For decades, psychiatrists thought that too little serotonin in the brain was the cause of impulsive decision making, primarily impulsive decisions such as suicide. The reason was that when the brains of suicide victims were examined, they were found to have lower levels of serotonin. However, more recent studies, in which healthy volunteers are temporarily depleted of serotonin, have not found a significant increase in impulsivity on standardized measures such as gambling tasks, although there is a suggestion that serotonin depletion causes reduced sensitivity to rewards of different magnitudes.12 If this is true, there may be a role for SSRIs in straightening out an individual’s utility curve, which would make him less risk averse. This could be a good thing for the iconoclast who is afraid to take a chance on his idea.
Apart from treating depression, the other major application of SSRIs is in the treatment of anxiety. If taken regularly for several weeks, SSRIs are effective in reducing panic attacks and generalized anxiety. They also seem to be quite good at reducing social anxiety. The precise mechanism by which this happens in the brain is not known, but because it takes several weeks of treatment, most scientists believe that the beneficial effect of these drugs does not result from the immediate blockade of serotonin reuptake. Instead, evidence points toward the turning on and off of specific genes within neurons.
Like all medications, the SSRIs have their share of side effects. Nausea and GI distress top the list. They usually go away after a week or so, but the problem of sexual side effects does not. Depending on which report you believe, the incidence of SSRI-induced sexual dysfunction may be as low as 15 percent or as high as 70 percent.
Sedatives and Alcohol
Anxiety is the great inhibitor of iconoclasts. The beta-blockers work well for performance anxiety. And although the SSRIs work for general anxiety, they take many weeks to kick in, and the side effects may be too burdensome. Many people want a quick fix—you know, something to take the edge off. Enter the class of drugs known as sedatives and hypnotics. Back in the day—say, the 1950s—these drugs were called minor tranquilizers. They were all derived from a class of drugs known as barbiturates. Some of these drugs are still around today—classics such as amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). These are the drugs your mom and pop took, but nobody really uses them much anymore. They’re just too dangerous. They globally depress the entire central nervous system. They work great as an anticonvulsant and for inducing anesthesia, but they knock most people for a loop. Plus, you can fatally overdose on them. You can become addicted to them, and if you try to kick the habit, suffer seizures. Stay away from barbiturates.
In the 1960s a much safer alternative to the barbiturates was discovered: Valium—mother’s little helper. This class of drugs is called the benzodiazepines (or benzos) and includes many of the all-time favorites such as alprazolam (Xanax), chlordiazepoxide (Librium), clonazepam (Klonopin), diazepam (Valium), lorazepam (Ativan), and triazolam (Halcion). Without a doubt, the benzodiazepines decrease anxiety—and quickly, too. They do this by binding to GABA receptors in the brain. GABA, which stands for gamma-aminobutyric acid, is an inhibitory neurotransmitter, which means it inhibits neurons from firing and is found all over the brain. GABA is necessary to keep the brain from firing out of control in seizures. Benzos are not too discriminating, and after ingestion, will bind all over the brain too. This is great in places such as the amygdala, where a benzo might decrease anxiety. Not so hot in the rest of the brain. They impair motor coordination, alertness, and memory. In fact, a common use of some benzodiazepines is to induce a state of amnesia during certain medical procedures, such as colonoscopy. Even so, many people find a small dose of a short-acting benzo helpful in situations of extreme anxiety. Just don’t operate a motor vehicle or heavy machinery. The short-acting benzos are alprazolam (Xanax) and lorazepam (Ativan). Triazolam is short acting but is no longer available in the United States because of reports of amnesia and hallucinations in people taking it. Actually, any of the benzos can cause these effects. Apart from these cognitive side effects, it is important to know that benzos can be habit forming. People get seriously addicted to this stuff and have a very hard time getting off of them. If you have problems with alcohol (see below), stay away from benzos. They act very similarly.
