The Drugs That Changed Our Minds

by Lauren Slater

  Ancient Placebos

  Remember that two-thirds of patients on an SSRI would likely have improved on a placebo alone. This may go some way towards explaining why ancient medicine, as unscientific as it was, could be so effective; it consisted almost entirely of placebos. For instance, Huang Ti, the Yellow Emperor, who ruled almost five millennia ago, lists over two thousand drugs and sixteen thousand prescriptions that were used largely unchanged in China for thousands of years. Likewise there are 265 drugs in the Sumerian-Babylonian-Assyrian annals, and more than six hundred touted in ancient India. The practice of using these various potions and concoctions persisted across time. According to psychiatrists and researchers Arthur and Elaine Shapiro, the London Pharmacopoeia, first published in the seventeenth century, includes all of the following so-called remedies:

  Usnea (moss from the skull of victims of violent death); Vigo’s plaster (viper’s flesh, live frogs and worms), Gascoyne’s powder (bezoar, amber, pearls, crabs’ eyes, coral and black tops of crabs’ claws); triangular Wormian bone from the juncture of the sagittal and lambdoid sutures of the skull of an executed criminal, theriac, mattioli, mithridate, bile, blood, bee glue, bones, bone marrow, claws, cuttlefish, cock’s comb, cast-off snake skin, fox lung, fat, fur, feathers, hair, horns, hooves, isinglass, lozenges of dried viper, oil of brick, ants and wolves, powder of precious stones, seasilk, sponge, scorpions, swallows’ nest, spider webs, raw silk, teeth, viscera, worms, wood lice, human placenta and perspiration, saliva of a fasting man, sexual organs and excreta of all sorts.

  Theriac, used to treat poison and buried there in that list, was an especially popular placebo. It had anywhere from thirty-three to a hundred different ingredients, the main one being viper’s flesh, with sometimes a dash of opium. Unicorn horn was one of the most expensive remedies, costing about four-hundred-thousand pounds in today’s money. Bezoar stone, which healers claimed was a crystallised tear from the eye of a deer bitten by a poisonous snake, was in fact gallstones, or deposits of gunk found in the stomachs of livestock. The Chinese sometimes used what they claimed were ground dragon bones to treat convulsions, and liver for blood diseases and night blindness. While almost all, if not all, of today’s medical men and women would claim that every cure just listed is bunk, the fact is that many people in prior centuries got sick and then got well on dried dung or crystallised tears or the flesh of vipers. How could this be?

  The answer is simple: placebo.

  The Pharmaceutical Factory in Our Heads

  In the 1970s came the discovery of endorphins, which are opiatelike chemicals the body manufactures all on its own and which play a key role in the placebo effect, especially in cases of pain. The discovery led scientists to uncover a rich supply of nerves linking the brain to the immune system, which in turn resulted in the rise of a new branch of medicine called psychoneuroimmunology. Studies in this new medicine suggested that placebos may work to decrease pain – something they are especially good at doing – by increasing endorphins in the brain.

  At the University of California, San Francisco, for example, in a 1978 double-blind experiment with young people who had recently had their wisdom teeth removed, most patients were given a placebo and reported significantly less pain. Then some of the subjects were given naloxone, a drug that is typically administered in A&E departments in cases when a patient has overdosed on heroin or morphine. Naloxone works by blocking the opiate, thereby immediately reversing the effect of the deadly ingestion. In this study with the wisdom teeth patients, once they were given naloxone, the pain relief they had experienced as a result of the placebo suddenly vanished. Once again the young people were in pain. This outcome provided researchers with a strong suggestion as to how placebos might work. It must indeed be that they released the brain’s natural opiates – endorphins – and that as long as this release wasn’t blocked by naloxone, or by some other organic means, then these endorphins would allow us to find real relief.

