Welcome to Your Brain (38 page)

tablet.

Did you know? Does marijuana cause lung cancer?

Everyone knows that tobacco causes cancer, whether it’s smoked (lung cancer) or

chewed (lip, tongue, cheek, and esophageal cancer). You might expect marijuana to pose a

similar risk because both marijuana and tobacco smoke contain tar. By this reasoning, a

marijuana joint might be about equivalent to an unfiltered cigarette. Most published studies

on this topic have failed to exclude tobacco users from the test group, making it hard to

know whether the cancers that occurred are attributable to tobacco or marijuana. Another

error in these studies is the failure to distinguish among types of marijuana use (smoking a

pipe or a joint, eating brownies, or smoking a water bong). So, as scientists like to say, the

question needs more study. Volunteers?

The tightness of LSD interactions is good for the physical safety of users. Basically, you can’t

overdose on LSD because it binds so specifically. Side effects occur because most drugs bind not

only to their intended receptor, but also to other receptors, usually with lower strength. (Imagine if

your front door key unlocked your neighbor’s house some of the time.) In contrast, natural

hallucinogens such as mushrooms contain many chemicals, which activate multiple receptors. Even

without physical side effects, though, some acid trips can be upsetting, with long-lasting

psychological effects. On rare occasions, LSD can cause psychosis, most often in users with an

existing tendency toward mental illness.

Hallucinogens often produce powerful, consciousness-altering experiences. LSD brings out

amazingly vivid imagery and appears to allow thoughts and perceptions that would otherwise be

inaccessible. Poet Anne Waldman once described to us a trip in which she stood in front of a full-

length mirror, seeing herself aging from a little girl to an old woman continuously. She saw herself at

every stage of her life, separately and together all at once.

Another psychoactive substance that acts through metabotropic pathways is delta-9-

tetrahydrocannabinol (THC), the active ingredient in marijuana. THC activates brain receptors that

normally respond to cannabinoid neurotransmitters, which occur naturally all over the brain. THC

reduces the likelihood that active neurons will release the neurotransmitters glutamate and GABA

(gamma-aminobutyric acid, the most abundant inhibitory neurotransmitter in the brain) to excite or

inhibit other neurons. In the normal brain, this depressed release is triggered by particular

postsynaptic neurons, which secrete cannabinoids that are picked up by the presynaptic neuron. Taken

as a drug, though, THC reduces the communication of many neurons nonselectively.

Another common drug, caffeine, has the opposite effect, enhancing transmission at many

glutamate- and GABA-releasing synapses by increasing the likelihood of neurotransmitter release.

Caffeine does this by blocking yet another metabotropic receptor, one whose normal job is to bind to

the neurotransmitter adenosine. In this way, coffee is the antipot, as the drugs have opposing effects

on brain function. Caffeine is a mild stimulant and a cognitive enhancer.

If it weren’t for the coffee, I’d have no identifiable personality whatsoever.

—David Letterman

Another cognitive enhancer is nicotine, one of the most addictive drugs known, in vulnerable

people, which acts on acetylcholine receptors in the brain. Nicotine addiction takes the form of

intense cravings that lead to continued use even in the face of cancer risk. Smoking by pregnant

women reduces birth weight and damages the brains of developing fetuses.

A major class of recreational drugs is the opiates, which include heroin, morphine, and many

prescription painkillers (like OxyContin and Percocet). They act on the body’s own pain-relief

system, through receptors called opioid receptors, which are activated by neurotransmitters called

endorphins. The greatest biological danger from opiate abuse is overdose, which can lead to

respiratory failure and death.

The abuse of opiate-based painkillers can cause profound hearing loss. In 2001, right-wing radio

personality Rush Limbaugh reported that he had lost most of his hearing. He later had an electronic

device placed in his skull to restore it (see
Chapter 7
). Although he claimed that his hearing loss was

due to a rare autoimmune disease, it eventually emerged that he was an abuser of OxyContin. This

provided a much more plausible explanation; opiate abusers often lose their cochlear hair cells for

reasons that are unclear, though it is known that cochlear hair cells make opioid receptors.

Despite his opiate dependency, Burroughs lived to the age of eighty-three. In some sense, his long

lifespan is not surprising. An opiate habit by itself is not life threatening, though withdrawal

symptoms are very unpleasant. In later life, Burroughs maintained himself on steady levels of

methadone, an opiate that prevents withdrawal symptoms but is slow-acting and therefore does not

give the transient high, and consequent desensitization, that leads to a need for larger doses. As an

experienced and wily user, Burroughs was able to function for many years.

Did you know? Hit me again: Addiction and the brain

Some people just can’t seem to stop. Drug use has enormous negative consequences in

their lives, but they keep on taking their favorite drug. If you’ve ever wondered, “What is

wrong with that person’s brain?” you’ve got plenty of company. Neuroscientists have spent

thousands of hours studying how drugs and addiction influence the brain.

Chronic drug use causes major changes in many brain areas. These areas include the

brain’s memory system, suggesting that powerful emotional memories or drug-taking

triggers are involved in the development of addiction, as we know from the tendency of

recovering addicts to relapse when confronted with drug-associated cues.

