Iconoclast: A Neuroscientist Reveals How to Think Differently (29 page)

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-HT
_2A
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.
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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-HT
_2A
receptor. When the 5-HT
_2A
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.
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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-HT
_1A
. 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.

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.