Pharmacology of human experimental anxiety
Open accessAbstract
This review covers the effect of drugs affecting anxiety using four psychological procedures for inducing experimental anxiety applied to healthy volunteers and patients with anxiety disorders. The first is aversive conditioning of the skin conductance responses to tones. The second is simulated public speaking, which consists of speaking in front of a video camera, with anxiety being measured with psychometric scales. The third is the Stroop Color-Word test, in which words naming colors are painted in the same or in a different shade, the incongruence generating a cognitive conflict. The last test is a human version of a thoroughly studied animal model of anxiety, fear-potentiated startle, in which the eye-blink reflex to a loud noise is recorded. The evidence reviewed led to the conclusion that the aversive conditioning and potentiated startle tests are based on classical conditioning of anticipatory anxiety. Their sensitivity to benzodiazepine anxiolytics suggests that these models generate an emotional state related to generalized anxiety disorder. On the other hand, the increase in anxiety determined by simulated public speaking is resistant to benzodiazepines and sensitive to drugs affecting serotonergic neurotransmission. This pharmacological profile, together with epidemiological evidence indicating its widespread prevalence, suggests that the emotional state generated by public speaking represents a species-specific response that may be related to social phobia and panic disorder. Because of scant pharmacological data, the status of the Stroop Color-Word test remains uncertain. In spite of ethical and economic constraints, human experimental anxiety constitutes a valuable tool for the study of the pathophysiology of anxiety disorders.
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SPST has apparent and predictive validity for SAD because fear of speaking in public is a cardinal manifestation of SAD, and pharmacological evidence shows response pattern to some substances in SPST is similar to clinical response in SAD.
“SPST has apparent and predictive validity for SAD because the fear of speaking in public is a cardinal manifestation of SAD, and there is pharmacological evidence that the response pattern to some substances in the SPST is similar to the clinical response presented by patients with SAD (Graeff et al, 2003; Brunello et al, 2000).”
From Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients (2011) · cites this paper as Graeff et al, 2003
The Simulated public speaking section (page not specified) calls public-speaking fear the most frequent social fear and says it is intensified in social phobia. The Conclusion (page not specified) links the test’s pharmacological profile to social phobia, but cautiously says the response may be related to it; it does not establish that responses to substances in the test match clinical responses in patients with social anxiety disorder. (LLM, conf=0.85)
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“Epidemiological as well as pharmacological evidence reviewed elsewhere (Graeff et al. 2003, Graeff 2004) led to the hypothesis that SPS mobilizes the same neural networks that are involved in the PA.”
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“This provides a neuropharmacological validation of our virtual AAC paradigm and thus distinguishes it from more common human anxiety tests such as public speaking anticipation, which is not sensitive to anxiolytic drugs and instead responds to acute administration of serotonergic substances (52).”
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“However, it is not entirely clear that this behaviour relates to subjective feelings of anxiety in humans, experimentally often elicited by procedures involving social evaluation [24] which are however unaffected by anxiolytic drugs [25].”
BackgroundParente, A. C. B. V., Garcia-Leal, C., Del‐Ben, C. M., Guimarães, F. S., & Graeff, F. G. (2005) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2005.05.002 · Cited by 59 · see citing works
Self-citationEffect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial
Bach, D. R., Korn, C. W., Vunder, J., & Bantel, A. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0206-7 · Cited by 46 · see citing works
Zack, M. H., Poulos, C. X., Aramakis, V. B., Khamba, B., & MacLeod, C. M. (2007) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2006.00322.x · Cited by 43 · see citing works
“The effects of speech stress, unlike those of physical stressors, are strongly influenced by serotonin—and particularly the 5-HT-2 receptors (Graeff et al., 2003).”
BackgroundGraeff, F. G. (2012) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x2012007500036 · Cited by 39 · see citing works
“For this reason, SPS is assumed to engage the same neural networks that control the PA (22).”
