg CBD/placebo augmented exposure therapy. Study medication was administered orally preceding 8 weekly sessions. Fear acquisition and suboptimal extinction took place prior to the first medication ingestion (T0). After the first medication ingestion (T1), we investigated effects on fear memory expression at retention and fear re-extinction. Subjective fear, shock expectancy, skin conductance, and startle responses to conditioned (CS+) and safety stimulus (CS−) were measured.
Results
Across the sample, CBD reduced shock expectancy at retention under low and ambiguous threat of shock, but fear re-extinction at T1 was unaffected by CBD. However, in AD users, re-extinction of subjective fear was impaired in the CBD condition compared to placebo. In female AD users, CBD interfered with safety learning measured with fear-potentiated startle.
Conclusions
The current findings provide no evidence for enhanced fear re-extinction by CBD. However, CBD acutely decreased threat expectation at retention, without affecting other indices of fear. More studies are needed to elucidate possible interactions with AD use and sex, as well as potential effects of CBD on threat expectancies.
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Data availability
The datasets used and/or analyzed during the current study from patients consenting to sharing their data are available from the corresponding author on reasonable request.
Notes
No administration of the task at T1 in three patients (explicit or implicit refusal or time constraints), data loss due to an administrative error in seven patients, an error in the task in five patients, premature ending of the task due to illness/task too aversive in three patients, a failure to record physiological measures in two patients, insufficient quality of recording of fear-potentiated startle in two patients, insufficient recording of skin conductance in one patient.
References
Atsak P, Hauer D, Campolongo P, Schelling G, McGaugh JL, Roozendaal B (2012) Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory. Proc Natl Acad Sci U S A 109:3504–3509. https://doi.org/10.1073/pnas.1200742109
Baas JMP, Grillon C, Böcker KB, Brack AA, Morgan CA 3rd, Kenemans JL, Verbaten MN (2002) Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology 161:233–247. https://doi.org/10.1007/s00213-002-1011-8
Baldwin DS, Anderson IM, Nutt DJ, Allgulander C, Bandelow B, den Boer JA, Christmas DM, Davies S, Fineberg N, Lidbetter N, Malizia A, McCrone P, Nabarro D, O’Neill C, Scott J, van der Wee N, Wittchen HU (2014) Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol 28:403–439. https://doi.org/10.1177/0269881114525674
Bates D, Kliegl R, Vasishth S, Baayen, H (2018) Parsimonious mixed models. Preprint at https://arxiv.org/abs/1506.04967.
Bergamaschi MM, Queiroz RHC, Crippa JAS, Zuardi AW (2011) Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf 6:237–249. https://doi.org/10.2174/157488611798280924
Black N, Stockings E, Campbell G, Tran LT, Zagic D, Hall WD, Farrell M, Degenhardt L (2019) Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis. Lancet Psychiatry 6:995–1010. https://doi.org/10.1016/S2215-0366(19)30401-8
Blumenthal TD, Cuthbert BN, Filion DL, Hackley S, Lipp OV, van Boxtel A (2005) Committee report: guidelines for human startle eyeblink electromyographic studies. Psychophysiology 42:1–15. https://doi.org/10.1111/j.1469-8986.2005.00271.x
Boddez Y, Baeyens F, Luyten L, Vansteenwegen D, Hermans D, Beckers T (2013) Rating data are underrated: validity of US expectancy in human fear conditioning. J Behav Ther Exp Psychiatry 44:201–206. https://doi.org/10.1016/j.jbtep.2012.08.003
Bolsoni LM, Crippa JAS, Hallak JEC, Guimarães FS, Zuardi AW (2022) Effects of cannabidiol on symptoms induced by the recall of traumatic events in patients with posttraumatic stress disorder. Psychopharmacology 239:1499–1507. https://doi.org/10.1007/s00213-021-06043-y
