The physiology of the placebo effect

Placebos may contain no active ingredients, but they have real effects on the human brain. This article is based on a presentation to the NZ Skeptics 2008 conference in Hamilton, September 26-28.

Earlier this year, Dr Tipu Aamir of the Auckland Pain Management Service drew my attention to something peculiar. In a double-blind, randomised, placebo-controlled trial of morphine after a standard knee operation, 30 percent of those receiving a placebo get pain relief. When those people are given a specific morphine antagonist (‘antidote’), their pain comes back! In the words of a former contributor at an annual conference of this society, this was an epiphany. I needed to know more.

After all, how could something that was ‘all in the mind’ be changed predictably by a substance with a known pharmacological action?

Any study of homeopathy raises the issue of the placebo effect. As a result of a meta-analysis in 2005 of a number of studies comparing homeopathic remedies with orthodox treatment, Shang et al stated in their conclusion that the effect of homeopathic remedies was no greater than that of a placebo. Not that they had no effect, but it was no greater than that of a placebo.

We skeptics are often happy to accept the explanation that if a response to some arcane practice is a placebo response, that settles the issue.

Over the last 30 years there has been a large amount of research into the undoubted effects of placebos. I thought it might be of interest to review this work in the context of our frequent use of ‘placebo effect’ to explain the unscientific.

Placebo is a Latin word for “I shall be pleasing, or acceptable”. It is the first word of the first antiphon of the Roman Rite of the Vespers for the Dead (!), Placebo Domino, dating from the seventh to ninth centuries. Chaucer called one of his characters Placebo in the Merchant’s Tale, because the word had come to mean a flatterer, a sycophant, or a parasite, by the 14th century.

“Placebo seyde: Ful little need had ye, my lord so deare, Council to ask, of any that are here But that ye be so ful of sapience.”

He also uses it in the Parson’s tale: “Flatterers be the Devil’s chaplains, which sing ever ‘Placebo’.”

In the 1811 edition of Hooper’s Medical Dictionary, placebo was defined as “an epithet for any medicine adopted more to please than benefit the patient”. In a recent edition of Collins’ Concise Dictionary of the English Language it is defined as “an inactive substance administered to a patient to compare its effects with those of a real drug, but sometimes for the psychological benefit of the patient through his believing he is receiving treatment”.

However, placebos do benefit patients, and they are certainly not inactive in the context in which they are given.

The most dramatic example of this that I saw in clinical practice involved a young man on artificial kidney treatment. When erythropoietin became available for the treatment of the severe anaemia seen so often in this situation, he was the first patient in our unit to receive it. Erythropoietin is a hormone made in the healthy kidney, which increases the number of red cells in the blood and the amount of the oxygen-carrying haemoglobin. The synthetic version has achieved notoriety as a performance enhancer in sport, for example in the Tour de France. We were all very enthusiastic about this improvement in management for our patient, and he was given his first dose with much interest from all of us. That night he went home, recovered his bicycle from the shed where it had been undisturbed for many months, and rode all around his town with great energy and pleasure. He hadn’t heard the information that the drug took three weeks to act on the anaemia.

We are left with some questions. What was the physiology of his sudden ability to exercise at a ‘normal’ rate, long before there was any change in his blood count? What does ‘it’s all in the mind’ mean? Was he somehow at fault, or was it me and the staff who were lacking in understanding?

I would like to consider:

  • The psychological processes involved in the placebo effect
  • The physiological mechanisms in the brain
  • The site of this activity in the brain
  • Why there is variation in the placebo effect from individual to individual
  • What are the implications for the classical drug trial format?

Psychological mechanisms

Those who study the psychological processes of the placebo effect cite two major mechanisms.

Conditioning. Pavlov (1849-1936) showed that dogs given meals as a bell rang would subsequently salivate when the bell rang despite not being given food. This process has been explored in humans, who will experience pain relief when a placebo is substituted for a pain reliever when a sequence of active analgesia has been associated with an environmental cue. It is an unconscious process. At the nerve cell level, conditioning leads to a stronger and more sustained response.

Expectancy. This effect is seen when the patient has ‘great expectations’ of the substance being given. These are raised by the conscious or unconscious attitude of the therapist. It is a conscious process on the part of the patient.

It is currently suggested that both conditioning and expectancy are active in the placebo effect, and that in fact, as an inert placebo can have no effect per se, what we see is the effect of the context in which the treatment is given.

Neurophysiology of placebo pain relief

Over the last 30 years, there has been much interest in the neuro-physiological mechanisms of the placebo response.

