The journey from iconoclast to icon goes beyond the three themes highlighted in this book. The “average” iconoclast possesses a perceptual system that can see things differently than other people. He conquers his fear of failure and fear of the unknown, and possesses enough social intelligence to sell his idea to other people. But the iconoclast who goes beyond mere success and becomes an icon, like Steve Jobs, possesses something even more elusive. He has the knack of wide appeal. For an iconoclast to become an icon, large numbers of people who are not themselves iconoclastic must come to accept an idea that is new to them. And that can only be achieved through one of the two roads: novelty or familiarity. Youth or experience.
APPENDIX
The Iconoclast’s
Pharmacopoeia
SO IT COMES DOWN TO THIS: perception, courage, and social skills. The successful iconoclast learns to see things clearly for what they are and is not influenced by other people’s opinions. He keeps his amygdala in check and doesn’t let fear rule his decisions. And he expertly navigates the complicated waters of social networking so that other people eventually come to see things the way he does.
Sounds like hard work.
Neuroscience continues to reveal many of the secrets of the brain and how biological functions sometimes get in the way of innovative thinking. Knowing which parts of the brain perform functions related to perception, fear, and social relationships lets us understand how these functions go awry and how to correct them. If we have learned anything about the brain, it is how amazingly adaptable it is. While genes set the biological foundation, the structure of the brain is not static. Almost any function in the brain can be changed through hard work, practice, and experience.
While it is human nature to want to improve ourselves, that takes hard work. Wouldn’t it be easier to swallow a pill that made you more daring or more willing to speak your mind? The brain contains all the machinery that runs the mind, and many, if not all, of the traits that make for iconoclastic thinking have their basis in how the brain functions. Because it is a biophysical organ, operating according to known biological and chemical reactions, the brain’s functioning can also be altered, at least temporarily through the ingestion of drugs.
What follows is a brief summary of the known effects of certain psychoactive drugs. In no way should this be taken as medical advice. Many of these substances are potentially harmful and may lead to death or disability. Some are controlled substances and are illegal to possess without a prescription. Others are flat-out banned.
Pharmacology 101
Every drug begins its journey by entering the body through some route. After that, its fate is determined by the competing processes of absorption and elimination. There are only a handful of ways to get a drug into the body. You either swallow it, inject it, or inhale it. The first is called the oral route; everything else is parenteral. Injections come in three flavors that depend on the depth of the shot. They can be in the skin (subcutaneous), in the muscle (intramuscular), or in a vein (intravenous). Finally, there is the mucosal route of administration, which includes absorption through membranes in the nose (intranasal) or under the tongue (sublingual).
Depending on the route of administration, a drug will be absorbed into the body at different rates. Intravenous administration, because it is directly into the bloodstream, is the fastest. Inhalation is almost as fast. Oral is the slowest because the drug must be absorbed through the GI tract, which can take anywhere from fifteen minutes to an hour. During absorption, the concentration of the drug increases steadily in the bloodstream. At the same time, the body begins to eliminate the drug, mainly through the kidneys. The rate of elimination depends on how water soluble the drug is and how well the individual’s kidneys function. Age takes a toll on this process. By age sixty, the kidneys filter at about 75 percent of the rate they do at age twenty. As a result, older individuals have a slower rate of elimination of most drugs. You will often hear of a drug’s half-life. This is the time it takes the body to cut the blood concentration of the drug in half. The slower the rate of elimination, the longer the half-life, and the longer the drug will exert its effect in the body. Short-acting drugs have half-lives of an hour or two, while long-acting drugs have half-lives of many hours, or even days.
Know the half-life of what you take. It determines how long you will be experiencing its effects!