Bradford DE, Starr MJ, Shackman AJ, Curtin JJ (2015) Empirically based comparisons of the reliability and validity of common quantification approaches for eyeblink startle potentiation in humans. Psychophysiology 52:1669–1681. https://doi.org/10.1111/psyp.12545
Bryk AS, Raudenbush SW (1992) Hierarchical linear models. Sage, Newbury Park, CA
Campolongo P, Morena M, Scaccianoce S, Trezza V, Chiarotti F, Schelling G, Cuomo V, Roozendaal B (2013) Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity. Neuropsychopharmacology 38:1276–1286. https://doi.org/10.1038/npp.2013.26
Chan CK, Lovibond PF (1996) Expectancy bias in trait anxiety. J Abnorm Psychol 105:637–647. https://doi.org/10.1037/0021-843X.105.4.637
Chesney E, Oliver D, Green A, Sovi S, Wilson J, Englund A, Freeman TP, McGuire P (2020) Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacology 45:1799–1806. https://doi.org/10.1038/s41386-020-0667-2
Cornwell BR, Johnson L, Berardi L, Grillon C (2006) Anticipation of public speaking in virtual reality reveals a relationship between trait social anxiety and startle reactivity. Biol Psychiatry 59:664–666. https://doi.org/10.1016/j.biopsych.2005.09.015
Craske MG, Hermans D, Vervliet B (2018) State-of-the-art and future directions for extinction as a translational model for fear and anxiety. Philos Trans R Soc Lond Ser B Biol Sci 373:1742. https://doi.org/10.1098/rstb.2017.0025
Craske MG, Liao B, Brown L, Vervliet B (2012) Role of inhibition in exposure therapy. J Exp Psychopathol 3:322–345. https://doi.org/10.5127/jep.0265
Cuijpers P, Cristea IA, Karyotaki E, Reijnders M, Huibers MJH (2016) How effective are cognitive behavior therapies for major depression and anxiety disorders? A meta-analytic update of the evidence. World Psychiatry 15:245–258. https://doi.org/10.1002/wps.20346
Das RK, Kamboj SK, Ramadas M, Yogan K, Gupta V, Redman E, Curran HV, Morgan CJ (2013) Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology 226:781–792. https://doi.org/10.1007/s00213-012-2955-y
de Oliveira AL, Engelke DS, Diehl F, Scheffer-Teixeira R, Haubrich J, de Freitas CL, Molina VA, Quillfeldt JA (2010) Stress response recruits the hippocampal endocannabinoid system for the modulation of fear memory. Learn Mem 17:202–209. https://doi.org/10.1101/lm.1721010
De Quervain D, Schwabe L, Roozendaal B (2017) Stress, glucocorticoids and memory: implications for treating fear-related disorders. Nat Rev Neurosci 18:7–19. https://doi.org/10.1038/nrn.2016.155
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 6:6395. https://doi.org/10.1038/ncomms7395
Duits P, Baas JMP, Engelhard IM, Richter J, Huisman-van Dijk HM, Limberg Thiesen A, Heitland I, Hamm AO, Cath DC (2021) Latent class growth analyses reveal overrepresentation of dysfunctional fear conditioning trajectories in patients with anxiety-related disorders compared to controls. J Anxiety Disord 78:102361
Duits P, Cath DC, Lissek S, Hox JJ, Hamm AO, Engelhard IM, van den Hout MA, Baas JM (2015) Updated meta-analysis of classical fear conditioning in the anxiety disorders. Depress Anxiety 32:239–253. https://doi.org/10.1002/da.22353
Duits P, Richter J, Baas JMP, Engelhard IM, Limberg-Thiesen A, Heitland I, Hamm AO, Cath DC (2017) Enhancing effects of contingency instructions on fear acquisition and extinction in anxiety disorders. J Abnorm Psychol 126:378–391. https://doi.org/10.1037/abn0000266
Englund A, Morrison PD, Nottage J, Hague D, Kane F, Bonaccorso S, Stone JM, Reichenberg A, Brenneisen R, Holt D, Feilding A, Walker L, Murray RM, Kapur S (2013) Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol 27:19–27. https://doi.org/10.1177/0269881112460109
Franzen JM, Werle I, Vanz F, de Oliveira BB, Martins Nascimento LM, Guimarães FS, Bertoglio LJ (2023) Cannabidiol attenuates fear memory expression in female rats via hippocampal 5-HT1A but not CB1 or CB2 receptors. Neuropharmacology 223:109316. https://doi.org/10.1016/j.neuropharm.2022.109316
Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF (2004) Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol 44:499–523. https://doi.org/10.2165/00003088-200948030-00001
