Universiteit Leiden

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Research project

Placebo research: Pharmacological conditioning

The major aim is to examine the potential of learning the body to produce a similar physiological (autonomic, neuroendocrine, or immune) and physical (e.g., desensitization of persistent physical symptoms) response to placebo medication than to active medication (pharmacological conditioning). If proven effective in clinical populations, such pharmacological conditioning could lead to reduced medication intake and accompanying side effects, while maintaining treatment effectiveness.

Andrea Evers
NWO Stevin
ERC Consolidator Grant
Dutch Arthritis Foundation
Diabetes Fund

Background/Scientific relevance

Expectancies have been shown to affect autonomous, endocrine, and immune responses as well as physical symptom reports. Through that route, a variety of health and disease outcomes could be impacted. Such expectancies can be brought about by (combining) different learning techniques, such as conditioning, verbal suggestions, and social learning.


Many chronic conditions are accompanied by the need for long-term and sometimes lifelong medication use. This medication use often has negative effects on the body as well as detrimental side effects, and is costly. By means of pharmacological conditioning paradigms, repeated administration of active medication (unconditioned stimuli) with specific previously-neutral contextual cues (e.g., the look and feel of the medication or a distinctively-tasting drink with which the medication is taken) can lead to these contextual cues becoming associated with the medication effects (the unconditioned response). If subsequently placebo medication is administered with the same contextual cues (e.g., identically-looking tablets or the same distinctive drink), the body could produce the same response (conditioned response) as when the active medication would be administered.

By means of pharmacological conditioning, dosages of active drugs could be reduced, leading to lower side effects and costs, while maintaining treatment effectiveness.

Aims for current research

The major aim is to examine the potential of learning the body to produce a similar physiological (autonomic, neuroendocrine, or immune) and physical (e.g., desensitization of persistent physical symptoms) response to placebo medication than to active medication by means of pharmacological conditioning. In previous studies by our group, the possibility to pharmacologically condition the endocrine system (cortisol and oxytocin) and the immune system (allergies) has been examined in healthy populations. Currently, (proof-of-principle) projects are being conducted in patients with different chronic conditions to examine the clinical applicability and effectiveness of pharmacological conditioning.

1. A proof-of-principle study on pharmacological conditioning as an add-on treatment to optimize standard pharmacological treatment in patients with recent-onset rheumatoid arthritis

Although treatment for chronic inflammatory conditions such as rheumatoid arthritis (RA) has improved considerably, most pharmacotherapeutic strategies are accompanied by more or less severe side effects. This project examines whether it is possible to improve disease progression  (e.g., percentage of drug-free clinical remission, self-reported disease activity, quality of life, inflammatory parameters) of pharmacotherapy in patients with chronic inflammatory conditions by means of pharmacological conditioning as an add-on treatment by means of variable treatment schedules. (PhD student: Meriem Manaï)


 2. The influence of pharmacological conditioning with S-ketamine on widespread pain in patients with fibromyalgia syndrome (FMS): a proof-of-principle study

Patients with fibromyalgia syndrome (FMS) experience chronic widespread pain. An important process involved in the chronification of their pain is central sensitization (CS). In CS, the central nervous system is in a state of hyperexcitability due to the involvement of glutamate at the NMDA receptor level. S(+)-ketamine (an NMDA receptor antagonist) has been proven an effective treatment for CS, but potential serious side effects are a downside to its use. One solution could be the application of pharmacological conditioning. The learned somatic response of conditioning with S(+)-ketamine might cause analgesia in patients with a lower required dose. This has the potential to lower the chance of side effects seen in S(+)-ketamine administration. (PhD student: Hans van Lennep)


3. Pharmacological conditioning of glucose and insulin in healthy individuals and patients with diabetes type 2

Preliminary research has shown that glucose and insulin properties can be trained in healthy controls by means of pharmacological conditioning; however, it is currently unclear whether these effects can also occur in patients with diabetes type two who have difficulties regulating glucose and insulin levels. This project examines whether it is possible to induce glucose and insulin responses in both healthy individuals and patients with diabetes type two by means of pharmacotherapeutic conditioning mechanisms. By establishing the ability to induce a glucose and/or insulin response by means of pharmacotherapeutic conditioning, new therapeutic strategies can be developed and implemented for those with weak glucose and insulin system responses (Postdoc: Aleksandrina Skvortsova).