As we explain in this chapter, recreational drugs act on many different neurotransmitter

systems, but they seem to converge on two areas that are part of the brain’s reward system

( s ee
Chapter 18
). All addictive drugs cause the release of dopamine in the nucleus

accumbens. Many also cause the release of endorphins and endocannabinoids in the nucleus

accumbens as well as the ventral tegmental area.

Chronic drug use leads to a reduction in dopamine release. This change seems to cause

reduced responses to natural rewards, such as food, sex, and social interactions, which

involve some of the same brain areas. In nonhuman animals, repeated drug taking is

associated with reduced functioning of prefrontal cortex neurons that project to the nucleus

accumbens, which normally controls response inhibition and planning. Human addicts also

show reduced prefrontal cortex activation in brain imaging studies.

A major problem with treating drug addiction is that responses to drugs and natural

rewards overlap in the brain, making it difficult, for example, to target the desire for heroin

without impairing the desire for food. Several drugs currently approved for the treatment of

drug abuse are also under study as treatments for overeating, including rimonabant, which

blocks cannabinoid receptors (see
Chapter 5)
. One way around this problem is to vaccinate

people so that they produce antibodies against particular drugs, which prevent them from

reaching the brain. A vaccine against cocaine is currently in clinical trials.

A telling contrast is his son, William Jr., who also wrote about his experiences with drugs, but

died of drug-induced liver failure at the age of thirty-three. The drug that killed him? Amphetamine.

Cocaine, amphetamine, and methamphetamine block the transport of dopamine. They are highly

addictive and can cause widespread brain damage, particularly in developing fetuses (which are

affected when drugs are taken by pregnant women).

All these drugs act by known pathways, though how they influence our behavior is not completely

clear. But there is another common drug that is more of a mystery. It interferes with many elements of

our biochemistry, and we still don’t know exactly how it intoxicates us. Heavy use can lead to

addiction, and in the long term, brain damage. Withdrawal symptoms brought on by sudden abstinence

can be fatal. In most cases, it’s legal. That drug is alcohol.

Until a few years ago, many scientists thought that alcohol led to intoxication by acting on the

membranes that form the boundaries of cells, which are made mostly of fats. The idea was that if

enough alcohol got into the membrane, these fats would move around more easily, interfering with the

operation of receptors and ion channels.

Researchers now believe that alcohol has specific effects on neurotransmitter receptors that sit in

the membrane. GABA’s major target in the brain is the GABAA receptor, which produces electrical

signals by allowing negatively charged ions to enter the cell, making neurons less likely to fire action

potentials. Ethanol makes this channel stay open longer than it normally would, increasing the strength

of this inhibitory signal, at a concentration similar to the one found in the blood of intoxicated people.

(Alcohol also affects other ion channels, so intoxication may have multiple components.)

“When you drink, you’re killing brain cells.” How many times has this been said in bars around

the world? The idea, firmly embedded in the culture and humor of drinking, rests on the mistaken

presumption that if a lot of alcohol causes a lot of damage (it does), then moderate amounts of alcohol

must cause some damage (not so).

Practical tip: Drinking and pregnancy

Although alcohol in moderate doses does not kill mature neurons, it can have strong

effects on developing neurons. Because nearly all neurons are formed and travel to their

destinations before birth, the fetal brain is vulnerable to drinking during pregnancy.

Alcohol can kill newborn neurons, prevent their birth, and interfere with their migration

from their birthplace to their eventual destination. In a fetus, even a brief elevation in blood

alcohol is enough to cause some neurons to die. Two major components of fetal alcohol

syndrome are a shrunken brain and a reduction in the number of neurons. Other factors that

prevent neuron migration and survival are cocaine use or exposure to radiation.

Compared with teetotalers, heavy drinkers are likely to have shrunken brains, especially in the

frontal lobes of the cortex, which is the seat of executive function. Magnetic resonance imaging was

used to examine the fluid space that cushions the front of the brain from the skull in more than fourteen

hundred Japanese people, ranging from abstainers to heavy drinkers. The skull does not change shape

in adulthood, so expansion in this space indicates brain shrinkage. On average, heavy drinkers were

more likely than nondrinkers to have brain shrinkage beyond that expected for their age. For instance,

about 30 percent of abstainers in their fifties had brain shrinkage, while over 50 percent of heavy

drinkers showed shrinkage. Changes were found in white matter, the axons that project from neurons

to other parts of the brain, and gray matter, which contains neuronal cell bodies, dendrites, and the

beginnings and endings of axons.

The reduction in gray matter is probably what started the idea that alcohol kills neurons, since an

obvious explanation for shrinking brains would be neuron loss. However, this is not what happens.

The cell bodies of neurons constitute only about one-sixth of the brain’s total volume, while dendritic

and axonal branches take up most of the space in gray matter. Indeed, no difference is seen between

alcoholics and nonalcoholics in careful counts of neurons. (Of course, researchers do not count all

fifty billion neurons. Instead, they sample the cortex at a number of locations and extrapolate the

totals.) So what could account for the decrease in brain volume? In laboratory animals, chronic

alcohol consumption leads to a reduction in the size of dendrites, which could yield decreases in

volume without affecting neuron count.

The distinction between losing neurons and losing dendrites or axons is important. Loss of

neurons would be very hard to make up, because in the cortex of adult brains, new neurons are