Alcohol really belongs in a class of its own, but as far as its effects, it is very similar to the benzodiazepines. Alcohol, along with tobacco, is probably the most widely available legal drug that directly affects the brain. We need not go into the subjective effects of alcohol, for they are already widely known. The term alcohol includes a number of chemically related molecules. The type you ingest, however, is ethanol. And although the ingestion of ethanol is subjectively felt as physically stimulating, its main effect on the brain, like the benzodiazepines, is as a depressant. Ethanol acts on a wide range of receptors in the brain, including the GABA receptor as well as excitatory receptors. Apart from the anxiolytic effects of alcohol, one study found that heavy drinkers exhibited steeper temporal discount functions for money, which means that heavy drinkers are generally more impatient than tee-totalers.13 There are potential cardiac health benefits to moderate alcohol consumption. That said, many people, about one out of every thirteen adults in the United States, have serious problems controlling their alcohol usage. The health risks are severe: hepatitis, cirrhosis, GI bleeding, and a bunch of cancers. It is also true that a lot of famous iconoclasts, such as Jackson Pollock, were alcoholics.
So: alcohol may have a role in decreasing anxiety, but use it in moderation.
Stimulants
Stimulants have an intimate relationship with the dopamine system and therefore one’s relationship to novelty seeking and the fear of the unknown. Cocaine binds to the dopamine transporter (DAT) and blocks the reuptake of dopamine into the neuron. The amphetamine-related compounds, which include amphetamine and methylphenidate (Ritalin), also bind to the dopamine transporter and, to varying degrees, block the reuptake of dopamine. They also exert their effect on other neurotransmitters, especially norepinephrine, which is kind of like adrenaline for the brain. Amphetamine comes in two forms, called stereoisomers. The more potent form is d-amphetamine, which is sold under the trade name Dexedrine. Adderall, a drug prescribed for attention deficit hyperactivity disorder, is a mixture of d- and l-amphetamine (the other stereoisomer), which results in a smoother onset and offset of its effects. Speaking of onsets and offsets, the rate at which a drug gets into the brain has a lot to do with the “high” that people get out of it. The faster the onset of action, the more powerful the high. Inhaling or injecting drugs, because the onset is so fast, leads to addiction very quickly.
Once inside the brain, the stimulants release both dopamine and norepinephrine and block their reuptake into the neuron. Most of the stimulants actually decrease blood flow to many parts of the brain. The psychological effects include increased wakefulness and alertness. Many people experience an elevation in mood with more initiative, self-confidence, and ability to concentrate. Higher doses may lead to euphoria and increased sexual drive. Appetite becomes suppressed, and this category of drugs is frequently used to treat obesity (the “phen” of fenphen infamy was phentermine—an amphetamine derivative). A recent entrant into the field of stimulants is modafinil, which is marketed under the trade name Provigil. The FDA approved modafinil for the treatment of narcolepsy, but its mechanism of action appears similar to that of amphetamine.
As for judgment, many of the stimulants, notably methamphetamine, are notorious for increasing impulsive decisions. This data originates from epidemiological studies showing a dramatic increase of high-risk behaviors in people addicted to methamphetamine. In one of the few studies that have examined financial risk taking and stimulant use, Martin Paulus, a psychiatrist at the University of California, San Diego, found that individuals addicted to stimulants, primarily of the amphetamine variety, exhibited greater risk-taking behavior on simple gambling decisions. He also found greate
r activity in the striatum of these individuals.14 Interestingly, another study, by Brian Knutson at Stanford, found that a single dose of amphetamine equalized the upside and downside of striatal activation when individuals were anticipating either gains or losses.15 The implication is that amphetamine might decrease loss aversion. Warren Bickel, a psychologist at the University of Arkansas, has also applied econometric techniques to study the effect of different drugs on financial decisions. In a 2006 study of delay discounting in cocaine addicts, Bickel found that the cocaine addicts had higher discount rates. This means that when it comes to financial decisions that span long periods of time, cocaine users behave much more impatiently than nonusers.16 So far, the argument in favor of stimulants does not seem good: bad judgment and impulsive behavior do not make an iconoclast. A major problem with stimulants, apart from their addiction potential, is that they are “dirty” drugs. They are promiscuous with the neural receptors and are not very discriminating on where they bind.