  Blue and Pink Tablets

  The form of the placebo has implications for its function. For instance, when it comes to tablets, scientists have discovered that blue placebos tend to make people drowsy, whereas red or pink placebos induce alertness. In the 1970s several professors at the University of Cincinnati took fifty-seven second-year medical students and divided them into four groups. Two groups received pink tablets and two groups blue tablets, and of the two groups receiving the same colour, one group received one tablet and the other group two tablets. All of the tablets were inert. The students then listened to a one-hour lecture and after that went back to the laboratory to fill out forms rating their moods.

  The results? The students who had received two tablets reported more intense responses than the students who had taken only one tablet. And of the students who had taken the blue tablets, 66 per cent felt less alert after the lecture compared to only 26 per cent of students who had taken the pink tablets. Medical anthropologist Daniel Moerman believes that the colour of a capsule or a tablet has a strong significance to the imbiber. Blues and greens are cool colours while reds and pinks are hot colours. A study in Texas showed that red and black capsules were ranked as strongest while white ones were weakest. ‘Colours are meaningful,’ Moerman wrote, ‘and these meanings can affect the outcome of medical treatment.’ Blue tablets make us drowsy while carmines perk us up. And large tablets have more power over us than medium-sized ones, especially if they are multicoloured.

  The research on the size and colour of tablets makes one wonder if we might also be more strongly affected by tablets embossed or engraved with a name: Tagamet (brand name for cimetidine), venlafaxine, olanzapine, Abilify (brand name for aripiprazole), Concerta (brand name for methylphenidate). Are drug companies not hoping that if they carefully and suggestively label their medicines, we will give their tablets extra credence? Clearly the name matters. It is always multisyllabic and often suggests technological prowess. You cannot call a placebo Tim, for instance. The name should bring to mind test tubes and Bunsen burners with their petal-shaped flames. The name should also connote, somewhere in its utterance, the pure peace of good health, the abilities with which Abilify will endow you, the consonance of Concerta, when all the world makes solid sense.

  Even more persuasive than tablets, at least in the treatment of headaches, are placebo injections. A meta-analysis of a drug called sumatriptan – which, when first introduced, was available only as an injection and then later as a capsule or a nasal spray – looked at thirty-five trials treating migraine sufferers with sumatriptan versus placebo and found that, of those patients taking a placebo tablet, only 25.7 per cent reported that their headache was mild or gone, compared to 32.4 per cent of those treated with a placebo injection reporting relief. This may seem like a small difference, but it is statistically significant and could be expected to happen by chance only twice if the experiment were repeated a thousand times. Over and over, research has revealed that when patients are injected with an inert substance they report more pain relief than those who have simply swallowed a tablet. Perhaps there is something about the needle, the press of the plunger as the supposed miracle liquid seeps below the skin and into the muscle, finding its way into the circulatory system, and at last to the wet red charm that sits within its curved cage. While a tablet can be quiet, simple, its magic subtler and singular, there is drama in a shot.

  But if placebos can be especially effective for pain relief, they decidedly do not work on people who have Alzheimer’s disease. Evolutionary biologist and sociobiologist Robert Trivers, in tracing the historical necessity of deceit, has found that what the brain expects to happen in the near future affects its physiological condition. This goes part of the way towards explaining why people in pain who receive a placebo they are told is a powerful pain reliever feel better after taking the inert substance. In fact, they feel better even before taking it. Our brains are anticipators. They prepare for the known future, and in the case of pain, that means they release endorphins. Peopl
e with Alzheimer’s, however, have lost the ability to see into the future and thus to prepare their brain and the associated neurotransmitters for the treatment.

  Hope

  Of course, none of this so far answers the question of exactly how endorphins get released in the first place. It seems to have something to do with belief, with hope, with faith. Even the smallest spark of it helps our heads to secrete chemicals so soothing that their analogues are illegal around the world. People who think they are drinking alcohol, but in fact are not, will nevertheless get tipsy. The opposite of hope is also very telling. Where it is absent, or unknown, medication sometimes fails to work. Diazepam, for instance, has been shown to affect a person only if he knows he is taking it.

