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==Explanation==
 
==Explanation==
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This comic is a joke about the difficulty of testing a drug that is supposed to block the {{w|placebo effect}}.
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{{Incomplete|Grammar correction and more references required.}}
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The {{w|placebo}} effect refers to the phenomenon in which  patients given an inactive treatment (such as a sugar pill) can still show improvement relative to an untreated patient. The placebo effect is thus very important to consider when testing new drugs, since even ineffective drugs can have a positive effect on the patients due to the placebo effect. Modern drug experiments are hence conducted as {{w|Blind experiment#Double-blind trials|double-blind trials}}, where the patients are randomly given either the treatment or a placebo without either they or the administering doctors knows who receives the new drug and who received the placebo pill.
  
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A placebo experiment is used for testing a drug candidate. It has two groups: one that gets a real drug candidate, and one that gets a fake. The placebo effect describes the observation that the group that gets the fake often show signs of having received a working drug - though commonly weaker than in the group that gets an effective real drug.
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Generally the patients need to believe that they are receiving an active treatment (or at least could be in a blind trial), but one [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015591 study] showed that the effect can occur even if the patients are told that they are receiving a placebo pill.
  
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[[Cueball]] states to [[Hairbun]], with a citation from the real world, that his team created a Placebo Blocker, a drug designed to prevent the placebo effect. Cueball begins to design a test for this new drug. Following typical experimental design, patients would be split into two groups: a control group, and the group that receives the treatment.
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Several reasons for the placebo effect have been proposed, from study artifacts - such as under-reporting of negative outcomes by patients who think they are being treated, to neurological explanations for how mental state can translate into physical outcomes.  
  
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Cueball knows that the treatment given to the control group is supposed to be designed so that it is not influenced by the variable trying to be isolated. As the placebo effect ''is'' the effect under investigation, a placebo can not be used as a control treatment as a comparison with a placebo blocker. Cueball tries to design around this. In his test, both groups would receive a placebo as a treatment for an unspecified condition (the ''Treatment Placebo''); in addition the test group would receive the Placebo Blocker drug, while the control group would get a placebo pill instead (the ''Placebo-Blocker Placebo''). If this works as expected, the ''Treatment Placebo'' would be blocked by the ''Placebo Blocker'' in the test group, while in the control group, the ''Placebo-Blocker Placebo'' may have a placebo effect in blocking the placebo effect of the ''Treatment Placebo'', and the difference between these effects can be measured to test the effectiveness of the ''Placebo Blocker''.
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This comic specifically refers to a study published in May 2015, the same month in which the comic was released, about possible mechanisms for the placebo effect:
  
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Cueball and Hairbun think about this trial until they both develop headache from frustration. Cueball then kindly offers Hairbun a sugar pill. While this might have helped cure the headache via the placebo effect had he told her it was a headache treatment, by revealing the pill as merely a sugar pill, it may reduce the effect (though it has been shown that placebos tend to work even if the subject is aware that they are placebos).
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:Kathryn T. Hall, Joseph Loscalzo, and Ted J. Kaptchuk. (2015) ''[https://dx.doi.org/10.1016/J.MOLMED.2015.02.009 Genetics and the placebo effect: the placebome.]'' Trends in Mol Medicine. Volume 21, Issue 5, May 2015, Pages 285–294
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<!--More links and references needed-->
  
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In the title text, Cueball mentions that his sugar pills against headache works even better together with the new experimental placebo ''boosters''. Incidentally, he indicates that he keeps those in the same bottle with his sugar pills. Assuming someone believes placebo ''boosters'' are in the jar this would allow them to take the sugar pills and receive a greater placebo effect, as the placebo effect is based upon faith in the treatment, regardless of whether there are placebo ''boosters'' in the jar.
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[[Cueball]] references the researchers from the above mentioned paper when he announces to [[Hair Bun Girl]] that his team have created a new drug designed to prevent the placebo effect from occurring: The '''Placebo Blocker'''.
  