Some drugs are eliminated unchanged in the urine. Others go through a chemical transformation in the body called metabolism. For most drugs, metabolism occurs in the liver. Sometimes the metabolism converts the drug to an inactive form, but other times, the liver converts it into an active form. No hard-and-fast rules here, but if you take other drugs that are metabolized by the liver, they can interact with each other. There are so many drugs out there that it is impossible to know which ones will interact with each other. In 1990, the Journal of the American Medical Association published a case report of a thirty-nine-year-old woman who suffered a serious heart arrhythmia while taking the allergy medicine Seldane, along with an antifungal drug, ketoconazole. The latter inhibited the metabolism of Seldane, which, at high blood concentrations, can cause a fatal heart arrhythmia. Along with several other drugs that caused the same side effect, Seldane was eventually taken off the market.
Be careful with mixing drugs, including over-the-counter medications.
Once inside the body, the drug is then free to do its voodoo, but first it has to get where it needs to be. How does a drug know where to go? It doesn’t. It goes everywhere but exerts its effect only on cells that have chemical receptors that the drug can bind to. Cells are little self-contained units. They are tiny bags of protoplasm with a tough skin of fatty, waxy material called the cell membrane. The membrane keeps the innards of the cell on the inside and the stuff on the outside out. The only way in or out is through special proteins and channels stuck in the cell membrane. This is where drugs work. They bind to a receptor in the cell membrane, and, as a result of this binding, cause a chain of biochemical events inside the cell.
The receptors, of course, don’t exist for man-made drugs. They bind chemicals and hormones within the body. Drugs just hijack these receptors. If a drug mimics the effect of a naturally occurring chemical at the receptor, it is called an agonist. Some drugs block the receptor, in effect preventing its natural function. These are called antagonists. Because there is a limited concentration of a given receptor on a cell, it is possible to saturate all of them with a drug. This happens when the concentration of the drug exceeds the concentration of receptors. At this point, it doesn’t matter how much more drug you take. No further effect is possible.
There is a subtlety here. Most drugs are not very discriminating. They will bind avidly to the receptor for which they are designed, but they will also bind, albeit weakly, to other receptors. When this happens, you get side effects.
Increasing the dose of a drug may increase its intended effect only to a point. After that, only the side effects will increase.
Drugs That Change Perception
Iconoclasm begins with perception, so our discussion of psychotropic drugs begins with the broad class of substances known as hallucinogens.1 The prototype, of course, is lysergic acid diethylamide—aka LSD. But there are many, many others.2 Discovered by the Swiss chemist Albert Hoffman in 1938, while working at the pharmaceutical company Sandoz, LSD was derived from a fungus that grew on grain. This broad class of naturally occurring chemicals, called ergot alkaloids, have been known for centuries to possess psychotropic properties. Some of the ergots are used to treat migraine headaches. What they all have in common is their resemblance to the neurotransmitter serotonin. LSD is startlingly potent. While most drugs require a dose from 1 to 100 milligrams to exert an effect, LSD needs only about 20 micrograms. This means that on a per-weight basis, LSD is about one thousand times more potent than most every other drug that acts on the brain. Even more interesting, there is little evidence that people become addicted to hallucinogens
. Nevertheless, LSD is classified by the Food and Drug Administration (FDA) as a Schedule I drug, which means that there is no therapeutic potential, and it is illegal to possess.
Once inside the brain, LSD binds to almost all the serotonin receptor subtypes. With such small doses, however, the drug concentration is extremely low, and most of LSD’s psychological effects are a result of binding to the 5-HT2A subtype. Nobody really knows how LSD causes its effects, but there are remarkably consistent elements of the experience. Strictly speaking, LSD does not cause hallucinations. Hallucinations are the hallmark symptom of schizophrenia, and having them means hearing voices that aren’t there, or, more rarely, seeing things that aren’t there. A hallucination represents a break with reality. But LSD doesn’t do this. LSD—and all the “hallucinogens,” for that matter—causes perceptual distortions. Users often describe the appearance of radiant colors, trails left by moving objects, and the perception that inanimate objects such as trees and buildings swell and breathe. Sometimes people and objects appear to morph into each other. A sense of time dilation is common. Some people experience a loss of their sense of self and feel as if they become disembodied.