In 1975, Hughes et al identified in the brain two related pentapeptides (a chain of five amino acids linked together) with potent opium-like action. There are many more now identified. These compounds act on specific receptors on the membranes of neurones, and via intracellular metabolic changes increase synaptic transmission. They are made in the pituitary and hypothalamus, and are called endorphins.

A digression

In pharmacology the term agonist denotes a drug with an effect, and antagonist, a drug which specifically blocks the effect of the first substance.

When I spent a year in the pharmacology lab in Dunedin (1959) it was becoming recognised that drugs exerted their effects by way of a specific receptor molecule at the cell surface. The actions of adrenaline, for example, were explained by the presence of two different molecules to which it could attach, which mediated different effects. Noradrenaline would latch on to only one, explaining its more limited range of action. With their usual desire for learned coherency, pharmacologists called them alpha and beta receptors. Antagonist molecules attach to the receptor molecule and block access by the agonist. Hence the term ‘beta-blockers’. These are substances which block the action of adrenaline on its beta receptor. They are widely known for their action in the control of blood pressure, and recently for their unwanted effects when given to protect patients at risk of heart trouble when undergoing operations.

Agonists and antagonists are related by similarities in molecular size, shape, and charge.

Morphine antagonists have been available for some time. In 1961 as a house surgeon in casualty, I was asked to manage an opium addict, brought in because he was deeply unconscious, and breathing perhaps once a minute. He had been without the drug for some weeks, due to market fluctuations. When access was resumed, he used a dose which was the same as his habituated dose. This was much more than he could now tolerate. I had access to nalorphine, a specific morphine antagonist, and 30 seconds after an IV injection, the patient took several deep breaths, sat up, expressed considerable surprise at his surroundings, and then lapsed back into his former state. I was able to repeat this dramatic procedure several times until he recovered!

In 1978 a group of dental surgeons working in California (Levine et al) carried out the following experiment. Patients who had had an impacted wisdom tooth extracted were treated routinely with nitrous oxide, diazepam and a local anaesthetic. At three hours after the procedure they were given either a placebo or naloxone, a specific morphine antagonist. At four hours they were given a placebo or naloxone. Those who had initial pain relief with the first dose of placebo (39 percent), when given naloxone had an increase in pain.

The authors concluded that “this was consistent with the hypothesis that endorphin release mediates placebo analgesia in dental postoperative pain.”

The elegance of this study lies in the unequivocal evidence that a supposedly psychological state (placebo analgesia) was reversed by a specific opioid antagonist. Note that none of the patients was given morphine. There must be a physiological cause for placebo analgesia.

This sort of study has been repeated many times, and always naloxone reverses placebo analgesia.

The site of action of opioids in the brain

The site of this process has been determined. The sites for opioid receptors in the brain can be found by specific cell staining methods and histology on brain tissue. But more exact, ‘real-time’ evidence comes from positron emission tomography (PET) scans.

Another digression

PET utilises short half-life radioactive elements which undergo spontaneous beta decay. In the process, they emit a positron, which collides with an adjacent electron resulting in mutual annihilation, and the generation of two high-energy photons at a near-180 degree angle. These can be detected, and with many, many such events, used to build up a tomographic picture of the source in relation to surrounding tissue. In the studies of the brain, radioactively-labelled glucose is injected, and congregates where activity (utilisation) is greatest. PET scans are used to monitor metabolic activity in specific organs. For example, the extent of heart muscle damage after a heart attack.

In 2002, Petrovic et al were able to show that both opioid and placebo analgesia are associated with increased brain activity in specific regions: the anterior cingulate cortex and the brain stem. There was no increase of activity in these regions with pain only.

Similar localised brain activity has been shown in placebo responses in Parkinsonism (dopamine) and some depressive states (serotonin).

I find these studies exciting and provocative.

Genetic predilection

A further question can be asked in the light of the evidence for a physiological mechanism for the placebo effect. Why does it occur in only 30-40 percent of us for a given situation? It may occur in a greater proportion of a population sample if the context is made more convincing. But why don’t we all have the benefits? Variation in a physiological function begs the question of a genetic predilection.

De Pascalis et al (2002) have shown that individual differences in suggestibility contribute significantly to the magnitude of placebo analgesia. The higher the suggestibility score (there are several tests available) the greater the placebo analgesic effect.

As early as 1970, Morgan et al showed that there was a correlation of suggestibility between monozygotic twins but not dizygotic (fraternal) twins. (Monozygotic twins are the result of the fertilisation of one ovum by one sperm. The resulting zygote splits into two cells which each develop into an individual. These individuals have exactly the same genes.)