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It is possible but unlikely that:
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The joke centers around the difficulty in designing an experiment which would be able to test whether such a drug actually worked. Cueball begins to tell how to test this new drug with a trial. Following the typical experimental design, patients experiencing the placebo effect (i.e. who had just taken a placebo pill and been told it was a treatment for some ailment) would be split into two groups. The first group would then receive the ''Placebo Blocker'' drug, while the second would receive yet another placebo pill.
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* Cueball's sugar pills are, in fact, the Placebo Blockers themselves and that, seeing Hairbun has a headache, Cueball is inspired to somehow use the opportunity as an experiment to test the Blockers
 
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* Cueball is suggesting Hairbun take a "placebo booster" which is really a "placebo blocker", thus testing the blocker he mentioned earlier in the comic.
 
  
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Questionable neuroscience research is also discussed in [[1453: fMRI]].
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However, Cueball then trails off after realizing the problems with such a trial, such as the fact that one group receives placebos twice. It is also unclear how the patients could be told what the second drug was designed for without negating the effect of the original placebo.
  
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===Placebos===
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Actually, it would be fairly simple if you can find a new drug that needed to be tested through a double-blind trial. But you require this to have a reason to give the patients the Placebo Blocker in the first place. Once this problem is solved the trial would run like this: Group 1 would receive the new drug and a placebo pill; group 2 would receive the new drug and a Placebo Blocker; group 3 would receive two identical placebo pills; and group 4 would receive one placebo pill and one Placebo Blocker.  If the Placebo Blocker do not work, then it would produce a placebo effect, identical to what is experienced with the placebo pill, but if the Placebo Blocker gives a different results than with the placebo pill, then it has an effect. If the effect is less that with the placebo pill, then the blocker actually works. If it is a larger effect then it would be a Placebo Booster instead (see title text). Of course there may be some problem with what to tell the patient about the second pill (which for sure has the sole purpose of reducing the effect of the treatment!)
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The {{w|placebo}} effect refers to the phenomenon in which patients given an inactive treatment such as a sugar pill can still show improvement relative to an untreated patient. The placebo effect is thus very important to consider when testing new drugs, since even ineffective drugs can have a positive effect on the patients due to the placebo effect. Modern drug experiments are hence conducted as {{w|Blind experiment#Double-blind trials|double-blind trials}}, where the patients are randomly given either the treatment or a placebo without either they or the administering doctors knowing who receives the new drug and who received the placebo pill. (It is important that the doctor does not know, as if they did, it may affect the way they interact with the patient.)
 
  
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Generally the patients need to believe that they are receiving an active treatment, but one [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015591 study] showed that the effect can occur even if the patients are told that they are receiving a placebo pill. The key factor seems to be that the patients must believe that a positive effect will occur. For example, (1) patients experience a greater effect if they believe that the treatment is expensive and (2) patients who know that they have not been given an active treatment will experience the effect if they are told that placebos can have a positive effect through the power of the mind. Furthermore, the placebo can increase the effectiveness of treatments which ''seem'' larger (this is why over-the-counter pain medication is often administered as two half-doses rather than just one full dose).
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Cueball and Hair Bun Girl thinks about this trial, without getting to the solution mentioned here above, at least not until they both develop headache from trying to think of how to design this trial. Cueball then kindly offers her a sugar pill from a pill bottle he has on him. While this might have helped cure the headache via the placebo effect had he told her it was a headache treatment, by revealing the pill as merely a sugar pill, it may suppress or reduce the effect. (Although as mentioned above it might still have an effect. Also if low blood sugar is contributing to her headache, then the sugar pill might even effective, and improve her condition, without a placebo effect.)  
  
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Several reasons for the placebo effect have been proposed, from study artifacts - such as under-reporting of negative outcomes by patients who think they are being treated, to neurological explanations for how mental state can translate into physical outcomes.
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It seems likely that the pill bottle with sugar pills is in fact his bottle with the Placebo Blockers, why would he else carry them around at this moment? This would thus mean that his Placebo Blockers are simple placebo sugar pills themselves.
  
 
Placebo-blockers do actually already exist. A side-effect of the opiate antagonist {{w|Naloxone}} is that it [http://healthland.time.com/2009/08/26/a-neurological-explanation-for-the-placebo-effect/ blocks the placebo effect].
 
Placebo-blockers do actually already exist. A side-effect of the opiate antagonist {{w|Naloxone}} is that it [http://healthland.time.com/2009/08/26/a-neurological-explanation-for-the-placebo-effect/ blocks the placebo effect].
  