  But while there have been many studies done to predict the personality type of placebo responders, they have proven inconclusive. If only we knew! Then we would have a clear class of people to whom we could confidently feed inert substances and who could be assured of getting real relief. No such study, however, has been able to find a personality type, or rather, it would be more accurate to say that all of the studies conflict with one another. Some claim that people who respond to placebos have neurotic personality types; others claim that introverts are more likely to be fooled by placebos; while research from the UK has found that extroverts are the group most susceptible to placebos. Scientists have claimed at different times that placebo responders are both quiet and ebullient, that they have poor ego formation and superegos the size of a city, that they are judgemental as well as easily swayed, that they are trusting and sceptical. The net sum suggests that there is no definitive profile of a person likely to respond to a placebo. Everyone is a responder – maybe not all of the time but some of the time, in some situations, in great pain or fear, perhaps, or with wants so large that they outstrip the self who holds them. We do not know. The only thing we can say for sure is that 30 to 60 per cent of the population can be fooled by a trick, by a sugar tablet, by water, by an injection of saline or a bright pink sphere glittering in the palm.

  Sham Surgery

  Still more powerful than tablets with even the most alluring of names and injections with even the keenest of needles is something called sham surgery, which has been performed not once, not twice, but many times, and to very good effect. There are of course ethical snarls involved, but despite these obstacles, sham surgeries do happen. In the late 1950s and early 60s two different surgical teams, one in Kansas City and one in Seattle, did double-blind trials of a ligation procedure – the closing of a duct or tube using a clip – for very ill patients suffering from severe angina, a condition in which pain radiates from the chest to the outer extremities as a result of poor blood supply to the heart. The surgeons were not told until they arrived in the operating theatre which patients were to receive a real ligation and which were not. All of the patients, whether or not they were getting the procedure, had their chest cracked open and their heart lifted out. But only half of the patients actually had their arteries rerouted so that their blood could more efficiently bathe its pump. Each patient was sutured up in the exact same manner and was followed up by a cardiologist who did not know whether the patient had received the sham surgery or the real surgery.

  The outcomes? Sixty-seven per cent of those who’d had an actual arterial coronary ligation reported subjective improvement – less pain and more energy – whereas fully 87 per cent of the sham surgery subjects felt better. The need for nitroglycerine uniformly decreased, dropping 34 per cent in the surgical patients and 42 per cent in the sham surgery patients. Both groups were able to exercise longer. All in all, the patients who’d undergone the sham surgery did even better than those who’d had the real thing. As one sham surgery patient put it: ‘Practically immediately I felt better. I felt I could take a deep breath.’ He estimated that he was 95 per cent better, and went from taking five doses of nitroglycerine a day before surgery to only twelve doses total in the first five weeks following the surgery.

  For perhaps even better effect, sham surgery can be done in conjunction with a high-tech laser rather than a scalpel. There is a procedure called transmyocardial laser revascularisation (TMR), ‘the latest whistle in the surgical approach to angina’. In TMR an incision is made in the side of the chest between two ribs. The outer layer of the heart is removed so that the heart muscle itself is exposed. A laser beam is then fired directly into the muscle, with the goal of carving a channel through which blood can flow, thereby unblocking a clogged pump and allowing oxygen-rich blood to saturate the heart. Afterwards, the outer layer of the heart is put back in place and the patient is stitched up.

  In one US study, published in 2000, three hundred very sick patients were enrolled in a placebo-controlled trial of a TMR-related procedure. Of these, 90 per cent had previously had bypass surgeries and 65 per cent had had heart attacks. The patients were divided into three groups. The group undergoing the mock procedure received only simulated laser treatment, while the low-dose group received fifteen laser shots and the high-dose group twenty-five laser shots. In the six months following these surgeries, all three groups had surprisingly similar results. Every patient, regardless of the group he or she was in, displayed striking improvement, with patients who’d received the mock procedure showing gains at a rate 8 per cent higher than for those who’d received the high dose. Exercise tolerance increased all around. Angina attacks went on the wane. ‘Electrical machines’, wrote one scientist, ‘have great appeal to patients, and recently anything with the word “laser” attached to it has caught the imagination.’

