Serotonin neurons fan out to many different part of the brain. When these signals are interpreted either separately or together, we describe the neural experience as some version of happiness. Presumably this is one reason why happiness has so many different definitions, manifestations, and inputs: because different interactions between regions of the brain influence different phenomena—joy, elation, love, etc. We know that serotonin is partially involved in contentment and well-being, but we don’t yet have all the details. What’s more, dopamine has only five different receptors in the brain (although most of the reward effects are mediated by the D1 and the D2 receptors). In contrast, serotonin has at least fourteen different brain receptors to which it binds, and while there are certain receptors that exert the majority of the serotonin effect, it makes it very difficult to piece together what is happening in any specific brain area. Thus, unlike dopamine, unraveling the role of serotonin in human happiness is a much tougher affair.
Fig. 7-2: Synthesis and metabolism of serotonin. The amino acid tryptophan receives a hydroxyl group from the enzyme tryptophan hydroxylase to form 5-hydroxytryptophan. This compound is then acted on by DOPA decarboxylase (the same enzyme in the dopamine pathway) to form serotonin. From there, serotonin clearance is achieved by monoamine oxidase.
Isolating serotonin neurons and figuring out what they do in humans would require some very questionable neurosurgery from some very questionable neurosurgeons (Gene Wilder as Dr. Fronkensteen?). For this reason we have had to primarily use animal models for this work. But this leads to a big question: Is happiness a human attribute exclusively? How can you tell if an animal is happy? Are there any behaviors that animals demonstrate that are reflections of happiness rather than the result of overlay by reward or pleasure? I’ve talked to several animal behaviorists at the Society for Behavioral Neuroendocrinology about this. One form of happiness, the nurturing behavior that occurs between parents and offspring, is mediated by oxytocin (the “bonding” hormone) rather than serotonin. But what about general happiness in animals? Ken Locavara, an eminent paleontologist (he discovered the biggest dinosaur remains in Patagonia), suggests that Antarctic penguins repeatedly slide down ice chutes into frozen water, with no secondary gain or reward. There’s no food involved, just an expenditure of energy. This behavior can’t have any survival advantage—just a general sense of “Wheeeee!!!” So perhaps this is their amusement park and they are demonstrating joy. Or is it pleasure? And that’s penguins. Are rats or mice happy? How are we able to tell when a rat or mouse is depressed? For one, we know what they like: sex and sugar. And when they don’t perform to get it, they’re depressed. Just like us. And we know that antidepressants will alter their behavior. And from the rodent work, we end up extrapolating to humans.
There still exists a large stigma toward the diagnosis and treatment of depression, as if it is a personal moral failing. For many who suffer from depression or have loved ones who do, the idea of it being their fault makes no sense. Who would choose this? Indeed, people with genetic differences anywhere in their brain’s serotonin system are at greater risk for suicide.8 Hardly a choice for these people.
The Sublime Science of Serotonin
Similar to that recounted for dopamine (see Chapter 3), serotonin physiology also has the same three points of regulation. Many things can go wrong, which may cause symptoms of depression. Optimizing each step in the process is necessary to reach our own individual Zen.
(1) Synthesis. Serotonin is an ongoing requirement throughout life. Its primary building block is the amino acid tryptophan, which you must eat—you can’t make it. It also happens to be one of the least available items in the human diet. Tryptophan is found in greatest quantity (but still pretty rare) in eggs, fish, and poultry. Many vegetable protein sources are notoriously low in tryptophan. Fewer building blocks means less product: not enough tryptophan in the diet means less serotonin can be made. (More about diet in Chapter 9.)
So, you have a limited amount of tryptophan in your system to make serotonin, which is actually a hot commodity in your brain (Fig. 7-2). Most of the tryptophan consumed is going to be used to produce serotonin in your gut. Only 1 percent is available for your brain. There isn’t just one serotonin factory in the body. In fact, once serotonin has been made in the gut or elsewhere, it can’t cross the blood-brain barrier. Your brain is on its own, it’s got to make serotonin itself. And the brain serotonin factory is localized to a long thin area deep in the most primitive part of the brain, called the raphe nuclei. (We’ll focus on the dorsal raphe nucleus, or DRN, from here on. See Fig. 2-1.)