The canon of literature on psychedelic trips is vast. A recent treatise, with a slightly more scientific bent, is John Horgan’s book Rational Mysticism.3 Horgan describes his journey to (no surprise here) the West Coast, to ingest ayahuasca, which is a mixture of herbs whose predominant psychotropic ingredient is dimethyltryptamine—DMT—a chemical cousin of LSD. Many naturally occurring tryptamines have hallucinogenic effects and are found in peyote, mescaline, and psilocybin (mushrooms).
It is hard to deny the effect that these substances have had on many people. Clearly, there is a bit of bias here. Those who have written about their psychedelic trips, or written songs about them, or created art based on them, are the people who had positive experiences. Many have had bad trips laden with paranoia and anxiety. These are not the stories that are popularized. Many people report effects lasting years. Now what is interesting from the perspective of the iconoclast is the effect on perception. While many well-accepted drugs act to calm the anxious person, and therefore help to quell the fear that gets in the way of iconoclasm, only the hallucinogens act directly on the perceptual system.
From the beginning, we have seen the importance of perception to the iconoclast. The ability to see things differently than other people, chemically aided or not, is the first requirement of iconoclasm. In a double-blind, placebo-controlled study of psilocybin, researchers found an increase in “indirect semantic priming,” which is a measure of the formation of remote associations.4 Unlike with other drugs, the psychological effects of hallucinogens depend on the prior expectations of the user and the environment that they are taken in. Both of these factors play heavily in their use during religious ceremonies. Thus, subjects given LSD in a hospital setting and told they might experience schizophreniclike symptoms and panic attacks, did.5
Since the heyday of psychedelic research waned in the 1960s and 1970s, relatively little hard science has been done on humans. We are left only with a large body of descriptive behavioral findings from the previous era and a paucity of data using modern brain imaging tools. In 1987, however, Dean Wong, a pharmacologist at Johns Hopkins, synthesized a radioactive tracer of LSD. Using positron emission tomography, Wong found that LSD bound to serotonin receptors located in the frontal, temporal, and parietal cortex. Binding was notably absent in the striatum.6 Other imaging studies have measured the change in brain metabolism after the ingestion of hallucinogens. These studies consistently find that LSD and related compounds increase metabolism by up to 25 percent in the frontal cortex.7 Activity in the thalamus, which is a sort of gateway for sensation coming from the body, is also affected. The location of LSD binding, because these brain regions are critically involved in perception, suggests that LSD’s psychological effect does, in fact, result from a chemical alteration of perceptual processes.
As we saw in chapter 1, visual stimuli are ambiguous, and so perception is a psychological and biological process that assigns categories to the things we see. LSD acts directly on the brain hardware that performs this function. LSD breaks down the effects of past experience and preexisting categories, creating the possibility of unlikely perceptions. There are minimal effects on memory, and there is some evidence that LSD may actually improve some types of learning, so the individual remembers their experience. Some of the persistent effects, such as flashbacks, may also result from activation of the 5-HT2A receptor. When the 5-HT2A receptor is stimulated, a cascade of reactions occur inside the neuron that, within about an hour, result in the activation of several genes. Many of these genes cause proteins to be synthesized in the cell that change the physical structure of the neuron itself.8
After reviewing all of these findings, it is hard to find compelling evidence against hallucinogens (apart from the fact that they are illegal). Their safety profile is as good as any of the other drugs and better than the stimulants and sedatives. The hallucinogens are the only class of drugs known to affect perception directly. The main risk, because they are illegal, is that it is impossible to know what one is actually taking. You might take amphetamine or ecstasy (an amphetamine derivative with some mild hallucinogenic effects), for example, thinking it was psilocybin.
Drugs That Decrease Fear
As we saw in chapter 3, fear is a major impediment to iconoclastic thinking. You can have the greatest idea in the world, but an aversion to risk is so deeply wired into the human brain that the fear of failure or looking like a fool kills many potential iconoclasts before they even get out of the gate. The fault lies with the autonomic nervous system.