  Sham surgeries have successfully been performed on hearts, on herniated discs, on sciatic nerves, on mangled knees and on the inner ears of patients with Ménière’s disease, which causes vertigo, tinnitus and hearing loss. In patients suffering from Parkinson’s, a disease caused by dopamine deficiency, sham surgeries are so powerfully persuasive that researchers have even discovered an increase in the patients’ dopamine levels afterwards. This terrible clenched condition can be ameliorated by the combination of a scalpel and a tall tale about how you, a Parkinson’s patient, suffering a partly paralysed body, have undergone a serious medical procedure designed to restore movement to your wayward limbs. Upon seeing the surgical scars, upon hearing how high-tech your procedure was, you can become fluid again, mobile again, for some period of time. As with the release of endorphins, it appears that the hope, the belief in the surgery, sparks an increase of dopamine production in the substantia nigra, a part of the brain that controls when we waltz, run, walk or fall.

  Clearly, placebo cures are subject to style and perception. But if patients are made drowsy by blue tablets and alert by red ones, and if they project more power on to a large tablet than they do on to a medium-sized one, why is psychopharmacology not taking all this rich information into account in its research and development? Why are not all antidepressants some beautiful shade of vermillion that brings to mind sunsets in Venice or Floridian warmth? And why are there not more sham surgeries being performed on patients, like Mr Wright, who are at the end of the road, those treatment-resistant souls who cannot be helped by any tablet no matter its size or shape? The field could be doing sham lobotomies and sham deep brain stimulations.

  Perhaps even more appealing would be the instituting of sham trans-cranial magnetic stimulation (TMS), as high-tech a procedure as one could ask for, which involves passing across the patient’s head magnets whose current collides with the brain’s own magnetic field and may cause a rerouting of the nerve cells, such that their stuckness, the sign of so much mental illness, finally loosens and floats away, taking with it the debris of depression, the confetti of mania, restoring the sufferer to sanity. While TMS and vagus nerve stimulation (VNS) – in which a battery pack is placed under the skin and connected by wire to one of the body’s vagus nerves, delivering constant current to the brain – mostly seem to help people achieve remission if their depression is mild, these treatments do have the flair, the fluor
escence, that is perfect for the placebo. Both could turn out to be stupendously powerful interventions.

  Pharmaceutical research often focuses on how to make medications so strong that they will trump the placebo in trials. For decades, in fact, psychiatry has bemoaned the placebo as the behemoth of its studies, as sugar tablets equalled or outperformed capsules of fluoxetine and sertraline and venlafaxine more than half the time in double-blind studies, and even in successful trials the advantage of drugs over the placebo, you’ll remember, was minimal. But viewed another way, placebos can be embraced as treatment methods in their own right rather than disdained as something with which psychiatry must contend or compete. Why, for instance, is no one asking the obvious question about how to strengthen the performance of the placebo so that it more regularly – and more spectacularly – beats the drug? A related issue is that even when the psychiatric drug does beat the placebo, researchers are failing to take into consideration the possibility that those patients on the drug may be having, at least in part, a placebo response of their own – that old adage of ‘working with the drug’.

  Talking Therapy

  Some say that psychotherapy is the purest form of placebo we have. People make this claim because patients who enter psychotherapy seem to improve: their morale goes up, their ability to care for themselves increases, they report feeling more hope and less loss. But these improvements are not due to any particular kind of cure, or indeed, as we shall see, any special expertise on the part of the doctor. So what, exactly, is happening to patients to cause their improvement? The answer: not much, or nothing medical anyway. It appears that people get better in psychotherapy because they endow the process with meaning, projecting on to it their hopes and their healing, just as they do with a sugar tablet, a shot in the biceps, or a sham surgery.