Tryptophan is only one type of amino acid (one of the building blocks of protein) that needs to make it into the brain. These building blocks hop on amino acid transporters to cross over from blood into brain. The problem is, the transporters, like a taxicab at 11:00 p.m. on a snowy New Year’s Eve, are sometimes difficult to come by. Tryptophan is in competition with at least two other amino acids, phenylalanine and tyrosine, which are the building blocks for dopamine. So guess what, folks? The more building blocks for dopamine (i.e., reward-seeking behavior) in your blood, the fewer taxis that are available for tryptophan to head to party central in the brain and whip up some contentment for the evening. This competitive mechanism of tryptophan transport into the brain is but one way by which reward trumps contentment. More are coming (see Chapter 10).
(2) Action. Similar to dopamine, serotonin is released from its nerve terminals and must traverse the synapse to meet up with its receptor. Serotonin nerve terminals are all over the brain in order to bind to different receptors to exert different effects. Thus, the actions of serotonin are much harder to quantify because: (a) there is no clear anatomic location, (b) there are too many receptors to keep track of, and (c) there are many different kinds of responses among people, and even within the same person. Unfortunately, we aren’t entirely sure which receptors work which way. For instance, triptans are a class of drugs that bind to two specific serotonin receptors, and they are the best anti-migraine medications that we physicians have at our disposal. But taking these medications does nothing for your state of mind (although if you’ve ever had a migraine, then not having one is a state of bliss).
One receptor in particular, the serotonin-1a receptor, seems to be uniquely involved in decreasing anxiety and mitigating depression. It’s the binding of serotonin to this receptor that is equated to well-being and contentment. We know this because we have been able to genetically remove that specific receptor from mice. When they don’t have it, they are extremely anxious and no amount of antidepressant is going to fix it because the receptor is gone.9 The serotonin-1a receptor has been a hotbed of concern for psychiatric disease for decades.10 In one Japanese study, genetic serotonin-1a receptor differences are associated with bipolar disorder (formerly called manic-depressive illness).11 Drugs that bind to the serotonin-1a receptor (known as agonists, or chemical mimics) are a mainstay of antidepressant therapy,12 and new drugs are coming online at a relatively rapid pace.13 For instance, buspirone (Buspar) is a commonly used serotonin-1a agonist in the treatment of severe anxiety.
(3) Clearance. After the packets of serotonin transmitters are released from the neuron, they need to traverse the synapse to get to the receptor. After they have bound to the receptor, they hang out in the synapse waiting to be recycled or deactivated. The same process takes place here as it does with dopamine, using the same enzyme monoamine oxidase (MAO), which will degrade serotonin into its waste product 5-hydroxyindole acetic acid (5-HIAA) (Fig. 7-2). The MAO acts as a Pac-Man here as well, essentially gobbling up and destroying serotonin molecules. This is why MAO inhibitors such as phenelzine (Nardil) work as antidepressants, by keeping the levels of serotonin elevated, fostering more chance to bind to a receptor.
Alternatively, the serotonin transporter is a protein that recycles serotonin from the postsynaptic neuron back to the presynaptic neuron so it can be repackaged and used again t
he next time the neuron fires. These serotonin recyclers/transporters perform the same function as the dopamine transporter mentioned in Chapter 3, acting as “hungry hungry hippos.” They will suck the serotonin back into the neuron to be recycled and released again. This is the site of action of all the newer selective serotonin reuptake inhibitors (SSRIs), like fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro) to increase the amount of serotonin within the synapse in order to elevate mood. So what these SSRIs do is basically put a muzzle on the hungry hungry hippos. They are still functional, just less so. However, you don’t want to knock them out of the game completely. Having too much serotonin in the synapse can also be a problem (read on).
Always Look on the Bright Side of Life
How well your serotonin recycler/transporter works has a lot to do with how happy you are. Temperament goes a long way in explaining happiness, and differences in the serotonin transporter go a long way in explaining differences in temperament.14 For instance, those born with a specific allele (genetic variation) of their serotonin transporter (the 5-HTTLPR) are quite anxious as children, and are more likely to suffer into adulthood as a result of an unstable home life15 (i.e., have a greater propensity for anxiety, depression, and drug abuse16).
