title: Acute effects of Sceletium tortuosum (Zembrin), a dual 5-HT reuptake and PDE4 inhibitor, in the human amygdala and its connection to the hypothalamus.
abstract: The South African endemic plant Sceletium tortuosum has a long history of traditional use as a masticatory and medicine by San and Khoikhoi people and subsequently by European colonial farmers as a psychotropic in tincture form. Over the past decade, the plant has attracted increasing attention for its possible applications in promoting a sense of wellbeing and relieving stress in healthy individuals and for treating clinical anxiety and depression. The pharmacological actions of a standardized extract of the plant (Zembrin) have been reported to be dual PDE4 inhibition and 5-HT reuptake inhibition, a combination that has been argued to offer potential therapeutic advantages. Here we tested the acute effects of Zembrin administration in a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neurocircuitry. In a double-blind, placebo-controlled, cross-over design, 16 healthy participants were scanned during performance in a perceptual-load and an emotion-matching task. Amygdala reactivity to fearful faces under low perceptual load conditions was attenuated after a single 25 mg dose of Zembrin. Follow-up connectivity analysis on the emotion-matching task showed that amygdala-hypothalamus coupling was also reduced. These results demonstrate, for the first time, the attenuating effects of S. tortuosum on the threat circuitry of the human brain and provide supporting evidence that the dual 5-HT reuptake inhibition and PDE4 inhibition of this extract might have anxiolytic potential by attenuating subcortical threat responsivity.
authors.affiliation: 1] Department of Psychology, Utrecht University, Utrecht, The Netherlands [2] Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
authors.forename: David
authors.initials: D
authors.lastname: Terburg
authors.forename: Supriya
authors.initials: S
authors.lastname: Syal
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Rosenberger
authors.forename: Sarah
authors.initials: S
authors.lastname: Heany
authors.forename: Nicole
authors.initials: N
authors.lastname: Phillips
authors.forename: Nigel
authors.initials: N
authors.lastname: Gericke
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Stein
authors.forename: Jack
authors.initials: J
authors.lastname: van Honk
mesh_terms: D000293:Adolescent; D035722:Aizoaceae / Q000737:chemistry; D000679:Amygdala / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004644:Emotions / Q000187:drug effects; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D008297:Male; D016488:Medicine, African Traditional; D009434:Neural Pathways / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D010100:Oxygen / Q000097:blood; D010465:Perception / Q000187:drug effects; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D055815:Young Adult
chemical_list: D010100:Oxygen; D058988:Phosphodiesterase 4 Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors
references.citation: J Altern Complement Med. 2013 Nov;19(11):898-904
references.pmid: 23441963
references.citation: J Med Chem. 1991 Jan;34(1):291-8
references.pmid: 1992129
references.citation: Mol Psychiatry. 2001 Jan;6(1):13-34
references.pmid: 11244481
references.citation: Learn Mem. 2012 Sep 19;19(10):495-8
references.pmid: 22993171
references.citation: Neuroimage. 2011 Aug 15;57(4):1317-23
references.pmid: 21640839
references.citation: Br J Psychiatry. 2009 Jun;194(6):535-40
references.pmid: 19478294
references.citation: J Chem Neuroanat. 2000 Dec;20(3-4):349-74
references.pmid: 11207431
references.citation: Biol Psychiatry. 2012 Oct 1;72(7):548-54
references.pmid: 22677471
references.citation: J Exp Psychol Hum Percept Perform. 1995 Jun;21(3):451-68
references.pmid: 7790827
references.citation: J Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57
references.pmid: 9881538
references.citation: Neuropharmacology. 2008 Nov;55(6):1029-37
references.pmid: 18621068
references.citation: Neuropsychopharmacology. 2009 Jul;34(8):1914-25
references.pmid: 19262466
references.citation: Drug Discov Today. 2007 Oct;12(19-20):870-8
references.pmid: 17933689
references.citation: Neuropsychopharmacology. 2009 Oct;34(11):2404-19
references.pmid: 19516250
references.citation: J Ethnopharmacol. 1996 Mar;50(3):119-30
references.pmid: 8691846
references.citation: Transl Psychiatry. 2012 May 15;2:e115
references.pmid: 22832959
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2011 Mar 30;35(2):545-9
references.pmid: 21184794
references.citation: Eur J Pharmacol. 2003 Feb 28;463(1-3):199-216
references.pmid: 12600711
references.citation: J Neurochem. 2000 Mar;74(3):1257-62
references.pmid: 10693959
references.citation: Pharmacol Biochem Behav. 2009 Feb;91(4):537-41
references.pmid: 18835293
references.citation: Bioorg Med Chem. 2009 Jan 1;17(1):337-43
references.pmid: 19014888
references.citation: Ann N Y Acad Sci. 2008;1129:141-52
references.pmid: 18591476
references.citation: Neuropharmacology. 2006 Oct;51(5):974-85
references.pmid: 16901513
references.citation: Neuropsychopharmacology. 2008 Dec;33(13):3221-5
references.pmid: 18463627
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2010 May 30;34(4):565-80
references.pmid: 20206659
references.citation: Neuropsychobiology. 1992;26(1-2):59-64
references.pmid: 1475038
references.citation: Pharmacol Biochem Behav. 2009 May;92(3):514-20
references.pmid: 19463268
references.citation: Science. 2002 Jul 19;297(5580):400-3
references.pmid: 12130784
references.citation: Neuroimage. 2007 Nov 1;38(2):357-66
references.pmid: 17870614
references.citation: J Ethnopharmacol. 2011 Oct 11;137(3):1124-9
references.pmid: 21798331
references.citation: J Neurosci. 2005 Dec 7;25(49):11489-93
references.pmid: 16339042
references.citation: Mol Psychiatry. 2008 Mar;13(3):325-33
references.pmid: 17579609
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2011 Aug 15;35(7):1586-92
references.pmid: 20673783
references.citation: Neuropsychopharmacology. 2005 Sep;30(9):1724-34
references.pmid: 15827569
references.citation: Neuroimage. 2012 Jan 2;59(1):168-80
references.pmid: 21777680
references.citation: Am J Psychiatry. 2007 Oct;164(10):1613-4
references.pmid: 17898358
references.citation: Psychiatry Res. 2009 Aug 15;168(3):242-9
references.pmid: 19564050
references.citation: Cereb Cortex. 2007 Jul;17(7):1595-603
references.pmid: 16956980
references.citation: Biol Mood Anxiety Disord. 2011 Sep 27;1(1):2
references.pmid: 22738071
references.citation: J Ethnopharmacol. 2011 Jan 7;133(1):31-6
references.pmid: 20816940
references.citation: Psychoneuroendocrinology. 2010 Jan;35(1):105-13
references.pmid: 19782476
references.citation: Behav Brain Res. 2011 Oct 1;223(2):403-10
references.pmid: 21536077
references.citation: Biol Psychiatry. 1999 Nov 1;46(9):1181-91
references.pmid: 10560024
references.citation: Psychol Bull. 2007 Jan;133(1):1-24
references.pmid: 17201568
references.citation: J Ethnopharmacol. 2008 Oct 28;119(3):653-63
references.pmid: 18761074
references.citation: J Comp Neurol. 1999 May 3;407(2):287-301
references.pmid: 10213096
references.citation: Br J Psychiatry. 2009 Aug;195(2):102-8
references.pmid: 19648538