BackgroundSelf-citationGenetic Approaches to Modeling Anxiety in Animals
Jacobson, L. H., & Cryan, J. F. (2009) · Current topics in behavioral neurosciences · doi:10.1007/7854_2009_31 · Cited by 39 · see citing works
Gilles, C., & Luthringer, R. (2007) · Journal of Psychopharmacology · doi:10.1177/0269881107077733 · Cited by 34 · see citing works
Paris, A., Schmidlin, S., Mouret, S., Hodaj, E., Marijnen, P., Boujedaini, N., Polosan, M., & Cracowski, J. (2011) · Fundamental and Clinical Pharmacology · doi:10.1111/j.1472-8206.2011.00993.x · Cited by 24 · see citing works
Giménez, M., Ortiz, H., Soriano‐Mas, C., López‐Solà, M., Farré, M., Deus, J., Martín‐Santos, R., Fernandes, S., Fina, P., Bani, M., et al. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.09.004 · Cited by 24 · see citing works
“The Public Speaking Test was often used to probe novel SSRIs at single dose in healthy volunteers and patients (Graeff et al., 2003).”
MethodGarcia-Leal, C., Del‐Ben, C. M., Leal, F. M., Graeff, F. G., & Guimarães, F. S. (2009) · Journal of Psychopharmacology · doi:10.1177/0269881108101782 · Cited by 24 · see citing works
Self-citationZuardi, A. W., Crippa, J. A. S., Hallak, J. E. C., & Gorayeb, R. (2013) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2012-0930 · Cited by 24 · see citing works
Kamath, A., Urval, R. P., & Shenoy, A. K. (2017) · BioMed Research International · doi:10.1155/2017/2450670 · Cited by 27 · see citing works
“Environmental stimuli or contexts have been used in healthy volunteers to induce anxiety under ethical conditions [15].”
BackgroundInfluentialEffects of lorazepam on brain activity pattern during an anxiety symptom provocation challenge
Schunck, T., Mathis, A., Erb, G., Namer, I. J., Demazières, A., & Luthringer, R. (2009) · Journal of Psychopharmacology · doi:10.1177/0269881109104864 · Cited by 22 · see citing works
Serotonin in panic and anxiety disorders
Zangrossi, H., Del‐Ben, C. M., Graeff, F. G., & Guimarães, F. S. (2020) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-444-64125-0.00036-0 · Cited by 21 · see citing works
Self-citationBehavioral Correlates of Anxiety
Risbrough, V. B. (2009) · Current topics in behavioral neurosciences · doi:10.1007/7854_2009_11 · Cited by 21 · see citing works
“1995), and public speaking (Graeff et al. 2003; Lee 2004).”
BackgroundBaas, J. M. P., Mol, N., Kenemans, J. L., Prinssen, E. P. M., Niklson, I. A., Xia-Chen, C., Broeyer, F. J. F., & van Gerven, J. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1516-5 · Cited by 21 · see citing works
“Conditioned skin conductance responses are affected by benzodiazepines, but mostly because overall responses are subject to dampening by drug treatments (Hellewell et al. 1999, see also Graeff et al. 2003 ).”
BackgroundInfluentialde Oliveira, D. R., Sanada, P. F., Filho, A. C., Conceição, G. M. S., Cerutti, J. M., & Cerutti, S. M. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.01.009 · Cited by 21 · see citing works
“Although further studies are necessary to understand the complex mechanisms underlying conditioned lick suppression, our results suggest that chronic treatment with EGb modulates conditioned suppression by modulating the neural circuits implicated in anxiety and fear, particularly the AC, DH and PFC (LeDoux, 2000; Gra…”
BackgroundResultKumar, A. J., Motta‐Teixeira, L. C., Takada, S. H., Lee, V. Y., Machado‐Nils, A. V., Xavier, G. F., & Nogueira, M. I. (2018) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2018.12.002 · Cited by 20 · see citing works
The effects of lorazepam on skin conductance responses to aversive stimuli in healthy subjects
Siepmann, M., Heine, B., Kluge, A., Ziemssen, T., Mück-Weymann, M., & Kirch, W. (2007) · Clinical Autonomic Research · doi:10.1007/s10286-007-0407-2 · Cited by 20 · see citing works
“iologic reactions and subjective mood have previously been described in healthy subjects and the validity of models of anxiety based on autonomic responses to aversive stimuli has been questioned [11, 21].”