Glass M, Faull RLM, Dragunow M (1997) Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77:299–318. https://doi.org/10.1016/S03064522(96)00428-9
Gloster AT, Hauke C, Höfler M, Einsle F, Fydrich T, Hamm A, Sthröhle A, Wittchen HU (2013) Long-term stability of cognitive-behavioral therapy effects for panic disorder with agoraphobia: a two-year follow-up study. Behav Res Ther 51:830–839. https://doi.org/10.1016/j.brat.2013.09.009
Grillon C, Morgan CA, Davis M (1998) Effects of experimental context and explicit threat cues on acoustic startle in Vietnam veterans with posttraumatic stress disorder. Biol Psychiatry 44:1027–1036. https://doi.org/10.1016/S0006-3223(98)00034-1
Guastella AJ, Lovibond PF, Dadds MR, Mitchell P, Richardson R (2007) A randomized controlled trial of the effect of D-cycloserine on extinction and fear conditioning in humans. Behav Res Ther 45:663–672. https://doi.org/10.1016/j.brat.2006.07.005
Gunduz-Cinar O, Flynn S, Brockway E, Kaugars K, Baldi R, Ramikie TS, Cinar R, Kunos G, Patel S, Holmes A (2016) Fluoxetine facilitates fear extinction through amygdala endocannabinoids. Neuropsychopharmacology 41:1598–1609. https://doi.org/10.1038/npp.2015.318
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 18:813–823. https://doi.org/10.1038/mp.2012.72
Haller J, Bakos N, Szirmay M, Ledent C, Freund TF (2002) The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety. Eur J Neurosci 16:1395–1398. https://doi.org/10.1046/j.1460-9568.2002.02192.x
Hallers-Haalboom ET, Maas J, Kunst LE, Bekker MHJ (2020) The role of sex and gender in anxiety disorders: being scared “like a girl”? In: Lanzenberger R, Kranz GS, Savic I (eds) Handbook of clinical neurology, Vol. 175 (3rd series) Sex differences in neurology and psychiatry. Elsevier Science Ltd, Amsterdam, pp 359–368
Hart G, Harris JA, Westbrook RF (2009) Systemic or intra-amygdala injection of a benzodiazepine (midazolam) impairs extinction but spares re-extinction of conditioned fear responses. Learn Mem 16:53–61. https://doi.org/10.1101/lm.1154409
Heitland I, Klumpers F, Oosting RS, Evers DJJ, Kenemans JL, Baas JMP (2012) Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1. Transl Psychiatry 2:e162. https://doi.org/10.1038/tp.2012.90
Hill MN, Bierer LM, Makotkine I, Golier JA, Galea S, McEwen BS, Hillard CJ, Yehuda R (2013) Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks. Psychoneuroendocrinology 38:2952–2961. https://doi.org/10.1016/j.psyneuen.2013.08.004
Hill MN, Froese LM, Morrish AC, Sun JC, Floresco SB (2006) Alterations in behavioral flexibility by cannabinoid CB1 receptor agonists and antagonists. Psychopharmacology 187:245–259. https://doi.org/10.1007/s00213-006-0421-4
Iffland K, Grotenhermen F (2017) An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis Cannabinoid Res 2:139–154. https://doi.org/10.1089/can.2016.0034
Jurkus R, Day HL, Guimarães FS, Lee JL, Bertoglio LJ, Stevenson CW (2016) Cannabidiol regulation of learned fear: implications for treating anxiety-related disorders. Front Pharmacol 7:454. https://doi.org/10.3389/fphar.2016.00454
Kasten CR, Zhang Y, Boehm SL (2019) Acute cannabinoids produce robust anxiety-like and locomotor effects in mice, but long-term consequences are age- and sex-dependent. Front Behav Neurosci 13:32. https://doi.org/10.3389/fnbeh.2019.00032
Katsidoni V, Anagnostou I, Panagis G (2012) Cannabidiol inhibits the reward facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus. Addict Biol 18:286–296. https://doi.org/10.1111/j.1369-1600.2012.00483.x
Klucken T, Kruse O, Schweckendiek J, Kuepper Y, Mueller EM, Hennig J, Stark R (2016) No evidence for blocking the return of fear by disrupting reconsolidation prior to extinction learning. Cortex 79:112–122. https://doi.org/10.1016/j.cortex.2016.03.015
Klumpers F, Denys D, Kenemans JL, Grillon C, van der Aart J, Baas JMP (2012) Testing the effects of Δ9-THC and D-cycloserine on extinction of conditioned fear in humans. J Psychopharmacol 26:471–478. https://doi.org/10.1177/026988111143162