The receptor side of the dopamine system is complicated. There are at least five different subtypes of dopamine receptor, each with a different effect on the neuron. The big differences, however, are in the D1 and D2/D3 dopamine receptor subtypes, which have almost opposite effects to each other. The end result of dopamine release depends on how many of each receptor subtype are expressed in a cell and how much dopamine is released. Better prospects for tweaking the dopamine system in a more productive way than stimulants might focus on these receptor subtypes.
A relatively new batch of drugs for Parkinson’s disease targets the D2/D3 dopamine receptor subtype. Ropinirole (Requip) and pramipexole (Mirapex) are agonists for the D2/D3 receptor. They seem to alleviate some symptoms in early-stage Parkinson’s disease, but they are weakly associated with an increase in impulsive behaviors such as gambling and sex addiction.17 On the plus side, both drugs have been reported to promote the release of nerve growth factors in cultures of dopamine neurons, but in general, the D2/D3 agonists do not look promising for iconoclasm either. Caution: there have been some reports of heart valve disease in patients taking these drugs. A safer alternative, with similar behavioral effects, is to take L-DOPA, which is a precursor in the synthesis of dopamine and is the first-line drug treatment for Parkinson’s disease. L-DOPA does improve reaction time in healthy people, but the effect is small.18 A recent imaging study found that healthy subjects who were given a single dose of L-DOPA earned more money when performing a simple gambling task. Although the effect was small, earning about 10 percent more money, the brain imaging results showed an enhancement of striatal activity when subjects stood to win money.19
The problem with all the stimulants is that people get addicted to them and then they do stupid things. Milder stimulants, such as caffeine, exert their effects indirectly on the dopamine system, and although you build up tolerance, it doesn’t cause a great deal of personal or societal harm. Caffeine blocks adenosine, which itself inhibits the dopamine system. Although subtle, caffeine’s behavioral effects are widespread. It improves reaction time, slightly decreases error rates, increases alertness, and even aids in disengaging from one task and switching to another.20 Although caffeine increases alertness slightly, there is no evidence that it changes risk attitudes, and most studies indicate that a good dose of caffeine has about the same effect as modafinil.21 Like all the stimulants, caffeine will not make someone an iconoclast.
Nicotine occupies a special place. Depending on the dose and the individual’s tolerance, nicotine can act as either a stimulant or a sedative (stimulant for someone not habituated to it; sedative for someone who is). Nicotine does not act through the dopamine system, but interestingly, a recent study found that smokers had steeper discount functions for money, which means that they are more likely to make impulsive decisions. They also had steeper probability discount functions, which means that they deviated from rational valuations more than nonsmokers.22 Do impulsivity and irrational valuations make someone an iconoclast? Probably not. Although it is impossible to assess whether nicotine was the causal agent of these behavioral differences, or people who were inherently this way gravitated to nicotine, it’s probably best to avoid nicotine. Plus, it’s bad for your health.
Antipsychotics
Although the stimulants have mood-elevating properties, their predominant effect on behavior is to make people more impatient. So, if stimulants aren’t the ticket, then it’s reasonable to ask whether blocking the dopamine system might have a beneficial effect. What’s the opposite of amphetamine? Answer: the class of drugs known as antipsychotics.