BackgroundMethodAnsiedad y miedo: su valor adaptativoy maladaptaciones
Garcia, A. M. B., Madalena, A. C., Estanislau, C. R., Rodríguez-Rico, J. L., Dias, H. M., Bassi, A., Chagas, D. A. B., & Morato, S. (2007) · Revista Latinoamericana de Psicología · Cited by 18 · see citing works
Puga, F., Veiga, H., Cagy, M., McDowell, K., Piedade, R. A. M., & Ribeiro, P. F. M. (2005) · Arquivos de Neuro-Psiquiatria · doi:10.1590/s0004-282x2005000200008 · Cited by 16 · see citing works
Serotonin in Panic and Anxiety Disorders
Guimarães, F. S., Zangrossi, H., Del‐Ben, C. M., & Graeff, F. G. (2010) · Handbook of behavioral neuroscience · doi:10.1016/s1569-7339(10)70105-3 · Cited by 16 · see citing works
Self-citationClassical conditioning of endocrine effects
Stockhorst, U. (2005) · Current Opinion in Psychiatry · doi:10.1097/00001504-200503000-00012 · Cited by 16 · see citing works
Serotonina, matéria cinzenta periaquedutal e transtorno do pânico
Graeff, F. G. (2003) · Brazilian Journal of Psychiatry · doi:10.1590/s1516-44462003000600010 · Cited by 13 · see citing works
Self-citationSymptoms and Vocal Risk Factors in Individuals with High and Low Anxiety
Gomes, V., Batista, D. D. C., Lopes, L. W., Aquino, R., & Almeida, A. A. (2018) · Folia Phoniatrica et Logopaedica · doi:10.1159/000494211 · Cited by 13 · see citing works
Graeff, F. G. (2007) · Archives of Clinical Psychiatry (São Paulo) · doi:10.1590/s0101-60832007000500008 · Cited by 12 · see citing works
Self-citationDefense-related emotions in humans.
Graeff, F. G. (2011) · Psychology & Neuroscience · doi:10.3922/j.psns.2011.2.003 · Cited by 9 · see citing works
“For a review of the evidence on the SPS test see Graeff et al. (2003).”
BackgroundSelf-citation'What is more familiar than I? Self, other and familiarity in schizophrenia
Ameller, A., Dereux, A., Dubertret, C., Vaïva, G., Thomas, P., & Pins, D. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.12.007 · Cited by 8 · see citing works
Alcohol selectively impairs negative self-relevant associations in young drinkers
Aramakis, V. B., Khamba, B., MacLeod, C. M., Poulos, C. X., & Zack, M. H. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881111416690 · Cited by 7 · see citing works
“Graeff and colleagues noted that different threat paradigms engage different neurochemical systems (Graeff et al., 2003).”
BackgroundNeurotransmitter and Behaviour: Serotonin and Anxiety
Rex, A., & Fink, H. (2011) · InTech eBooks · doi:10.5772/26114 · Cited by 6 · see citing works
“To trigger anxiety, the subjects receive either fear-inducing agents (caffeine, pentylenetetrazol, lactate infusions or CO2 inhalation), or they undergo psychological tests in an aversive environment (Graeff et al. 2003).”
Transtorno de ansiedade social e habilidades sociais de falar em público: estudo experimental
Angélico, A. P., Crippa, J. A. S., & Loureiro, S. R. (2012) · Estudos e Pesquisas em Psicologia · doi:10.12957/epp.2012.8302 · Cited by 6 · see citing works
“Segundo Graeff et al. (2003), este modelo modificado tem sido amplamente utilizado em estudos farmacológicos, e também em estudos relativos a outros transtornos de ansiedade, a exemplo do pânico (HETEM et al., 1996).”