Klumpers F, van Gerven JM, Prinssen EPM, Niklson I, Roesch F, Riedel WJ, Kenemans JL, Baas JMP (2010) Method development studies for repeatedly measuring anxiolytic drug effects in healthy humans. J Psychopharmacol 24:657–666. https://doi.org/10.1177/0269881109103115
Kwee CMB, Baas JMP, van der Flier FE, Groenink L, Duits P, Eikelenboom M, van der Veen DC, Moerbeek M, Batelaan NM, van Balkom AJLM, Cath DC (2022b) Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: a randomized controlled trial. Eur Neuropsychopharmacol 59:58–67. https://doi.org/10.1016/j.euroneuro.2022.04.003
Kwee CMB, Leen NA, van der Kamp RC, van Lissa CJ, Cath DC, Groenink L, Baas JMP (2023) Anxiolytic effects of endocannabinoid enhancing compounds: a systematic review and meta-analysis. Eur Neuropsychopharmacol 72:79–94. https://doi.org/10.1016/j.euroneuro.2023.04.001
Kwee CMB, van Gerven JMA, Bongaerts FLP, Cath DC, Jacobs G, Baas JMP, Groenink L (2022a) Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration-effect relations using the IB-de-risk tool. J Psychopharmacol 36:1299–1314. https://doi.org/10.1177/026988112211247
Lafenêtre P, Chaouloff F, Marsicano G (2007) The endocannabinoid system in the processing of anxiety and fear and how CB1 receptors may modulate fear extinction. Pharmacol Res 56:367–381. https://doi.org/10.1016/j.phrs.2007.09.006
Leen NA, Duits P, Baas JMP (2021) Trajectories of fear learning in healthy participants are able to distinguish groups that differ in individual characteristics, chronicity of fear and intrusions. J Behav Ther Exp Psychiatry 72:101653. https://doi.org/10.1016/j.jbtep.2021.101653
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:e94. https://doi.org/10.1038/tp.2012.15
Lonsdorf TB, Menz MM, Andreatta M, Fullana MA, Golkar A, Haaker J, Heitland I, Hermann A, Kuhn M, Kruse O, Meir Drexler S, Meulders A, Nees F, Pittig A, Richter J, Römer S, Shiban Y, Schmitz A, Straube B et al (2017) Don’t fear ‘fear conditioning’: methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear. Neurosci Biobehav Rev 77:247–285. https://doi.org/10.1016/j.neubiorev.2017.02.026
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgänsberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534. https://doi.org/10.1038/nature00839
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 25:993–1005. https://doi.org/10.1038/s41380-018-0215-1
Mayo LM, Asratian A, Lindé J, Morena M, Haataja R, Hammar V, Augier G, Hill MN, Heilig M (2020) Elevated anandamide, enhanced recall of fear extinction, and attenuated stress responses following inhibition of fatty acid amide hydrolase: a randomized, controlled experimental medicine trial. Biol Psychiatry 87:538–547. https://doi.org/10.1016/j.biopsych.2019.07.034
McDonald AJ, Mascagni F (2001) Localization of the CB1 type cannabinoid receptor in the rat basolateral amygdala: high concentrations in a subpopulation of cholecystokinin-containing interneurons. Neuroscience 107:641–652. https://doi.org/10.1016/S0306-4522(01)00380-3
Moltke J, Hindocha C (2021) Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems. J Cannabis Res 3:5. https://doi.org/10.1186/s42238-021-00061-5
Myers KM, Davis M (2007) Mechanisms of fear extinction. Mol Psychiatry 12:120–150. https://doi.org/10.1038/sj.mp.4001939
Ney LJ, Matthews A, Hsu CK, Zuj DV, Nicholson E, Steward T, Nichols D, Graham B, Harrison B, Bruno R, Felmingham K (2021) Cannabinoid polymorphisms interact with plasma endocannabinoid levels to predict fear extinction learning. Depress Anxiety 38:1087–1099. https://doi.org/10.1002/da.23170
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 188:641–649. https://doi.org/10.1007/s00213-006-0514-0
Parker LA, Burton P, Sorge RE, Yakiwchuk C, Mechoulam R (2004) Effect of low doses of D9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology 175:360–366. https://doi.org/10.1007/s00213-004-1825-7
Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180. https://doi.org/10.1016/S0163-7258(97)82001-3