Wallace and Persanyi (1989) looked at hypnotic susceptibility and familial handedness. Subjects with close left-handed relatives scored lower in a test for hypnotic susceptibility.

At the 2008 conference, I carried out an experiment with a group of clearly non-suggestible Skeptics. I asked those in the audience to raise their hands if they, or a close relative, were left-handed. If the hypothesis was correct, more than 10 percent of our attendees should have been left-handed. In the event, 22 of 84 attendees indicated they or a close relative were left-handed.

The control study should be done with a church congregation, Protestant or Catholic. In fact, we could do this on both and answer the question as to which is the less suggestible! I haven’t had the nerve to ask. Thomas Bouchard, beginning in 1979, has carried out a number of studies on twins who for a variety of reasons were reared apart. He compared correlations between identical twins and between fraternal twins. The studies from his group (in Minnesota) have shown a large group of correlations in identical twins reared apart, which do not occur in fraternal twins reared apart. The correlations differ very significantly. Table 1 has some examples in twins reared apart:

Similar studies have given similar results in Australia and Western Europe.

Because the nurture of these twins is different, and identical twins have identical genes, the similarities must be genetic. This approach to behaviour has lead to the science of behaviour genetics. (Physical attributes are of course also correlated more between identical twins reared apart, than fraternal twins reared apart.)

Amir Raz (2005, 2008) and his group in New York State have shown that a genetic polymorphism (more than one version of a specific gene) exists for a gene on chromosome 22, which codes for an enzyme active in the breakdown of dopamine, a neurotransmitter. One amino acid substitution (valine for methionine) in the gene alters the enzyme activity by a factor of four times. Since we have a copy of this gene from each parent, we may have val/val, or val/meth, or meth/meth genotypes.

Val/meth heterozygote confers the greater suggestibility. The enzyme is called COMT or catechol-o-methyl transferase.

Brain pathways in which opioid receptors are active are linked to those in which dopamine is the transmitter (nerve to nerve). If there is genetically conferred variation in dopamine activity it is likely that this will influence the result of changes in activity in the opioid pathways.

We must remember that we are talking of a genetic predisposition to be suggestible, and not a gene for suggestibility. It is not that 69 percent of identical twins vote Republican, but that if one does there is a 69 percent probability that the other one does too.

The implications for drug trials

In 2003, Benedetti and his colleagues in Turin examined pain relief in patients after thoracotomy. Patients were allocated to either open infusions of morphine, with information about the efficacy of the drug, or to receive hidden doses of morphine by infusion without any information and without any doctor or nurse present (the open / hidden model for drug trials).

With the same dose, same infusion rate, same timing and same drug, pain relief was less in the ‘hidden’ group.

In the ‘open’ group, the ‘meaning-induced’ expectations had enhanced the drug effect.

This research group has gone on to postulate that in all drug treatment the effect is the sum of actual physiological effect and the effect of expectations. This means that the placebo effect will always cause part of the usual ‘physiological’ response to active drugs. They say that the classical double blind randomised placebo-controlled trial does not allow for expectation effects, and may suggest that a drug has a specific effect gre’open/hidden paradigm’ will give more meaningful results.


  • The analgesic placebo effect is accompanied by a distinct, observable, and locatable physiological event in the brain.
  • Susceptibility to the placebo effect varies in the population at large.
  • This susceptibility is at least in part genetically determined.
  • It may be possible to harness this facet of human behaviour for the benefit of individuals, and to prevent its on-going exploitation by charlatans.
  • Although placebos are inert and cannot have any effect on the healing processes, their meaning and the context in which they are given can.
  • All drug effects include some placebo effect, except when the drug is given surreptitiously. This should alter the classic clinical trial structure.

We have come a long way from the Vespers for the Dead!

Placebos are inert substances but the context in which they are given can alter neurophysiology in such a way as to cause subjective and objective effects.

This is not due to the ‘molecular memory’ of water, nor to strange force-fields as yet unknown to physicists. It is due to our human nature, how we react to our environment, and the relationship, between our minds and our bodies.

Full references available from the editor.

Superstitious? Me? That depends

When the Sunday Star-Times decided to survey the nation on how superstitious New Zealanders are and about what, Vicki Hyde got used as a guinea pig. Part One of her responses was published in the last issue of the NZ Skeptic. This is Part Two.

The Paranormal

Paranormal phenomena are things that cannot be explained and/or proven by current scientific methods. Put a number between 1 and 7 next to each item to indicate how much you agree or disagree with that item.