BackgroundPapapetropoulos, S., Doolin, E. E., Odontiadis, M., Paul, D., Jaros, M. J., Rolan, P. E., Taylor, C. T., & Stein, M. B. (2025) · Psychiatry Research · doi:10.1016/j.psychres.2025.116387 · Cited by 7 · see citing works
Chapter 4.3 Modulation of anxiety behaviors by 5-HT-interacting drugs
Guimarães, F. S., Carobrez, A. P., & Graeff, F. G. (2008) · Handbook of behavioral neuroscience · doi:10.1016/s1569-7339(07)00012-4 · Cited by 5 · see citing works
Self-citationHow Does Anxiety Influence Analogical Mapping
Feldman, V., Hristova, P., & Kokinov, B. N. (2010) · eScholarship (California Digital Library) · Cited by 5 · see citing works
Modelling Anxiety in Humans for Drug Development
Siepmann, M., & Joraschky, P. (2007) · Current Neuropharmacology · doi:10.2174/157015907780077114 · Cited by 5 · see citing works
“patory anxiety, suitable to model generalized anxiety disorders [46].”
BackgroundKuczek, M., Szpitalak, M., & Polczyk, R. (2022) · Polish Psychological Bulletin · doi:10.24425/ppb.2021.139168 · Cited by 4 · see citing works
“In experiments using SPS, respondents are usually informed that their statements will be recorded, which is an additional factor that induces anxiety (e.g. Graeff et al., 2003; Phillips & Giancola, 2008).”
MethodTranstorno de ansiedade social e habilidades sociais: estudo psicométrico e empírico
Angélico, A. P. (2009) · doi:10.11606/t.17.2009.tde-02112009-151551 · Cited by 2 · see citing works
The effects of lavandula angustifolia on animal and human laboratory models of anxiety
Bradley, B. F. (2008) · CLOK (University of Central Lancashire) · Cited by 1 · see citing works
Efeito do sumatriptano no teste da simulação de falar em público
de Rezende, M. G. (2012) · doi:10.11606/d.17.2012.tde-15022012-113246
Bowman, A. (2018) · Digital Commons (Liberty University)
Mallari, P., & Paramanik, V. (2022) · Research Square · doi:10.21203/rs.3.rs-1869548/v1
Honeycutt, D., Sablon, W. D., Jung, D., Redmond, C., Serna, K., Lucas, B., & Campisi, J. (2022) · BIOS · doi:10.1893/bios-d-21-00010
Autorregulação Emocional e Estados Afetivos de alunos de pós-graduação Stricto Sensu
da Silva, J. G. C., Furtado, M. R. M., Silva, E. P., Ramos, É. M. L. S., & Ramos, M. F. H. (2023) · Práticas Educativas Memórias e Oralidades - Rev Pemo · doi:10.47149/pemo.v5.e10621
- Authors
- Graeff, F. G., Parente, A., Del-Ben, C. M., & Guimarães, F. S.
- Affiliations
- Universidade de São Paulo (BR)
- Universidade de São Paulo
- Venue
- Brazilian Journal of Medical and Biological Research
- Publisher
- FapUNIFESP (SciELO)
- Published
- 2003-04
- Volume
- 36
- Issue
- 4
- Pages
- 421-432
- ISSN
- 0100-879X (ISSN-L)
- OpenAlex
- W1999737192
- Cited by
- 70
- References
- 58
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 3 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 4 · 2012: 4
- FWCI
- 0.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Brazilian Journal of Medical and Biological Research (publishedVersion, cc-by)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Americanae (AECID Library) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- anxiety disorders, benzodiazepine anxiolytics, serotonergic neurotransmission, aversive conditioning, skin conductance, fear-potentiated startle, blink reflex, Stroop task, anticipatory anxiety, generalized anxiety disorder, social anxiety disorder, panic disorder, animal models of anxiety
- MeSH terms
- Anxiety, Color Perception, Conditioning, Classical, Galvanic Skin Response, Humans, Speech, Reflex, Startle, Test Anxiety Scale, Anti-Anxiety Agents
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