Beta-blockers
When you get excited, whether it is from something wonderful or something awful, your body responds by releasing adrenaline. Adrenaline, which is also called epinephrine (yes, the same stuff in an EpiPen), is released by the adrenal glands into the bloodstream and circulates throughout the body. Epinephrine affects pretty much every organ in the body. It constricts blood vessels, raising blood pressure. It makes the heart beat faster and stronger. It dilates air passages in the lung, allowing more oxygen to diffuse into the blood. It shuts down the GI tract. And of course, it gets into the brain. In fact, a chemical cousin, called norepinephrine, acts as a neurotransmitter. The physiological term for this is arousal. All of this is good, and necessary, if you’re being chased by a lion on the African savanna, or if you’re in pursuit of that strikingly hot man or woman hanging out at the bar. Too much arousal, though, and you may find yourself paralyzed by anxiety. This is where beta-blockers come in.
There are two broad classes of receptors for adrenaline, which are called alpha and beta. In general, the alpha- and beta-receptors cause opposing effects. Different organs express different types of receptors, which is why adrenaline can simultaneously dilate bronchi in the lungs and constrict blood vessels. Primarily because of the effect of beta-receptors on blood vessels, drugs that block them are quite effective at lowering blood pressure. Lots of these drugs exist—for example, propranolol (Inderal), metaprolol (Lopressor, Toprol-XL), and atenolol (Tenormin). Because they block many of the effects of adrenaline, beta-blockers can eliminate many of the physical manifestations of anxiety. Beta-blockers are frequently used by performers to stop subtle shaking of the hands or warbling of the voice. Indeed, for performance anxiety, it is hard to beat beta-blockers. They do not cause addiction or physical tolerance. They are short acting, and the side effects are fairly minimal. The main things to worry about are their effects on blood pressure and heart rate, which could cause a person to faint. Several controlled studies have suggested that the optimal time to take a beta-blocker is about one hour before performance. This could be quite helpful, for example, for the would-be iconoclast who has to make a presentation. This type of situation, speaking in front of others, puts many people on edge and is truly the most common phobia, which is a shame, because many people have great
ideas but are too inhibited or scared to present them to groups of other people. Ten to 40 mg of propranolol, an hour before a presentation, is often enough to take the edge off.9
Beta-blockers may have effects in the brain that go well beyond their actions on the body. Receptors for norepinephrine are found throughout the brain, but the amygdala has been a site of much interest for neuroscientists. Fearful, traumatic memories depend critically on the amygdala, and it has been demonstrated recently that beta-blockers might actually prevent the formation of traumatic memories by interfering with these receptors. The effect might work even after the trauma, essentially preventing the individual from reliving the event.10 Of all the beta-blockers, propranolol is the one that most readily gets into the brain. As in the movie Eternal Sunshine of the Spotless Mind, soon it may be possible to selectively erase unpleasant memories through such pharmacologic manipulations. Because perception is, in part, determined by experience, the selective erasure of experiences has the potential to alter perception as well. So, in addition to their efficacy in treating performance anxiety, beta-blockers may help to blunt the unpleasant memory should your idea go down in flames. This would be a boon for helping people “get back on the horse.”
Antidepressants
The other big class of drugs that have potential for decreasing fear are the antidepressants. Although there is a long history of drugs that have been demonstrated to have mood-elevating effects, it is really only the modern versions of these that have captured the public’s attention. We are, of course, referring to Prozac and all the Prozac-like drugs. Ever since Peter Kramer wrote Listening to Prozac, the possibility of using serotonin selective reuptake inhibitors (SSRIs) to tweak personality has been on the table.11 Serotonin receptors are found all over the brain, and as with dopamine, there are several subtypes of receptors. In fact, there are a lot of subtypes, designated by descriptions such as 5-HT1A. In addition to the receptors, there is the serotonin transporter, which, like the dopamine transporter, mops up free-floating serotonin. The SSRIs block the serotonin transporter, presumably making more serotonin available to work its action. The most common drugs that do this are fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). As this is one of the most commercially lucrative classes of drugs, there are lots more. Some of the variants, such as venlafaxine (Effexor), also block norepinephrine reuptake.
Iconoclast: A Neuroscientist Reveals How to Think Differently Page 21