7 = Strongly agree, 1 = Strongly disagree, 4 = Neutral

Astrology is a way to accurately predict the future.

1 – Having done lots of charts, I know it’s applied psychology – people will read into it what they want to. No accuracy, no prediction.

Psychokinesis, the movement of objects through psychic powers, does exist.

7 or 1 – If you’d said mental abilities instead of psychic powers, I would have agreed. We have a growing number of examples of neurological manipulation of an external environment, such as people able to move cursors around a computer screen by thinking at it. That’s real with the right kind of technology behind it. And pretty darned amazing, not to mention hugely inspiring for people with motor disabilities, given the possibilities for future development.

However, using psychic powers, a la X-Men, to shift things, that’s not been demonstrated.

During altered states, such as sleep or trances, the spirit can leave the body.

1 – Presupposes the existence of the spirit in the first place …

Out-of-body experiences (OOBEs) are fascinating and real in the sense that the people who experience them – me, for one! – feel as if they are real. However, neuroscience is starting to paint a very interesting picture of how these experiences occur and even how to induce them. This does not involve the spirit departing the body, nor have such experiences been able to demonstrate conclusive proof of knowledge gained solely from such a spirit wandering.

The Loch Ness monster of Scotland exists.

1 – Though it would be great if it did. Imagine a plesiosaur living in these times; that would be a magnificent survival story. But you only have to stop and think for a bit to see how unlikely it is. We’ve got much more chance for the Fiordland moose or the moa to pop up here than Scotland’s favourite cryptozoological beastie lurking in the depths.

The number ’13’ is particularly unlucky or particularly lucky

1 – Only if you’re culturally responsive to it. Other cultures don’t like four or seven or NEE!

Reincarnation does occur.

1 – I haven’t seen any good evidence for agreeing with this, and it presupposes a whole host of entities and processes to support it for which there is no evidence.

There is life on other planets.

7 – I’d prefer if it you said “likely to be life on other planets”, as we still don’t have any specific examples, but I’ll take a punt and be definite on this one. It’s a big universe out there and it would be rather presumptuous of us to assume that our planet was the only one to experience the right conditions for life to occur.

Most card-carrying skeptics would agree with this one. Where we tend to demur is the idea that that life must therefore be intelligent and buzzing our planet teasing the natives …

Some psychics can accurately predict the future.

1 – Only if you define accurately to mean “roughly right if you let them reinterpret what they said after the event”. Anything other than their very generalised predictions have failed on a regular basis. Here’s some examples:

For 2001, psychics predicted that:

  • the nine US Supreme Court judges would vanish without a trace
  • the Mississippi River would flood, forming a new ocean in the US heartland
  • Pope John Paul II would die and his successor would be Italian

And the big story they missed – the 9/11 attack on the Twin Towers in New York.

In 2005, professional psychics saw the usual mix of the banal and bizarre, including that:

  • terrorists would start World War III by shooting a nuclear missile into China
  • the winner of a new reality TV show would gain fame by killing and eating a contestant
  • the San Andreas Fault in California would have a massive rupture on June 17 with a death toll reaching 4,568,304

What did they miss – Hurricane Katrina, which made thousands homeless in the southern US, and the devastating earthquake that hit Pakistan and India in October, killing 73,000 people.

There are actual cases of witchcraft.

5 – It depends on your definition of witchcraft, which is a culturally and historically complex concept. Riding on broomsticks, outside the Harry Potter movies, is right out, though there might be a technological fix for that in the future, which could be fun.

In a strong cultural context, makutu, maleficus, pointing the bone, voodoo and a whole pile of other psychological techniques can certainly affect a compliant individual immersed in the belief system.

It is possible to communicate with the dead.

1 – Certainly not going by the current crop of rather banal, self- similar pronouncements by those professionals claiming to have this ability.

Taniwha do exist.

4 – Culturally yes, physically no. And this makes it different to the Loch Ness Monster or the Yeti, where people claim such things can be found and photographed.

During the 2002 furore over the Waikato taniwha lurking inconveniently in the path of the main south highway no-one went and actually looked for Karu Tahi. It was understood that the taniwha was a cultural matter, not a physical matter, and that regardless of that, it had a role to play in the debate about development.

Have you ever had a ‘paranormal’ experience – one that can’t be explained scientifically, or ‘proven’ in ways that a scientist would accept? If so, what was it?

Not one that I haven’t been able to think of an alternative non-paranormal explanation for.