Antipsychotics are now the frontline treatment for major psychiatric illnesses in which hallucinations and bizarre behavior are prominent symptoms. We’re talking schizophrenia and manic depression here. The first antipsychotics were derived from aniline dyes in the 1930s, and when ingested, found to have sedative effects. By the 1950s, chlorpromazine (Thorazine) quickly gained acceptance as a treatment alternative to convulsive therapy and frontal lobotomy in schizophrenia. Many drugs like Thorazine have been synthesized since. The more common ones today are haloperidol (Haldol), risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel). All these drugs have the pharmacological effect of blocking the dopamine D2 receptor. Some also block serotonin receptors. As a general rule, the main effect of these drugs is to decrease exploratory behavior, decrease vigilance, and generally impair cognitive performance. When healthy subjects were given a dose of haloperidol and scanned while performing a gambling task, they earned less money, and their striata were less active.23 Plus, the side effects of these drugs are bad: slow movements, a risk of developing Parkinson’s disease, painful muscle contractions, weight gain, and diabetes.
Nothing good here. Unless you are mentally ill, stay away from them.
Hormones That Affect Social Intelligence
The final category may seem like an odd one for iconoclasm, but the growing availability and use of hormones warrants some comment. And it is hormones that may ultimately affect one’s social intelligence. Hormones are different from any of the other neurotransmitters such as dopamine or serotonin. Neurotransmitters are released only between neurons and therefore remain in the brain. Hormones, on the other hand, are secreted by some organ in the body and released into the bloodstream. Because hormones enter the bloodstream, they exert effects all over the body. So, in this sense, they’re very similar to drugs. In the old days, the only way to get hormones was to extract them from the part of the body that made them. Insulin, for example, used to be extracted from pig pancreas. Nowadays, most hormones are created in the laboratory by chemical methods.
The first class of hormones to consider is the steroids. All steroids begin with cholesterol. The adrenal glands, which sit like globs of fat on top of each kidney, convert cholesterol into several chemicals with different effects on the body. But there are really only two main types of steroid: glucocorticoids and mineralocorticoids. Aldosterone is the main mineralocorticoid, and it regulates the balance of salt and water in the body. The main glucocorticoid in humans is called cortisol, which is also known by the name hydrocortisone. This is the same stuff you can buy over the counter as an anti-itch cream. Cortisol is the front line stress hormone of the body. Whenever you encounter something stressful or frightening, cortisol is released. Cortisol affects so many parts of the body that it is hard to even begin to categorize them. Metabolically, cortisol inhibits cells from using glucose, stimulates the liver to synthesize more glucose, and accelerates the breakdown of fat and protein. Because it raises levels of glucose in the blood, cortisol—and, in fact, all steroids—worsens diabetes. Cortisol causes the heart to beat more vigorously and, as a result, raises blood pressure. Perhaps most prominently, cortisol inhibits the immune system, which means it works great as an anti-inflammatant.
Cortisol also has direct effects on the brain. Synthetic versions of steroids, such as prednisone, are an order of magnitude more potent than cortisol and sometimes result in b
izarre changes in mood and thought. For many years, both synthetic and natural steroids were thought to alter moods in a negative way, but in the 1990s two different classes of steroid receptor were discovered in the brain, each with a different effect on mood. The mineralocorticoid receptor (MR) is a steroid receptor concentrated in the hippocampus, while the glucocorticoid receptor (GR) is found throughout the brain but especially in the striatum. The overall effect of steroids on mood appears linked to the ratio of activated MRs and GRs.24 Under the right conditions, cortisol increases arousal, concentration, and mood.25 Cortisol also acts synergistically with dopamine. As a result, many of cortisol’s acute effects resemble amphetamine’s. At high doses, however, steroids hit the receptors in the hippocampus and interfere with memory. Because of cortisol’s wide-ranging effects on the body, chronic use of cortisol, or any steroid, will cause detrimental effects to many organ systems. Side effects of regular steroid use include hypertension, GI bleeding, diabetes, obesity, osteoporosis, and because of the redistribution of fat, “moon face” and “buffalo hump.”
Iconoclast: A Neuroscientist Reveals How to Think Differently Page 22