As an interesting aside, despite consistently experiencing more adverse circumstances throughout American society, African-American adults routinely exhibit a lower incidence of clinical depression than do Caucasians and Latinos.17 This is not explainable by sampling differences, sex differences, or levels of education. African-Americans exhibit less anxiety than Caucasians do.18 There may be several reasons for this dichotomy. One thought is that these questionnaires may be culturally biased, which may in fact be true. Another possibility is that the African-American population of the U.S. exhibits a higher affiliation with a religious denomination than any other racial group,19 which may provide them with a social basis for achieving happiness despite socioeconomic adversity. But there may be a biochemical reason as well. African-Americans are known to have a genetic difference in the gene that encodes the 5-HTTLPR (serotonin transporter, aka hungry hungry hippos), which reduces the ability to clear serotonin from the synapse.20 Thus, African-Americans may have their own built-in SSRI, so they get less depressed in the face of adverse circumstances.
But just as with dopamine, too much of a good thing can become a bad thing. Serotonin can have serious side effects, including irritability and suicidal thoughts and actions.21 Excessive serotonin effects can lead to negative levels of mood, and outward behaviors such as impulsive aggression, because of binding to receptors other than the -1a receptor.22 Serotonin syndrome, which results from too much serotonin activity because of SSRI overdose or interactions with other drugs, is characterized by changes in mental state and muscle tone, and autonomic nervous system problems.23 Going overboard on serotonin can take someone who’s morose and give them just enough brain activity and mental energy to make them suicidal, which is why people on antidepressants shouldn’t dose themselves. Just as with dopamine, the goal is not to increase your serotonin status indiscriminately but rather to find your sweet spot.
Most of us, as numerous surveys indicate, concede that the most important goal of life is happiness. But the quest for happiness begins and ends with optimization of your serotonin neurotransmission24—clearly no easy feat. Chances are you’ve seen a commercial for an antidepressant. It generally starts with a woman looking forlorn and in cold, gray weather. Then, magically, the sun is shining, she is smiling, her kids are well behaved, and they all live happily ever after.
Alas, there is no one magic pill. Medications work differently on different people and they may lose or gain effectiveness over the life span. The dosage of Prozac taken by an eighteen-year-old may not work the same way when he or she is forty. After giving birth, women’s hormones go into a tailspin and they may experience postpartum depression, necessitating the usage of antidepressants. After a year or so, their serotonin may go back to normal on its own, or it might not. Anti-depressant medications can work wonders, but only 25 percent of those who take them experience a full remission.25 The remaining 75 percent may experience some relief but not complete reversal of symptoms. More aid is needed. Even for those of us who do not suffer from depression, few of us know how to attain contentment. Short of SSRIs, what hope do we have of achieving any meaningful happiness in this life?
Are we really Prozac Nation? Not quite. Read on.
8.
Picking the Lock to Nirvana
If you’re afloat, peering up at a panorama of tangerine trees and marmalade skies, lower your gaze. Chances are your shipmate just might be a girl with kaleidoscope eyes.
John Lennon was one of the chief spokespeople of the counterculture of the 1960s. “Lucy in the Sky with Diamonds” (1967), composed by Lennon and Paul McCartney, extolled the benefits of the synthetic psychedelic lysergic acid diethylamide (LSD), and the growing desire of young people to, in the words of Harvard psychiatrist, political activist, and eventual public enemy number one, Dr. Timothy Leary, “Turn on, tune in, and drop out.”
LSD was first manufactured in a Swiss lab by pharmaceutical chemist Albert Hofmann in 1938, but first ingested by Hofmann in 1943.1 Immediately, scientists and researchers saw its potential—it was used in attempts to cure autism and treat convicts, among others—and the first commercial preparation, Delysid, hit the European market in 1947. Many different mind-altering drugs entered our societal lexicon during this period. Mescaline, a phenylethylamine derivative used in traditional Native American worship rituals, was purified from the peyote cactus. Psilocin, the active form of the tryptamine precursor psilocybin, was purified from indigenous “magic mushrooms” found in Mexico. While new to the American mainstream, these plants had been used for hundreds, sometimes even thousands, of years by different indigenous groups and cultures. Rituals involving naturally occurring hallucinogens have played a central role in the religions, and sometimes even the language of various tribes—in quests to find spirit animals, communicate with the dead, and seek out the divine. When Hofmann created LSD, all of a sudden scientists wanted in.