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It should be noted that placebo does not actually improve the objective condition, only the patient's subjective perception of it (i.e. the patients do not get better more than they randomly would, but the placebo makes them think they do).{{Actual citation needed}}
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In title text, Cueball mentions that his sugar pills against headache works even better together with the new experimental placebo boosters. Incidentally he keeps those in the same bottle with his placebo sugar pills. This makes the above suggestion that all his pills are just plain sugar even more likely, as he is now suggesting that also the ''placebo boosters'' are just sugar pills.  
  
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===Mechanisms of the placebo effect===
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It's unclear whether it would be ''called'' a placebo booster in front of the patients, which would possibly have the effect of ''diminishing'' the effect of the first placebo.
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The placebo effect is one of the greatest mysteries in modern medicine. It is typically found that the placebo effect is an effective treatment in itself in addition to the effectiveness of drugs and other treatments, and it has been found to cause small improvements to cancer outcomes. In other cases such as pain relief, the placebo effect is claimed to be comparable with the effectiveness of the drug itself - but this is a misunderstanding: this is not evidence of placebo working, but of the drug <em>not working</em>.
 
  
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The comic refers to the recent study by Kathryn T. Hall, Joseph Loscalzo, and Ted J. Kaptchuk. (2015) ''[https://dx.doi.org/10.1016/J.MOLMED.2015.02.009 Genetics and the placebo effect: the placebome.]'' Trends in Mol Medicine. Volume 21, Issue 5, May 2015, Pages 285–294 - however, bear in mind that one has to treat studies very carefully ''[https://sciencebasedmedicine.org/ted-kaptchuk-versus-placebo-effects-again/ Kaptchuk vs Placebo]''
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Alternatively, what if the placebo booster was actually effective. However since it's kept in the same bottle as the placebo Hair Bun Girl won't know if she got the placebo (sugar pill) or the real booster, which might then reactivate the placebo effect in her brain since she doesn't actually know which one she got. But if she got the booster but didn't get the placebo, would the booster boost the placebo effect from her not knowing if she got the placebo or not, or would she also need to have received the placebo (sugar pill) itself?  She should probably take two, as the title text suggests. But then would she get two placebos, two boosters, or one of each?
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It is possible to test the placebo blocker using three groups: a test group who receive a placebo and a placebo blocker, a control group who receive a placebo but no blocker, and a second control group who receive no treatment whatsoever, as a lack of treatment is the variable that an actual placebo is designed to control for. Still it might be hard to determine if the pills are having a negative effect or blocking the placebo effect, so multiple trials with multiple illnesses may have to be carried out.
 
  
 
==Transcript==
 
==Transcript==
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:[Hairbun is standing in front of Cueball who does all the talking. Below them is a footnote.]
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:[Hair Bun Girl is standing in front of Cueball who does all the talking. Below them is a footnote.]
 
:Cueball: Some researchers* are starting to figure out the mechanism behind the placebo effect.
 
:Cueball: Some researchers* are starting to figure out the mechanism behind the placebo effect.
 
:Cueball: We've used their work to create a new drug: A ''placebo effect blocker''.
 
:Cueball: We've used their work to create a new drug: A ''placebo effect blocker''.
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:Cueball: ...wait.
 
:Cueball: ...wait.
  
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:[Hairbun holds her chin, while Cueball just stand there for a beat panel.]
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:[Hair Bun Girl holds her chin, while Cueball just stand there for a beat panel.]
  
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:[Hairbun looks again at Cueball who begins to take the lid off of a medicine bottle.]
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:[Hair Bun looks again at Cueball who begins to take the lid off of a medicine bottle.]
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:Hairbun: ...My head hurts.
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:Hair Bun Girl: ...My head hurts.
 
:Cueball: Mine too.
 
:Cueball: Mine too.
 
:Cueball: Here, want a sugar pill?
 
:Cueball: Here, want a sugar pill?
  
 
{{comic discussion}}
 
{{comic discussion}}
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<!-- Include any categories below this line. -->
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[[Category:Comics featuring Cueball]]
 
[[Category:Comics featuring Cueball]]
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[[Category:Comics featuring Hairbun]]
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[[Category:Comics featuring Hair Bun Girl]]
 
[[Category:Science]]
 
[[Category:Science]]
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[[Category:Biology]]
 
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[[Category:Psychology]]
 
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[[Category:Scientific research]]
 
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[[Category:Footnotes]] <!-- non-digetic -->
 

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