Placebo effect - is it a valid argument?
Randomised, double-blind, placebo-controlled trials
Randomised, double-blind, placebo-controlled trials (RCT) currently represent the gold standard in medical research.
In this type of study, participants are randomly allocated to two groups: one group is given the medicine with the active substance to test, and the second group - with comparable characteristics – is given a medicine with an inactive substance resembling the medicine being tested in all aspects (placebo). The latter group serves as the control group. To ‘pass the test’ and be considered as an efficacious medicine which has beneficial effects on the disease, the group receiving the tested medicine should do significantly better than the placebo group. So, this would be a randomized, placebo-controlled study.
The ‘placebo effect’ is symptom improvement which occurs in participants taking the inactive preparation due to their belief that they have received the active one. It is tied to high expectations that the medicine has beneficial effects.
Neither the participants included in the two groups nor the investigators know who is getting which treatment (the new treatment to test or the placebo with the inactive ingredient). In this way, they are not influenced by expectations, until the end of the trial. Both researchers and participants are therefore “blind” to which treatment is being given to whom. This study will then be a double-blind study.
Randomised, double-blind, placebo-controlled trials (RCT) currently represent the gold standard in medical research.
In this type of study, participants are randomly allocated to two groups: one group is given the medicine with the active substance to test, and the second group - with comparable characteristics – is given a medicine with an inactive substance resembling the medicine being tested in all aspects (placebo). The latter group serves as the control group. To ‘pass the test’ and be considered as an efficacious medicine which has beneficial effects on the disease, the group receiving the tested medicine should do significantly better than the placebo group. So, this would be a randomized, placebo-controlled study.
The ‘placebo effect’ is symptom improvement which occurs in participants taking the inactive preparation due to their belief that they have received the active one. It is tied to high expectations that the medicine has beneficial effects.
Neither the participants included in the two groups nor the investigators know who is getting which treatment (the new treatment to test or the placebo with the inactive ingredient). In this way, they are not influenced by expectations, until the end of the trial. Both researchers and participants are therefore “blind” to which treatment is being given to whom. This study will then be a double-blind study.
The placebo effect
Persons with Parkinson's disease (PwP) show a high placebo response rate in clinical trials. There has been impressive research in the past decades into the neurobiology of placebo effects in Parkinson’s Disease (PD).
Placebo effects complicate clinical trials in PD. Strategies to reduce them during RCT have been suggested (Witek, 2018).
In PwP taking placebo with high expectations for improvement, the placebo effect is actually responsible for real changes in the brain, followed by symptom improvement (Quattrone, 2018; Hideto Miwa, 2007).
Raúl de la Fuente-Fernández and A Jon Stoessl through PET imaging (positron emission tomography) found that the placebo effect is due to the release of dopamine in the striatum resulting from a reward mechanism tied to high expectations of clinical benefits. (de la Fuente-Fernández, 2002).
Neuroscientific studies have shown that placebo effects are genuine psychobiological responses to the administration of placebo (Frisaldi, 2022).
Studies using positron emission tomography (PET) and functional magnetic resonance imaging (MRI) have suggested that frontal cortical areas play an important role in the expectations of symptom improvement and the ventral striatum is involved in the expectation of reward and, together with the prefrontal cortex, in the expectation of therapeutic benefit (Lidstone, 2007).
The placebo effects in PD described above were found to last long, with an improvement in motor scores of up to 20-30%, persisting for up to 6 months (Goetz, 2008). The higher the expectation of an effect, the higher the placebo effect.
Persons with Parkinson's disease (PwP) show a high placebo response rate in clinical trials. There has been impressive research in the past decades into the neurobiology of placebo effects in Parkinson’s Disease (PD).
Placebo effects complicate clinical trials in PD. Strategies to reduce them during RCT have been suggested (Witek, 2018).
In PwP taking placebo with high expectations for improvement, the placebo effect is actually responsible for real changes in the brain, followed by symptom improvement (Quattrone, 2018; Hideto Miwa, 2007).
Raúl de la Fuente-Fernández and A Jon Stoessl through PET imaging (positron emission tomography) found that the placebo effect is due to the release of dopamine in the striatum resulting from a reward mechanism tied to high expectations of clinical benefits. (de la Fuente-Fernández, 2002).
Neuroscientific studies have shown that placebo effects are genuine psychobiological responses to the administration of placebo (Frisaldi, 2022).
Studies using positron emission tomography (PET) and functional magnetic resonance imaging (MRI) have suggested that frontal cortical areas play an important role in the expectations of symptom improvement and the ventral striatum is involved in the expectation of reward and, together with the prefrontal cortex, in the expectation of therapeutic benefit (Lidstone, 2007).
The placebo effects in PD described above were found to last long, with an improvement in motor scores of up to 20-30%, persisting for up to 6 months (Goetz, 2008). The higher the expectation of an effect, the higher the placebo effect.