Drinking the Electric Kool-Aid
In 1953 the structure of serotonin and its presence in the brain was confirmed.2 Scientists soon thereafter discovered the incredible structural similarities between serotonin and some of these compounds—especially psilocybin and LSD (Fig. 8-1). Thus began a seventeen-year scientific and existential quest to unravel the hidden mysteries of the mind, and in particular, the quest for happiness—both natural and artificial. One set of scientists started altering the molecular structure of these compounds to increase their potency, while another set of scientists labeled them with radioactivity to look at their binding sites in the brain and their mechanisms of action. After years of trial and error, they discerned that these compounds acted as a serotonin agonist, meaning that they mimicked serotonin and would bind to specific serotonin receptors in the brain; namely, the -1a (see Chapter 7) and the -2a receptors.
Fig. 8-1: Serotonin receptor “skeleton keys.” Psychedelics are modifications of the structure of the parent compound serotonin. These changes allow different compounds to bind selectively to individual serotonin receptors instead of all sixteen. But some still cross-react. The tryptamine derivatives psilocybin and LSD can bind to both the serotonin-2a receptor (the mystical experience) and the serotonin-1a receptor (contentment). The phenylethylamine compound mescaline binds only to the serotonin-2a receptor. MDMA, or ecstasy (see Chapter 10), not only binds to the serotonin-2a receptor, it binds to the dopamine receptor as well.
The 1960s was the golden age of LSD research. The U.S. government subsidized at least 116 experiments (that we know of) over this interval to unlock its secrets. Dr. Stanislav Grof, one of the early experimenters, described LSD as a “non-specific amplifier of the unconscious,”3 for both good and bad. The suggestion was that LSD might
be a primary modulator of the unconscious mind, and unlocking its mysteries would answer the questions of who we are, why we are here, and what’s to become of us. Big questions indeed. Maybe too big to be left to scientists?
As hard as you may try, you can’t keep something this big locked up in the lab. These molecules escaped from the ivory tower and started a (relatively) bloodless revolution within America, especially among young people, who were disillusioned with the U.S. government, and the handling of the Vietnam War and the civil rights movement. Psychedelics were all the rage in the late 1960s throughout the country. College campuses were the testing ground for this social experiment, and some still are.
Three observations about the use and users of psychedelics should be made at this point.
Some users of psychedelics would experience “bad trips”; that is, they would experience unwanted fear and paranoia. Hallucinogenic experiences can’t be easily predicted. Maybe someone will have a good/mellow trip, feel at one with the universe, and talk to the deities—or maybe they will feel that their face is melting off and the world is contracting. It’s hard to predict what, who, and how these drugs cause a bad trip. In general, hallucinogens magnify the emotional and mental state of the user at the time. If someone is depressed or manic, a hallucinogen, taken on its own, would likely intensify the feeling in the same direction. Based on anecdotal data, the psychedelic experience is, in the words of Timothy Leary, responsive to both “set” (i.e., mind-set) and “setting” (i.e., place and people you are with). Perhaps this was best typified by the inconsistent and incoherent results of a clandestine CIA operation called the MK-ULTRA program (aka Operation Midnight Climax), which between 1953 and 1964 dosed unsuspecting military personnel and unwitting victims in New York and San Francisco with LSD in their alcoholic drinks.4 Ostensibly, the reason for this covert program was that the CIA was concerned that Russia, Communist China, and North Korea were using these drugs to brainwash American prisoners of war—think Laurence Harvey in The Manchurian Candidate (1962) (Queen of Diamonds, anyone?)—and they needed to fight back. The responses of these “volunteers” ranged from anxiety to sheer paranoia to apparent psychosis: their world did not make sense, because they were navigating blind. Thus, the need for informed consent and a tour guide for your metaphysical trip.
The Hacking of the American Mind Page 10