You’ve got to remember that, based on general experiences and basic maths, you should experience a million-to-one coincidence roughly every two years – so the world will throw up mysterious experiences from time to time. How we explain those experiences by observation, examination, replication and just plain hard thinking is a lot of fun, and far more interesting than the quick jump to a paranormal pablum.


How frequently do you buy a Lotto ticket?

Not in about 10 years.

If you buy one often, do you regularly use the same numbers? (Y/N)

Nope, but I do know what numbers to use to increase my winnings. Send me $10 and I’ll tell you how … 🙂

But seriously, you can improve your winnings by doing the following:

  • select sequences -most people think these can’t come up as they aren’t random, but they are as random as another other set of numbers (don’t choose 1, 2, 3, 4… or …37,38,39,40 as these are more likely to be chosen for sequences).
  • don’t choose any numbers with 7 in them; seven is commonly considered a lucky number, so when the numbers 7,10,17,23,27,33,37 came up in one draw, 21 people shared the first division prize and 80 people took the second division. The average number of winners at that time were 3 and 19 respectively, so any winner of that draw had a much smaller part of the pie.
  • don’t choose double digits or numbers ending in 0 – these are more likely to be picked by people playing numbers.

These strategies do not affect your chances of winning, but can be used to improve the amount you win. This is because you are not playing merely against the machine, but also against everyone who has a Lotto ticket. Pick the more ‘popular’ numbers and you’ll have to share the prize with more people. Select ‘uncommon’ numbers or ‘unlikely’ sequences and you have a good chance of not having to share the winnings.

Who said maths wasn’t useful …


Do you consider yourself to be a religious/spiritual person? (Y/N)

No. Ethical, yes; moral, yes; honourable yes, but I don’t think you have to be religious or spiritual for any of that.

If so, what religion/teachings do you follow?

I guess the closest I’d get to one would be the Golden Rule, found in many a religion and philosophy – variously described as “do as you would be done by”. Sure there are critiques of this ethic of reciprocity, but it’s not a bad one-liner to start with.

Conspiracy Theories

Below is a list of theories about the causes of important or controversial events. Please read through, and indicate how likely these are as actual explanations.

7 = very likely, 1 = extremely unlikely

The All Blacks were deliberately poisoned before the 1995 rugby world cup final

5 – Put enough people together in a group environment under stress and it’s not unlikely some will fall ill. ‘Course the circumstances can seem more suspicious depending on the situation, and I’d tip this one on the more likely side just because of the circumstances surrounding it. On the other hand, sh*t happens …

Princess Diana was killed by British secret service in order to prevent a Royal scandal

1 – I just don’t think they’re that competent …

A secret cabal of American and European elite control the election of national leaders, the world economy, and direct the course of history in their favour

1 – At some times, in some places, there have been powerful non-elected forces at work behind the scenes, but an all-powerful Illuminati seems very unlikely.

There is a deliberate political conspiracy to suppress the rights of minorities in NZ

3 – Not a conspiracy, but possibly just basic human psychology at work. Never put down to malice what can be achieved through thoughtlessness …

Of course, you could argue that democracy and consensus-building, by their very nature, are going to ride over minorities in their general quest for the greatest good for the greatest number. But I’d need a lot more red wine in me to get into that debate …

NASA faked the first moon landings for publicity

1 – Only the first?

I think the saddest thing about this one is that my kids, and a whole lot of other people, are growing up in a world where they’ve never seen a moon shot to inspire them with a sense of awe at what humanity is capable of achieving. When everyone in my fourth form class had a poster of the Bay City Rollers stuck to their desk-lid, I had the famous shot of Buzz Aldrin standing on the Moon. It still makes my heart lift.

The war in Iraq has less to do with promoting democracy than it does with controlling oil production in the East

6 – The reasons for going into Iraq were pretty shonky in the first place. But few things are done for just one reason …

Elvis Presley faked his death to escape the pressures of fame, the shame of his decline, or the unwanted attentions of the Mob

1 – Nope, he just carked it. Now if you’d cited Jim Morrison I might’ve wondered as I think he’d have been smart enough to pull it off …

World governments are hiding evidence that the earth has been visited by aliens

1 – Too big a story, too incompetent a collection to let that one run for any length of time.

The American government was either involved in, or knew about, the September 11 attacks before they happened

2 – I gather they were aware that an attack of some kind was being planned, but the rest of the conspiracy ideas around this are just sickening and demonstrably incorrect in many cases. People want to find an explanation for such things and someone to blame and, for some, governments or Big Business or the MIB or the Gnomes of Zurich serve as the first port of blame.