The issue about the placebo effect in high-dose vitamin B1 therapy
Case reports and an open-label study on HDT in Parkinson’s disease conducted so far have not been double-blind, placebo-controlled trials. It has then been argued that the findings observed may be due to the placebo effect.
The question then arises: can the placebo effect be invoked to explain symptom improvements associated with high dose vitamin B1 administration also when such improvements persist for years, well beyond the 6 months documented in the above studies?
PD is a neurodegenerative disease which, by definition, is bound to get worse over time. Cilia and colleagues have calculated a progression rate of UPDRS motor scores of 3.3 points per year (Cilia, 2020). Only a disease-modifying intervention can slow down disease progression at a lower rate or even halt it.
As far as we currently know from available research, a placebo can not explain such improvements in PD for years as those observed in PwP who take high dose vitamin B1 and have been followed up for years (Costantini, 2015).
Anectodal, unpublished reports from thousands of PwP on B1 therapy support the findings of the preliminary scientific reports published to date on the potential effects of high doses of vitamin B1 administration.
Furthermore, the complexity of the process to find vitamin B1 right dose often entails months of trials and errors with much frustration. This process challenges expectations, gradually lowering them up to the extent of causing PwP to abandon the B1 trial phase in some cases. This difficult dosing process is more likely to discourage PwP initially rather then increase their expectations and, thus, the placebo effect.
Hall et al. (2018) have reported that increasingly new and already available medicines are failing to perform better than the placebo. This has a negative effect on promising medicines which would then never reach the patient. Hall notes that “while treatment efficacy has remained unchanged over the years, the placebo response rate has crept up” in certain conditions, including PD (Hall, 2018). Recent evidence suggests the existence of a link between genetic variation and the variability in placebo response. Hall et al. identify the need to establish “how genetic variation in the placebo response pathway might affect our interpretation of clinical trial results” (Hall, 2018). Some of the findings from their studies would tend to support the hypothesis that “gene-drug/placebo interactions be an unexplored confounder of observed outcomes” (Hall, 2018).
The need for RCTs to validate the HDT therapy findings remains, before concluding that vitamin B1 therapy can slow down or even halt Parkinson’s progression.
Meanwhile, an explanation should be proposed for a different mechanism than the placebo effect for the long-term improvements in PwP which have been documented and reported using standard assessment tools – such as the MDS-UPDRS.
Case reports and an open-label study on HDT in Parkinson’s disease conducted so far have not been double-blind, placebo-controlled trials. It has then been argued that the findings observed may be due to the placebo effect.
The question then arises: can the placebo effect be invoked to explain symptom improvements associated with high dose vitamin B1 administration also when such improvements persist for years, well beyond the 6 months documented in the above studies?
PD is a neurodegenerative disease which, by definition, is bound to get worse over time. Cilia and colleagues have calculated a progression rate of UPDRS motor scores of 3.3 points per year (Cilia, 2020). Only a disease-modifying intervention can slow down disease progression at a lower rate or even halt it.
As far as we currently know from available research, a placebo can not explain such improvements in PD for years as those observed in PwP who take high dose vitamin B1 and have been followed up for years (Costantini, 2015).
Anectodal, unpublished reports from thousands of PwP on B1 therapy support the findings of the preliminary scientific reports published to date on the potential effects of high doses of vitamin B1 administration.
Furthermore, the complexity of the process to find vitamin B1 right dose often entails months of trials and errors with much frustration. This process challenges expectations, gradually lowering them up to the extent of causing PwP to abandon the B1 trial phase in some cases. This difficult dosing process is more likely to discourage PwP initially rather then increase their expectations and, thus, the placebo effect.
Hall et al. (2018) have reported that increasingly new and already available medicines are failing to perform better than the placebo. This has a negative effect on promising medicines which would then never reach the patient. Hall notes that “while treatment efficacy has remained unchanged over the years, the placebo response rate has crept up” in certain conditions, including PD (Hall, 2018). Recent evidence suggests the existence of a link between genetic variation and the variability in placebo response. Hall et al. identify the need to establish “how genetic variation in the placebo response pathway might affect our interpretation of clinical trial results” (Hall, 2018). Some of the findings from their studies would tend to support the hypothesis that “gene-drug/placebo interactions be an unexplored confounder of observed outcomes” (Hall, 2018).
The need for RCTs to validate the HDT therapy findings remains, before concluding that vitamin B1 therapy can slow down or even halt Parkinson’s progression.
Meanwhile, an explanation should be proposed for a different mechanism than the placebo effect for the long-term improvements in PwP which have been documented and reported using standard assessment tools – such as the MDS-UPDRS.