Pertwee RG (1999) Pharmacology of cannabinoid receptor ligands. Curr Med Chem 6:635–664
Quirk GJ (2002) Memory for extinction of conditioned fear is long-lasting and persists following spontaneous recovery. Learn Mem 9:402–407. https://doi.org/10.1101/lm.49602
Sah P (2002) Never fear, cannabinoids are here. Nature 418:488–489. https://doi.org/10.1038/418488b
Schiller D, Monfils MH, Raio CM, Johnson DC, LeDoux JE, Phelps EA (2010) Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463:49–53. https://doi.org/10.1038/nature08637
Soeter M, Kindt M (2010) Dissociating response systems: erasing fear from memory. Neurobiol Learn Mem 94:30–41. https://doi.org/10.1016/j.nlm.2010.03.004
Song C, Stevenson CW, Guimaraes FS, Lee JL (2016) Bidirectional effects of cannabidiol on contextual fear memory extinction. Front Pharmacol 7:493. https://doi.org/10.3389/fphar.2016.00493
Stern CA, Gazarini L, Vanvossen AC, Zuardi AW, Galve-Roperh I, Guimaraes FS, Takahashi RN, Bertoglio LJ (2015) Δ9-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption. Eur Neuropsychopharmacol 25:958–965. https://doi.org/10.1016/j.euroneuro.2015.02.001
Tabatadze N, Huang G, May RM, Jain A, Woolley CS (2015) Sex differences in molecular signaling at inhibitory synapses in the hippocampus. J Neurosci 35:11252–11265. https://doi.org/10.1523/JNEUROSCI.1067-15.2015
Terlizzi EP, Norris T (2021) Mental health treatment among adults: United States, 2020. In: NCHS Data Brief, no 419. National Center for Health Statistics, Hyattsville, MD
Tovote P, Fadok J, Lüthi A (2015) Neuronal circuits for fear and anxiety. Nat Rev Neurosci 16:317–331. https://doi.org/10.1038/nrn3945
Van der Flier FE, Kwee CMB, Cath DC, Batelaan NM, Groenink L, Duits P, van der Veen DC, van Balkom AJLM, Baas JMP (2019) Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias: study protocol of a randomized controlled trial. BMC Psychiatry 19:69. https://doi.org/10.1186/s12888-019-2022-x
Van Dis EAM, Van Veen SC, Hagenaars MA, Batelaan NM, Bockting CLH, Van den Heuvel RM, Cuijpers P, Engelhard IM (2020) Long-term outcomes of cognitive behavioral therapy for anxiety-related disorders: a systematic review and meta-analysis. JAMA Psychiatry 66:265–273. https://doi.org/10.1001/jamapsychiatry.2019.3986
Vervliet B, Craske MG, Hermans D (2013) Fear extinction and relapse: state of the art. Annu Rev Clin Psychol 9:215e248. https://doi.org/10.1146/annurev-clinpsy-050212-185542
Zuardi AW, Cosme RA, Graeff FG, Guimarães FS (1993) Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol 7(1_suppl):82–88. https://doi.org/10.1177/026988119300700112
Zuardi AW, Rodrigues NP, Silva AL, Bernardo SA, Hallak JEC, Guimarães FS, Crippa JAS (2017) Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front Pharmacol 8:259. https://doi.org/10.3389/fphar.2017.00259
Zucker I, Prendergast BJ (2020) Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol Sex Differ 11:32. https://doi.org/10.1186/s13293-020-00308-5
Acknowledgements
This work was supported by ZonMw and the Dutch Brain Foundation, Programme Translational Research, project number 40–41200–98–9269; and by research grants awarded by the Helmholtz Institute, Utrecht University, and Espria/MHC Drenthe (GR 18-130a; GR 18-130b). The authors are indebted to the patients who were willing to participate in this study, and to the following people who assisted with data collection: Elise Boonstra, Inge van Loenen, Kim Veenman, and other research assistants; and analysis: Anaïs Thijssen. We also would like to thank Mirjam Moerbeek for her statistical advice.
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Kwee, C.M.B., van der Flier, F.E., Duits, P. et al. Effects of cannabidiol on fear conditioning in anxiety disorders: decreased threat expectation during retention, but no enhanced fear re-extinction. Psychopharmacology 241, 833–847 (2024). https://doi.org/10.1007/s00213-023-06512-6
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DOI: https://doi.org/10.1007/s00213-023-06512-6