4. Pharmacological conditioning of a hormonal cream in patients with psoriasis

The aim of this study is to replicate and extend a previous proof-of-principle study (by Ader et al., 2010) on the effectiveness of pharmacological conditioning in patients with psoriasis. A novel element is the inclusion of an open-label group, in which participants are made aware that they receive a lower active medication dosage, to compare with a closed-label group. If proven effective, open-label dose-reduction strategies could be implemented into clinical care much easier as closed-label strategies that require deception.

Meeuwis, S. H., van Middendorp, H., van Laarhoven, A. I., van Leijenhorst, C., Pacheco-Lopez, G., Lavrijsen, A. P., Veldhuijzen, D.S. & Evers, A. W. (2020). Placebo and nocebo effects for itch and itch-related immune outcomes: A systematic review of animal and human studies. Neuroscience & Biobehavioral Reviews113, 325-337.

Meeuwis, S.H., van Middendorp, H., Pacheco-Lopez, G., Ninaber, M.K., Lavrijsen, A.P.M., van der Wee, N., Veldhuijzen, D.S., & Evers, A.W.M. (2019). Antipruritic placebo effects by conditioning H1-antihistamine. Psychosomatic Medicine, 81(9), 841-850. [Impact 4.31]

Smits, R.M., Veldhuijzen, D.S., Van Middendorp, H., Hissink Muller, P.C.E., Armbrust, W., Legger, E., of Pain 21(3-4): 430-439. [Impact 5.82]

Skvortsova, A., Veldhuijzen, D.S., Pacheco-Lopez, G. Bakermans-Kranenburg, M., Van IJzendoorn, M., Smeets, M.A.M., Wilderjans, T.F., Dahan, A., Van den Bergh, O., Chavannes, N.H., Van der Wee, N.J.A., Grewen, K.M., Van Middendorp, H., & Evers, A.W.M. (2020). Placebo effects in the neuroendocrine system: conditioning of the oxytocin responses. Psychosomatic Medicine, 82(1), 47- 56. doi:10.1097/PSY.0000000000000759

Skvortsova, A., Veldhuijzen, D.S., De Rover, M., Pacheco-Lopez, G., Bakermans-Kranenburg, M., Van IJzendoorn, M., Chavannes, N.H., Van Middendorp, H., & Evers, A.W.M. (2020). Effects of oxytocin administration and conditioned oxytocin on brain activity: An fMRI study. PLoS ONE, 15(3): e0229692. doi:10.1371/journal.pone.0229692

Skvortsova, A., Veldhuijzen, D.S., van Middendorp, H., van den Bergh, O., & Evers, A.W.M. (2018). Enhancing placebo effects in somatic symptoms through oxytocin. Psychosomatic Medicine, 80, 353-360.

Skvortsova, A., Pacheco-Lopez, G., Kloosterman, I., Veldhuijzen, D.S., Meijer, O., van Middendorp, H., & Evers, A.W.M. (2019). Conditioned hormonal responses: a systematic review in animals and humans. Frontiers in Neuroendocrinology, 52, 206-218.

Wulffraat, N.M., & Evers, A.W.M. (2020). Pharmacological conditioning for Juvenile Idiopathic Arthritis: A potential solution to reduce methotrexate intolerance. Pediatric Rheumatology, 18(1): 12. doi:10.1186/s12969-020-0407-5

Smits, R.M., Veldhuijzen, D.S., Wulffraat, N.M., & Evers, A.W.M. (2018). The role of placebo effects in immune-related conditions: mechanisms and clinical considerations. Expert Review of Clinical Immunology, 14,761-770.

Tekampe, J., Van Middendorp, H., Sweep, F.C.G.J., Roerink, S.H.P.P., Hermus, A.R.M.M., & Evers, A.W.M. (2019). Conditioning cortisol in humans: Design and pilot study of a randomized controlled trial. Pilot and Feasibility Studies, 5: 9.

     Tekampe, J., van Middendorp, H., Meeuwis, S.H., van Leusden,         J.W.R., Pacheco-López, G., Hermus, A.R.M.M., & Evers, A.W.M.       (2017). Conditioning Immune and Endocrine Parameters in               Humans: A Systematic Review. Psychotherapy and                               Psychosomatics, 86, 99-107.

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