Selected References
Natalie Witek, Glenn T. Stebbins, Christopher G. Goetz, What influences placebo and nocebo responses in Parkinson's disease?, Movement Disoders, 2018 Aug;33(8):1204-12
https://movementdisorders.onlinelibrary.wiley.com/doi/full/10.1002/mds.27416
Aldo Quattrone,Gaetano Barbagallo,Antonio Cerasa,A. Jon Stoessl, Neurobiology of placebo effect in Parkinson's disease: What we have learned and where we are going, Movement Disorders, 19 September 2018.
https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.27438
Hideto Miwa, Placebo effect in Parkinson's disease, Brain Nerve. 2007 Feb;59(2):139-46
https://pubmed.ncbi.nlm.nih.gov/17380778/
Raúl de la Fuente-Fernández 1, A Jon Stoessl, The placebo effect in Parkinson's disease, Trends Neurosci. 2002 Jun;25(6):302-6
https://pubmed.ncbi.nlm.nih.gov/12086748/
Elisa Frisaldi, Aziz Shaibani, Marco Trucco, Edoardo Milano, Fabrizio Benedetti, What is the role of placebo in neurotherapeutics? Expert Rev Neurother. 2022 Jan;22(1):15-25
https://pubmed.ncbi.nlm.nih.gov/34845956/
Sarah C Christine Lidstone, A Jon Stoessl, Understanding the placebo effect: contributions from neuroimaging, Mol Imaging Biol. 2007 Jul-Aug;9(4):176-85.
https://pubmed.ncbi.nlm.nih.gov/17334853/
Goetz CG, Wuu J, McDermott MP, Adler CH, Fahn S, Freed CR, Hauser RA, Olanow WC, Shoulson I, Tandon PK; Parkinson Study Group, Leurgans S. Placebo response in Parkinson’s disease: comparisons among 11 trials covering medical and surgical interventions. Mov Disord. 2008 Apr 15;23(5):690-9.
https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.21894
Roberto Cilia, Emanuele Cereda, Albert Akpalu, Fred Stephen Sarfo, Momodou Cham, Ruth Laryea, Vida Obese, Kenneth Oppon, Francesca Del Sorbo, Salvatore Bonvegna, Anna Lena Zecchinelli, Gianni Pezzoli, Natural history of motor symptoms in Parkinson’s disease and the long-duration response to levodopa’, Brain. 2020 Aug; 143 (8):2490–2501.
https://academic.oup.com/brain/article/143/8/2490/5867803
Kathryn T. Hall, Joseph Loscalzo, and Ted Kaptchuk, Pharmacogenomics and the Placebo Response, ACS Chem. Neurosci. 2018, 9, 4, 633–635
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309549/
Natalie Witek, Glenn T. Stebbins, Christopher G. Goetz, What influences placebo and nocebo responses in Parkinson's disease?, Movement Disoders, 2018 Aug;33(8):1204-12
https://movementdisorders.onlinelibrary.wiley.com/doi/full/10.1002/mds.27416
Aldo Quattrone,Gaetano Barbagallo,Antonio Cerasa,A. Jon Stoessl, Neurobiology of placebo effect in Parkinson's disease: What we have learned and where we are going, Movement Disorders, 19 September 2018.
https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.27438
Hideto Miwa, Placebo effect in Parkinson's disease, Brain Nerve. 2007 Feb;59(2):139-46
https://pubmed.ncbi.nlm.nih.gov/17380778/
Raúl de la Fuente-Fernández 1, A Jon Stoessl, The placebo effect in Parkinson's disease, Trends Neurosci. 2002 Jun;25(6):302-6
https://pubmed.ncbi.nlm.nih.gov/12086748/
Elisa Frisaldi, Aziz Shaibani, Marco Trucco, Edoardo Milano, Fabrizio Benedetti, What is the role of placebo in neurotherapeutics? Expert Rev Neurother. 2022 Jan;22(1):15-25
https://pubmed.ncbi.nlm.nih.gov/34845956/
Sarah C Christine Lidstone, A Jon Stoessl, Understanding the placebo effect: contributions from neuroimaging, Mol Imaging Biol. 2007 Jul-Aug;9(4):176-85.
https://pubmed.ncbi.nlm.nih.gov/17334853/
Goetz CG, Wuu J, McDermott MP, Adler CH, Fahn S, Freed CR, Hauser RA, Olanow WC, Shoulson I, Tandon PK; Parkinson Study Group, Leurgans S. Placebo response in Parkinson’s disease: comparisons among 11 trials covering medical and surgical interventions. Mov Disord. 2008 Apr 15;23(5):690-9.
https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.21894
Roberto Cilia, Emanuele Cereda, Albert Akpalu, Fred Stephen Sarfo, Momodou Cham, Ruth Laryea, Vida Obese, Kenneth Oppon, Francesca Del Sorbo, Salvatore Bonvegna, Anna Lena Zecchinelli, Gianni Pezzoli, Natural history of motor symptoms in Parkinson’s disease and the long-duration response to levodopa’, Brain. 2020 Aug; 143 (8):2490–2501.
https://academic.oup.com/brain/article/143/8/2490/5867803
Kathryn T. Hall, Joseph Loscalzo, and Ted Kaptchuk, Pharmacogenomics and the Placebo Response, ACS Chem. Neurosci. 2018, 9, 4, 633–635
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309549/
Text author: Sergio Pièche
Page updated - 24/04/23
Page updated - 24/04/23
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